Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout
REVIEW ARTICLE

Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout

The Open Rheumatology Journal 24 Jul 2018 REVIEW ARTICLE DOI: 10.2174/1874312901812010094

Abstract

Gout is a common form of inflammatory arthritis caused by hyperuricemia and the deposition of Monosodium Urate (MSU) crystals. It is also considered as a complex disorder in which multiple genetic factors have been identified in association with its susceptibility and/or clinical outcomes. Major genes that were associated with gout include URAT1, GLUT9, OAT4, NPT1 (SLC17A1), NPT4 (SLC17A3), NPT5 (SLC17A4), MCT9, ABCG2, ABCC4, KCNQ1, PDZK1, NIPAL1, IL1β, IL-8, IL-12B, IL-23R, TNFA, MCP-1/CCL2, NLRP3, PPARGC1B, TLR4, CD14, CARD8, P2X7R, EGF, A1CF, HNF4G and TRIM46, LRP2, GKRP, ADRB3, ADH1B, ALDH2, COMT, MAOA, PRKG2, WDR1, ALPK1, CARMIL (LRRC16A), RFX3, BCAS3, CNIH-2, FAM35A and MYL2-CUX2. The proteins encoded by these genes mainly function in urate transport, inflammation, innate immunity and metabolism. Understanding the functions of gout-associated genes will provide important insights into future studies to explore the pathogenesis of gout, as well as to develop targeted therapies for gout.

Keywords: Gout, Single nucleotide polymorphism, Genome-wide association study, Case-control study, Imume regulatory genes, MSU.

1. INTRODUCTION

Gout is a chronic inflammatory arthritis resulting from high levels of serum urate (hyperuricemia) and monosodium urate crystal deposition in joints and soft tissues. The prevalence of gout is about 1-4% in the general population, and certain racial/ethnic groups may have a higher incidence such as 13.9% in Māori men in New Zealand [1]. Urate is formed from dietary purines (about 20%) and catabolism of endogenously synthesized purines (about 80%). In humans, two thirds of urate are excreted from kidneys and the rest via intestine. The balance of the production and the secretion determines the level of serum urate. According to patient's fractional excretion of urate clearance (urate clearance/creatinine clearance ratio, FEUA) and Urinary Urate Excretion (UUE), gout is classified into two distinct types, Renal Overload (ROL) gout and Renal Underexcretion (RUE) gout [2]. ROL gout results from urate overproduction and/or extra-renal underexcretion, both of which are characterized by increased UUE.

Genetic contribution to hyperuricemia and gout appears very complex [3, 4]. Some rare monogenic metabolic disorders are associated with gout. For example, Hypoxanthine-Guanine Phosphoribosyltransferase (HPRT) deficiency [5, 6] and Phosphoribosyl Pyrophosphate Synthetase 1 (PRPS1) superactivity [7-9] result in uric acid overproduction, which leads to gout. HPRT1, an important enzyme in the salvage pathway of purine nucleotide synthesis, catalyzes hypoxanthine to Inosine Monophosphate (IMP) and guanine to Guanosine Monophosphate (GMP). PRPS1, a crucial enzyme in the de novo synthesis of purine nucleotide pathway, catalyzes Adenosine Triphosphate (ATP) and ribose-5- phophate to Phosphoribosylpyrophosphate (PRPP). At present, more than 600 mutations in HPRT1 gene [10] and 9 mutations in PRPS1 gene associated with PRPS1 superactivity [9, 11] have been reported.

Over the past 20 years, extensive studies have been performed in searching for genetic factors contributing to hyperuricemia and gout. In this review, we systemically reviewed original papers of genetic association studies of gout from November 2007 to March 2018 through PubMed, and summarized the genes with polymorphisms that have been reported in associations with gout. These genes are mainly involved in urate transport, inflammation, innate immunity and material metabolism. A complete list of gout-associated genes and genetic loci is summarized in Table 1.

Table 1.
A complete list of gout-associated genes and genetic loci.
Variant Location Effect allele OR P value Population Reference
Discovery Replication
rs121907892 (W258X) Exon G infinity 2×10-2 Japanese male Japanese male [35, 36]
rs121907896 (R90H) Exon G     Japanese male [36]
rs11231825 (H142H) Exon T 1.631 3.26×10-2 Spanish [37]
rs475688 Intron C 1.84 1×10-4 Han Chinese and Solomon Islanders [38]
T 1.26 4.3×10-2 New Zealand European Caucasian [39]
    No association New Zealand Polynesian [39]
rs505802 5’ intergenic A 0.747 9.88 ×10-4 Han Chinese male [40]
    No association German [41]
rs2285340 Intron A 1.4 4.61×10-11 Japanese male [2]
    No association New Zealand Polynesian [2]
rs734553 Intron G 0.66 5.6×10-7 German Han Chinese male [40, 41]
rs16890979 (V253I) Exon T 0.59 7.9×10 -14 US Caucasian New Zealand Māori, Pacific Island, Caucasian, Spanish, Chinese [57-59]
    No association   Korean, Japanese men, Han Chinese male, Czech [60-63]
rs1014290 Intron C 1.4 1×10-4 Scottish Japanese male, Han Chinese [64, 2, 61, 65, 35]
    No association Solomon Islanders [65]
rs6449213 Intron T 1.32 3×10 -2 Scottish German, US Caucasian [64, 66, 57]
    No association Korean [60]
rs3733591 (R265H) Exon G 1.52 7.3×10-4 Japanese male Han Chinese [61, 65]
    No association Solomon Islanders, New Zealander, Chinese Han and Minnan population in China [65, 67, 68, 69]
rs6855911 Intron G 0.62 3.2×10-7 German German [66, 41]
    No association Minnan population in China [69]
rs12510549 5’ intergenic C 0.67 5.1×10-5 German New Zealand Caucasian [66, 58]
    No association New Zealand Māori,pacific Island [58]
rs11722228 Intron T 1.619 2.4×10-6 Han Chinese male [62]
    No association Malaysian male [70]
rs3775948 Intron G 1.61 5.5×10-27 Japanese male [71]
G 0.738 3.09 ×10-3 Han Chinese male [62]
rs13129697 Intron T 1.4 4.66 × 10-3 African American [72]
rs7663032 Intron T 1.46 3.97 × 10-3 African American [72]
rs5028843 Intron A 0.13 7.2 × 10-5 New Zealand Māori New Zealand, Caucasian [58]
rs11942223 Intron C 0.06 3.7 × 10-7 New Zealand Māori New Zealand, Caucasian [58]
rs13124007 promoter C 1.709 6×10-3 Chinese male [74]
rs17300741 Intron A 1.85 2×10-2 Spanish [37]
G 1.63 4.9×10-2 Japanese [76]
    No association New Zealander, German, Chinese Han, Japanese male [39, 41, 68, 40, 35]
rs3579352 Intron C 0.71 1.08×10-3 Chinese [59]
rs1183201 Intron T 0.67 3× 10-6 Caucasian Han Chinese male [80, 40]
    No association German [41]
rs1165196 (I269T) Exon C 0.6 5.5×10-3 Japanese male Caucasian, Spanish, Japanese male [81, 80, 37, 35]
    No association   Chinese Han [68]
rs1179086 Intron T 0.69 1.2×10-2 Japanese male [81]
rs3757131 Intron T 0.6 5.9×10-3 Japanese male [81]
rs12664474 5’ UTR G 1.36 1.2 × 10-3 Caucasian [80]
    No association Polynesian [80]
rs1165205 Intron A 0.85 2·0×10 -3 White American [57]
    No association Chinese Han and Minnan population [68, 69]
rs9358890 Exon G 1.19 1.8×10-2 Chinese [59]
    No association Caucasian, Polynesian [80]
rs2242206 (K258T) Exon G 1.28 1.2×10-2 Japanese male [86]
rs2231137 (V12M) Exon T 0.55 2.55×10-6 Chinese Han male Chinese [91, 59, 92]
rs1481012 Intron G 2.5 1.55×10-43 Chinese [59]
rs3114018 Intron A 1.71 2.6×10-2 Chinese Han Chinese [93, 92]
rs2728125   C 2.05 1.5×10-27 Japanese male [71]
rs72552713 (Q126X) Exon T 4.25 3.04 × 10-8 Japanese male Chinese and Japanese male [94, 91, 35, 95]
rs3114020 promoter T 1.58 4.8×10-2 Chinese Han [93]
C 2.03 1.17×10-20 Japanese male [2]
rs2231142 (Q141K) Exon T 1.74 3.3×10-15 White American Japanese, Spanish, German, Korean, Chinese, American, New Zealand Pacific Island and Caucasian [57, 35, 37, 41, 60, 68, 69, 71, 72, 88, 91, 92, 94-98]
    No association New Zealand Māori , Chinese Han [97, 93]
rs4148500 Intron A 1.3 3.8×10-3 New Zealand Māori and Pacific Island [104]
rs179785 Intron G 0.82 1.28 × 10-8 Han Chinese male [107]
rs1967017 promoter C 0.705 1.6×10-2 male Han Chinese New Zealander, American [109, 110, 111]
    No association American [112]
rs12129861 5’ Intergenic A 0.727 1.5×10-2 male Han Chinese Japanese [109, 113]
    No association Japanese and Chinese male, German [35, 40, 41, 114]
rs11733284 Intron A 1.34 1.13×10-8 Japanese male [2]
rs1143623 Promoter G 1.1 2×10-2 European and Polynesian [118]
rs2569190 Promoter A 1.08 3.6×10-2 European and Polynesian [118]
rs4073 (–251T/A ) promoter T 1.229 3.1×10-2 Chinese male Chinese [121, 122]
rs3212227 (1188A/C ) 3’ UTR A 1.404 < 1×10-3 Chinese male [121]
rs7517847 Intron G 0.826 4×10-2 Chinese Han male [127]
rs10889677 3’ UTR A 1.137 5.9×10-2 Chinese Han male [128]
rs1800630 (-863C/A ) promoter A 2.3 <1×10-3 male Taiwanese [130]
rs1024611 (-2518A/G) promoter G 1.182 7×10-3 Chinese male [131]
rs3806268 Exon G 1.83 <3×10-2 Chinese [135]
rs45520937 Exon A 1.85 6.66×10 -9 Han Chinese [137]
rs2143956 Exon T 1.48 3.58× 10 -5 Chinese male [140]
T 1.122 1.2×10-2 European [141]
T 0.8 1.1×10-2 NZ Polynesian [141]
rs2043211 (C10X) Exon T 1.12 7×10-3 European [118]
    No association NZ Polynesian, Chinese male, Korean male [118, 144, 145]
rs1653624 Exon A 1.608 2×10-2 Chinese [147]
rs7958316 Exon A 1.698 8×10-3 Chinese [147]
rs17525809 Exon T 2.728 0.000 Chinese [147]
rs2298999 Intron T 0.77 6.42×10-3 male Chinese Han [153]
rs10821905 5’ UTR A 1.61 1.57×10-3 Chinese [59]
rs2941484 3’ UTR T 1.28 1.08×10-3 Chinese [59]
rs4971101 3’ UTR G 1.37 3.25×10-4 Chinese [59]
rs2070803 3’ UTR A 1.22 3.1×10-2 Chinese [59]
rs2544390 Intron T 1.32 2.5×10-2 Japanese male Chinese, New Zealander [35, 155, 156]
T 0.79 2×10-2 European [156]
    No association Japanese male [157]
rs780093 Intron T 1.17 4.7×10-4 American Han Chinese male [112, 160]
rs1260326 (L446P) Exon T 1.36 1.9×10-12 Japanese male Japanese male, Chinese [71, 2, 62, 59]
rs6547692 Intron A 0.696 2.20×10-4 Han Chinese male [62]
rs780094 Intron A 1.518 4.00×10-4 Han Chinese male Chinese, Japanese male [160, 40, 59, 35]
    No association German [41]
rs4994 (W64R) Exon C 1.5 1.30×10-2 Chinese male [162]
    No association combined Polynesian [163]
rs671 (E504K) Exon G 1.88 1.70×10 -18 Japanese male Japanese and Han Chinese male [164, 165, 62, 166]
rs1229984 (H48R) Exon A 1.16 3.70×10-2 Japanese male [165]
rs4680 (V158M) Exon A 0.77 1.50×10-2 Chinese [155]
    No association Taiwanese aborigines [170]
rs1137070 (D470D) Exon T 1.46 2.00× 10 -4 Taiwanese aborigines [170]
rs2283725 Intron A 1.38 6.00× 10 -4 Taiwanese aborigines [170]
rs5953210 5’ Intergenic G 1.34 1.00× 10 -3 Taiwanese aborigines [170]
rs7688672 Intron A 1.96 7.00×10-3 Taiwanese [172]
    No association Chinese male [173]
rs10033237 Intron G 1.302 8×10-3 Chinese male [173]
    No association Taiwanese [172]
rs3756230 Intron C 0.64 1.3×10-2 Han Chinese [176]
rs12498927 Intron A 1.377 2.7×10-2 Han Chinese [176]
rs11726117 (M861T) Exon C 1.44 3.78×10-6 Taiwan aborigines Taiwanese Han [178]
    No association male Japanese [179]
rs231247 (R1084R) Exon G 1.46 2×10-6 Taiwan aborigines Taiwanese Han [178]
rs231253 3’ UTR G 1.45 3.48×10-6 Taiwan aborigines [178]
    No association Taiwanese Han [178]
rs742132 Intron A 1.3 1.5×10-2 Japanese male Japanese male [180, 181]
    No association German, Han Chinese [41, 40]
rs12236871 5’ UTR G 0.81 1.48 ×10-10 Han Chinese male [107]
rs9895661 Intron C 0.594 6.94×10-7 Han Chinese male [62]
rs9905274 Intron T 0.79 6.45 × 10-13 Han Chinese male [107]
rs11653176 Intron T 0.79 1.36 × 10-13 Han Chinese male [107]
rs4073582 Intron G 1.66 6.4×10 -9 Japanese male Japanese and Han Chinese male [71, 2, 62]
rs7903456 Intron A 1.34 4.29×10-8 Japanese male [2]
rs2188380 intergenic T 1.75 1.6×10 -23 Japanese male [71]
rs4766566 Intron T 1.51 4.03 × 10 -20 Japanese male [2]

2. MEMBRANE TRANSPORTERS - SOLUTE CARRIER FAMILY

2.1. URAT1

Urate transporter 1 (URAT1), also known as solute carrier family 22, member 12 (SLC22A12), is a transmembrane protein on the proximal tubule apical surface. It mediates the re-absorption of uric acid from the proximal tubule [12]. In the studies on gout patients from Japan [12-27], Korea [28-30], Iraq [31], China [32], and Czech Republic [33, 34], loss-of-function mutations of SLC22A12 (R90H, R92C, V138M, G164S, R203C, T217M, A226V, R228E, W258X, Q297X, E298D, Q312L, D313A, Q382L, R406C, M430T, L418R, G444R, R477H, A51fsX64, V547fsX602, L415_G417del, IVS2+1G>A, c.935_997delinsTGG) were associated with hypouricemia. Two frequent causative mutations, rs121907892 (W258X) [35, 36] and rs121907896 (R90H) [36], appeared protective against gout, and were associated with a decreased urate-transport function [12, 14]. A study of a Spanish cohort showed that T allele of URAT1 rs11231825 (H142H) was associated with gout, in particular with patients who presented a reduced uric acid excretion [37]. In addition, there are some other URAT1 SNPs examined, but achieved conflicting results from different study populations, such as rs475688 [38, 39], rs505802 [40, 41] and rs2285340 [2].

2.2. GLUT9

Glucose transporter type 9 (GLUT9), also known as solute carrier family 2 member 9 (SLC2A9), has two distinct isoforms based on the alternative splicing of the N-terminal, GLUT9-L and GLUT9ΔN [42, 43]. Loss-of-function mutations of SLC2A9 (W23X, G72D, L75R, Ile118HisfsX27, T125M, R171C, R198C, G207X, G216R, N333S, R380W,P412R, dupExon1a-11, delExon7, c.1215+1 G>A) could result in renal hypouricemia [24, 34, 44-56]. Multiple genetic studies on GLUT9 gene have been conducted in gout. Rs734553 was associated with gout in German [41] and Han Chinese male [40] populations. Some of the reported gout-associated polymorphisms appeared inconsistent in different study populations. For instance, rs16890979 (V253I) was associated with gout in a Genome-Wide Association Study (GWAS) of US Caucasian [57], which was replicated in the studies of New Zealand Māori, Pacific Island, Caucasian [58], Spanish [37] and Chinese [59] cohorts, but inconsistent in some Asia cohort studies including Korean, Japanese male and Han Chinese male [60-62] populations and a Czech population [63]. In addition, rs1014290 was associated with gout in British [64], Japanese and Chinese populations [2, 35, 61, 65], but the study in a Solomon Islanders population indicated a negative result [65]; rs6449213 in British [64], German [66] and US [57] populations, but not in Korean population [60]; rs3733591 (R265H) in Japanese male [61] and Han Chinese [65] populations, but not in Solomon Islanders [65], New Zealand Māori, Pacific Island, Caucasian [67] and inconsistent in Chinese populations [68, 69]; rs6855911 in German [41, 66], not in a Chinese cohort [69]; rs12510549 in German [66] and New Zealand Caucasian populations [58], not in New Zealand Māori and Pacific Island populations [58]; rs11722228 in a Han Chinese male cohort [62], not in a Malaysian male cohort [70]. The G allele of rs3775948 was reported as a risk to gout in a Japanese male [71], but protective in a Han Chinese male cohort [62]. A study on African American population showed that rs13129697 and rs7663032 were associated with gout [72]. Rs5028843 and rs11942223 were associated with gout in New Zealander populations [58]. Recently, a study showed that rs11942223 was not associated with tophi in people with gout in New Zealander populations [73].In addition, the SNP rs13124007 at the promoter region was associated with gout in a Chinese male cohort [74], and its C to G substitution led to a loss of a binding site for interferon regulatory factor 1 (IRF-1) [74].

2.3. OAT4

Organic anion transporter 4 (OAT4), also named solute carrier family 22 member 11 (SLC22A11), is a low-affinity uric acid transporter [75]. The G allele of rs17300741 was associated with RUE type gout in a Japanese cohort [76]. However, it was the A allele of this SNP in a Spanish cohort [37], and no association was observed in Chinese [40, 68], German [41], New Zealander [39] populations, and another Japanese male cohort [35].

2.4. NPT1 (SLC17A1)

Sodium-dependent phosphate cotransporter type 1 (NPT1) also named solute carrier family 17 member 1 (SLC17A1) is a member of the SLC17 phosphate transporter family [77, 78]. It is located in the renal proximal tubule involved in urate excretion [79]. Genetic associations with gout were observed in several NPT1 SNPs. Rs3579352 was associated with gout in a Chinese cohort [59]; rs1183201 in both cohorts of Chinese [40] and New Zealander Caucasian [80], but which appeared conflicting in a German cohort [41]; rs1165196 was associated with gout in Japanese male, Caucasian, Spanish cohorts [35, 37, 80, 81], but not in a Chinese cohort [68]. The SNPs rs1165196, rs1179086 and rs3757131 were associated with the development of gout in a Japanese male population [81]. Among them, rs1165196 (I269T) is a missense variant, and 269T allele was correlated with an increased NPT1-mediated urate export [79, 82].

2.5. NPT4 (SLC17A3)

Sodium phosphate transporter 4 (NPT4) or solute carrier family 17 member 3 (SLC17A3) is a voltage-dependent efflux transport for urate, anionic compounds and drugs in renal proximal tubule cells [83]. The conflicting results were observed in studies of rs12664474 of the NPT4 gene in New Zealander, in which it was associated with gout in a Caucasian cohort, but not in three Polynesian cohorts [80]. In addition, rs1165205 was linked with gout in US Caucasians [57], but it was not replicated in two Chinese cohorts [68, 69].

2.6. NPT5 (SLC17A4)

Sodium/phosphate cotransporter homologue (NPT5) or solute carrier family 17 member 4 (SLC17A4) is an organic anion exporter located in the intestinal duct [84]. Similar to the studies of NPT4, conflicting results of NPT5 were observed in different populations. Rs9358890 was associated with gout in Chinese patients [59], but not in New Zealander [80].

2.7. MCT9 (SLC16A9)

Monocarboxylate transporter 9 (MCT9) or solute carrier family 16 member 9 (SLC16A9) facilitates transportation of monocarboxylates such as lactate and pyruvate across plasma membrane [85]. Rs2242206 of SLC16A9 gene was associated with ROL gout but not with overall gout in a Japanese male cohort [86].

3. ATP-BINDING CASSETTE TRANSPORTER FAMILY

3.1. ABCG2

The ATP-Binding Cassette subfamily G member 2 (ABCG2) protein, also known as breast cancer resistance protein (BCRP), is a member of the ATP-binding cassette family which transports a wide range of substrates [87]. It is highly expressed in the renal proximal tubular cells, the apical membrane of the intestinal epithelium and liver hepatocytes that regulate excretion of uric acid [88-90]. Several SNPs of the ABCG2 gene were associated with gout. Among them, rs2231137 (V12M), rs1481012 and rs3114018 were associated with gout in Chinese cohorts [59, 91-93]; rs2728125 in a Japanese cohort [71]; and rs72552713 (Q126X) in both Japanese male and Chinese male cohorts [35, 91, 94, 95]. The conflicting results were observed in a study of rs3114020, in which the risk allele was C allele in a Japanese male cohort [2], but T allele in a Han Chinese cohort [93].

The SNP rs2231142 (Q141K) of the ABCG2 gene was extensively investigated. It was associated with gout in multiple studies of different ethnic populations [35, 37, 41, 57, 60, 68, 69, 71, 72, 88, 91, 92, 94-98], except in a New Zealand Māori [97] and a Han Chinese cohort [93]. Compared to the wild-type of rs2231142 Q141, the K141 was correlated to a 54% reduction of urate transport rates [88]. Furthermore, this SNP was reported as an important influence factor of drug response [99-102]. For example, the T allele of rs2231142 was associated with a reduced response and a poor response to allopurinol [101, 102].

3.2. ABCC4

The ATP-binding cassette subfamily C member 4 (ABCC4) or Multidrug Resistance Protein 4 (MRP4) is an ATP-dependent unidirectional efflux transport for urate [103]. A study in New Zealand Māori and Pacific populations showed that rs4148500 was significantly associated with gout, as well as with reduced fractional excretion of uric acid in men [104].

4. OTHER MEMBRANE TRANSPORTERS

4.1. KCNQ1

KCNQ1, a potassium voltage-gated channel protein that forms a functional potassium selective pore [105] and plays crucial roles in cardiac rhythm and extra-cardiac effects such as secretion of insulin [106]. Mutations in KCNQ1 gene were associated with congenital Long QT Syndrome (LQTS) and some variants were associated with diabetes. The GWAS in a Han Chinese male cohort showed that rs179785 of the KCNQ1 gene was associated with gout [107].

4.2. PDZK1

PDZ Domain containing 1(PDZK1) is a scaffolding protein that interacts with many proteins at the plasma membrane, including urate transporter [108]. The SNPs rs1967017 and rs12129861 of the PDZK1 gene were associated with gout in men of Han Chinese [109]. The former was replicated in a New Zealand study [110], but was conflict in two US studies [111, 112]. The latter was concordant in one Japanese cohort [113], but discordant with other 4 studies in Japanese male, Han Chinese male, and German cohorts [35, 40, 41, 114].

4.3. NIPAL1

The Nipa-Like Domain containing 1 (NIPAL1), also known as NIPA3, is a magnesium transporter [115]. The GWAS in Japanese male cohort showed that rs11733284 of NIPAL1 gene was associated with renal underexcretion gout [2]. Although NIPAL1 was not a urate transporter, it might be involved in the indirect regulation of urate transport kinetics [2].

5. INTERLEUKIN FAMILY AND OTHER INFLAMMATORY RESPONDING GENES

5.1. IL1β and CD14

Interleukin-1β (IL1β) is an inflammatory cytokine. It plays a key role in sustaining inflammation in multiple inflammatory diseases, such as gout and atherosclerosis [116]. CD14 is a lipopolysaccharide-binding protein, which functions as an endotoxin receptor. It is critical for TLR2-mediated M1 macrophage activation [117]. IL1B rs1143623 and CD14 rs2569190 were associated with gout in a study of European and New Zealand Polynesian populations [118]. It was reported that bothrs1143623 and rs2569190 can affect transcriptional activities of their own promoter [119, 120].

5.2. IL-8

Interleukin-8 (IL-8), a member of the CXC chemokine superfamily, is a macrophage-secreted chemokine that recruits neutrophils and causes angiogenesis. Rs4073 (-251T/A) was associated with gout in two Chinese cohorts [121, 122]. Functionally, compared with the T allele, the A allele of rs4073 was correlated with an enhanced transcriptional promoter activity in response to TNF-ɑ or IL-1β [123].

5.3. IL-12B

IL-12, a heterodimer of p35 subunit (encoded by IL-12A gene) and p40 subunit (encoded by IL-12B gene), plays an important role in antibody-induced joint inflammation [124]. A study of a Chinese cohort showed that rs3212227 (1188A/C) of the IL-12B gene was associated with gout [121]. Another study indicated that this SNP was correlated with an enhanced IL-12 production [125].

5.4. IL-23R

IL-23R is the receptor of IL-23. The binding of IL-23 to its receptor is believed to play an important role in driving gouty inflammation by production of inflammatory factors, such as IL-1 and TNF-ɑ [126]. Rs7517847 and rs10889677 of the IL-23R gene were associated with gout in studies of Chinese Han male cohorts [127, 128].

5.5. TNF-A, MCP-1/CCL2, NLRP3, PPARGC1B, TLR4, CARD8 and P2X7R

Tumor Necrosis Factor-ɑ (TNF-ɑ) is a proinflammatory cytokine mediating inflammation and apoptosis [129]. A promoter region SNP of the TNF-A gene rs1800630 (-863C/A) was associated with gout in a male Chinese cohort [130].

Monocyte Chemoattractant Protein 1 (MCP-1), also known as CCL2 (CC chemokine ligand 2) is an important member of the C-C (Cysteine-Cysteine) chemokine family and plays a crucial role in the recruitment of monocytes, memory T cells, and basophils into inflamed tissues. A functional SNP in CCL2 gene promoter region, rs1024611 (-2518A/G) was associated with gout in a study of a Chinese male cohort [131]. This SNP was reported to impact CCL2 expression in patients with Systemic Sclerosis (SSc) [132].

Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) is a component of NLRP3 inflammasome that mediates innate inflammatory responses, and is involved in onset and progression of various diseases, including metabolic disorders, as well as auto-immune and auto-inflammatory diseases [133, 134]. The NLRP3 rs3806268 was associated with primary gout in a Chinese cohort [135].

Peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1β (PPARGC1B) is a transcriptional coactivator of PPARγ that inhibits proinflammatory cytokine production [136]. Rs45520937 of the PPARGC1B gene was associated with gout in a Chinese cohort [137], and the A allele of this SNP was found to significantly augment the expression of NLRP3 and IL-1β [137].

Toll-like receptor 4 (TLR4) plays a crucial role in MSU-mediated inflammatory disease [138, 139]. A suggestive association of the TLR4 rs2149356 was first reported in a study of a Chinese cohort [140]. It was then reexamined in European and New Zealand Polynesian cohorts. However, the former indicated a gout-risk T allele of rs2149356 that appeared protective in the latter [141].

Caspase activation and recruitment domain 8 (CARD8) is involved in innate immunity including the suppression of IL-1β expression and NF-κB (nuclear factor κB) activation [142, 143]. The CARD8 rs2043211 (C10X) is a nonsense variant that causes the expression of a truncated protein CARD8-S leading to loss of inhibitory function on NF-κB transcriptional activity [142]. It was associated with gout in a European cohort [118], but which was not concordant with the results from the studies in New Zealand Polynesian, Chinese male and Korean Men cohorts [118, 144, 145]. In addition, there was a significant multiplicative interaction between CARD8 rs2043211 and IL1B rs1143623 that appeared to amplify gout risk [118]

Purinergic receptor P2X ligand-gated ion channel 7 (P2X7R) is an ATP gated ion channel expressed in immune cells, and participates in process of activating inflammation [116]. It was suggested that the P2X7R/NLRP3/IL-1β pathway is involved in many inflammatory diseases including gout [116, 146]. Rs1653624, rs7958316 and rs17525809 of the P2X7R gene were associated with gout in a Chinese cohort [147].

6. CELL PROLIFERATION, DIFFERENTIATION AND MIGRATION

6.1. EGF, A1CF, HNF4G and TRIM46

Epidermal Growth Factor (EGF), a ligand of EGF Receptor (EGFR), plays important roles in cell proliferation, differentiation and migration [148]. Apobec-1 Complementation Factor (A1CF), a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family that function in cell migration and survival [149]. Hepatocyte nuclear factor 4 gamma (HNF4G) is an orphan member of the nuclear receptor subfamily [150]. In bladder cancer cells, miR-34a-HNF4G axis is an important pathway regulating cell viability, proliferation, and invasion [151]. The protein tripartite motif 46 (TRIM46) is a member of the tripartite motif-containing protein family, which involved in many biological processes, including transcriptional regulation, cell differentiation, apoptosis, and signaling pathways [152]. A study in a male Chinese population linked rs2298999 of EGF gene with gout [153]. Another Chinese study showed that rs10821905 of A1CF gene, rs2941484 of HNF4G gene, and rs4971101 and rs2070803 of TRIM46 gene were associated with susceptibility to gout [59].

7. METABOLISM AND ENZYMES

7.1. LRP2

Low-density Lipoprotein Receptor-Related Protein 2 (LRP2), also known as megalin, is a member of the Low-Density Lipoprotein Receptor (LDLR) family that functions in lipid metabolism and signal transduction [154]. The LRP2 rs2544390 was examined for association with gout in Japanese male, Chinese, New Zealander and European cohorts. The results were conflicting, in which Chinese [155] and New Zealander [156] showed a positive association, European a negative [156], and Japanese a contradictory in two independent cohorts [35, 157].

7.2. GKRP

Glucokinase Regulatory Protein (GKRP) or Glucokinase Regulator (GCKR) is a hepatocyte-specific inhibitor of the glucose-metabolizing enzyme glucokinase (GCK), and plays important roles in hepatic glucose and lipid metabolism [158, 159]. Studies in American, Chinese and Japanese cohorts showed that rs780093, rs1260326, rs6547692 and rs780094 of GCKR gene were associated with gout in general, or male population [2, 35, 40, 59, 62, 71, 112, 160]. The result of rs780094 was contrary to that in a German cohort [41].

7.3. ADRB3

Beta-3-Adrenergic Receptor (ADRB3) is involved in the regulation of fat metabolism and thermogenesis [161]. The results of association studies of ADRB3 with gout were conflicting between male Chinese and combined populations of Polynesian and European patients, the former reported Arg64 allele of rs4994 as a risk to gout [162], but latter no association [163].

7.4. ADH1B and ALDH2

Alcohol Dehydrogenase 1B (ADH1B) and Aldehyde Dehydrogenase 2 (ALDH2) are key enzymes in the alcohol metabolism. ADH1B catalyzes alcohol into acetaldehyde, and subsequently ALDH2 oxidizes acetaldehyde into acetate. Rs671 (E504K) of ALDH2 gene was associated with gout in Japanese male and Chinese male populations [62, 164-166]. In addition, a missense SNP of ADH1B gene rs1229984 (H48R) was also associated with gout in a Japanese population [165].

7.5. COMT and MAOA

Catechol-O-Methyltransferase (COMT) is an important enzyme involves in the metabolism of dopamine [167]. Monoamine Oxidases A (MAOA) is involved in the deamination of dopamine, which plays a crucial role in the regulation of renal functions, including glomerular filtration, renin production, sodium transport [168], and urate excretion [169]. After the combined action of MAOA and COMT, dopamine is converted to DOPAC, 3-MT and HVA, which can pass through renal tubular proximal epithelial cells. A Chinese study showed that rs4680 (V158M) of COMT gene was associated with gout [155], but the association was negative in a Taiwanese aborigines population [170]. In contrast, the latter identified that three other SNPs including rs1137070 (D470D), rs2283725, rs5953210 of MAOA gene were associated with gout [170].

7.6. PRKG2

Protein Kinase, cGMP-dependent 2 (PRKG2) is an important regulator of intestinal secretion and bone growth, and was found to be an inflammation exciter in gout disease [171]. Genetic reports of the association between the PRKG2 gene and gout were inconsistent. In which gout was associated with rs7688672 of PRKG2 in a Taiwanese study [172] and rs10033237 of PRKG2 in a study of male Chinese cohort [173], but two studies could not replicate the results from each other [172, 173], and in a Japanese study, no PRKG2-gout association was found by examining four variants (rs11736177, rs10033237, rs7688672, and rs6837293) of PRKG2 [174].

8. GENES INVOLVED IN FUNCTIONS OF CYTOSKELETON, MYOSIN AND TRANSCRIPTION AND OTHERS

8.1. WDR1

WD-Repeat protein 1 (WDR1), also called Actin-Interacting Protein 1 (AIP1), plays a crucial role in dynamic reorganization of the actin cytoskeleton [175]. The G allele of rs3756230 and the A allele of rs12498927 of WDR1 were reported to be gout risk in a study of a Han Chinese cohort [176]. However, the sample size of this study was relatively small (143 gout cases and 310 controls), and there has not been any replication study.

8.2. ALPK1

Alpha-Kinase 1 (ALPK1) is a component of raft-carrying apical vesicles that functions in the phosphorylation of myosin I in the apical trafficking of raft-associated sucrose-isomaltase [177]. Rs11726117and rs231247 of the ALPK1 gene were associated with gout in a study including a Taiwan aborigines cohort and a Han Chinese cohort [178]. Another SNP rs231253 was only associated with gout in the Taiwan aborigines cohort [178]. However, rs11726117 was not associated with gout in a Japanese male cohort [179].

8.3. CARMIL (LRRC16A)

Capping protein ARP2/3 and Myosin-I Linker (CARMIL), or Leucine-Rich Repeat-Containing 16A (LRRC16A) plays an important role in cell-shape changes and motility. Two studies of Japanese male cohorts showed that rs742132 of the LRRC16A gene was associated with gout [180, 181], but the results appeared to be conflict in Han Chinese and Germany cohorts [40, 41].

8.4. RFX3

Regulatory factor X 3 (RFX3) is a transcription factor involved in the formation of thalamocortical tract [182], beta-cell [183] and the expression of glucokinase [182]. Rs12236871 of RFX3 gene was associated with gout in a Han Chinese male cohort [107].

8.5. BCAS3

Breast Cancer Amplified Sequence 3 (BCAS3) is a cytoskeletal protein involved in human embryogenesis and tumor angiogenesis [184]. Three BCAS3 SNPs, rs9895661, rs9905274, rs11653176, were associated with gout in Han Chinese male populations [62, 107].

8.6. CNIH-2

Cornichon-2 (CNIH-2) is a α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-associated

protein that regulates the function of AMPA receptors through the transmembrane AMPA receptor regulatory protein (TARP) isoform composition within the receptor complex [185, 186]. Rs4073582 of CNIH-2 gene was associated with gout in three independent cohorts including two Japanese male and a Han Chinese male [2, 62, 71].

8.7. FAM35A

FAM35A is a protein whose function is totally unknown. Rs7903456 of FAM35A gene was associated with renal underexcretion gout [2]. The cytosolic immunoreactivity of FAM35A is mainly in the distal tubule showed that the distal nephron is involved in urate handling in humans [2].

8.8. MYL2-CUX2

Myosin light chain-2 (MYL2) is a member of EF-hand calcium binding protein superfamily [187]. A GWAS showed that MYL2 was associated with high-density lipoprotein cholesterol metabolism [188]. Cut-like homeobox 2 (CUX2) is an accessory factor in the repair of DNA damage [189]. An intergenic SNP rs2188380 located between MYL2 and CUX2 gene, and rs4766566 of CUX2 gene were associated with gout in two reports of Japanese male population [2, 71].

CONCLUSION AND FUTURE DIRECTIONS

In summary, genetic studies have identified a number of genes with polymorphisms conferring susceptibility to or protection from gout. Among them, specific polymorphisms of membrane transporters, especially solute carrier family, and inflammatory responding genes appeared to be the major ones, and some of them also were linked to functional changes of the corresponding genes. On the other hand, some of the reported associations were inconsistent in different studies. The discordance may result from several aspects. First, the distribution of alleles and genotypes of some polymorphic loci vary greatly among different ethnic populations; second, the sample size of some studies is too small to reach acceptable statistic power, which may induce bias; third, lack of consideration of disease subtypes (such as ROL and RUE gout) and gender of gout patients in some studies may lead to mask the true association of the studied alleles. In addition, although overall studies have found multiple gout-related genetic loci, functional studies of many of these loci have not been conducted. Therefore, exploring functional significances of the identified polymorphisms is also one of the directions of the study on gout in the future.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

This study was supported by the project of studying abroad for young and Middle-aged teachers of Nanchang University.

REFERENCES

1
Klemp P, Stansfield SA, Castle B, Robertson MC. Gout is on the increase in New Zealand. Ann Rheum Dis 1997; 56(1): 22-6.
2
Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.
3
Wilk JB, Djousse L, Borecki I, et al. Segregation analysis of serum uric acid in the NHLBI family heart study. Hum Genet 2000; 106(3): 355-9.
4
Reginato AM, Mount DB, Yang I, Choi HK. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol 2012; 8(10): 610-21.
5
Puig JG, Torres RJ, Mateos FA, et al. The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. Medicine (Baltimore) 2001; 80(2): 102-12.
6
Kostalova E, Pavelka K, Vlaskova H, Musalkova D, Stiburkova B. Hyperuricemia and gout due to deficiency of hypoxanthine-guanine phosphoribosyltransferase in female carriers: New insight to differential diagnosis. Clin Chim Acta 2015; 440: 214-7.
7
Zoref E, De Vries A, Sperling O. Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts. J Clin Invest 1975; 56(5): 1093-9.
8
Chen P, Li J, Ma J, Teng M, Li X. A small disturbance, but a serious disease: The possible mechanism of D52H-mutant of human PRS1 that causes gout. IUBMB Life 2013; 65(6): 518-25.
9
Mittal R, Patel K, Mittal J, et al. Association of PRPS1 mutations with disease phenotypes. Dis Markers 2015; 2015: 127013.
10
Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 2014; 137(Pt 5): 1282-303.
11
Porrmann J, Betcheva-Krajcir E, Di Donato N, et al. Novel PRPS1 gain-of-function mutation in a patient with congenital hyperuricemia and facial anomalies. Am J Med Genet A 2017; 173(10): 2736-42.
12
Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417(6887): 447-52.
13
Tanaka M, Itoh K, Matsushita K, et al. Two male siblings with hereditary renal hypouricemia and exercise-induced ARF. Am J Kidney Dis 2003; 42(6): 1287-92.
14
Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 2004; 15(1): 164-73.
15
Komoda F, Sekine T, Inatomi J, et al. The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia. Pediatr Nephrol 2004; 19(7): 728-33.
16
Iwai N, Mino Y, Hosoyamada M, Tago N, Kokubo Y, Endou H. A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese. Kidney Int 2004; 66(3): 935-44.
17
Wakida N, Tuyen DG, Adachi M, et al. Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia. J Clin Endocrinol Metab 2005; 90(4): 2169-74.
18
Takahashi T, Tsuchida S, Oyamada T, et al. Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese. Pediatr Nephrol 2005; 20(5): 576-8.
19
Inazu T. A case of renal hypouricemia caused by urate transporter 1 gene mutations. Clin Nephrol 2006; 65(5): 370-3.
20
Komatsuda A, Iwamoto K, Wakui H, Sawada K, Yamaguchi A. Analysis of mutations in the urate transporter 1 (URAT1) gene of Japanese patients with hypouricemia in northern Japan and review of the literature. Ren Fail 2006; 28(3): 223-7.
21
Mima A, Ichida K, Matsubara T, et al. Acute renal failure after exercise in a Japanese sumo wrestler with renal hypouricemia. Am J Med Sci 2008; 336(6): 512-4.
22
Ochi A, Takei T, Ichikawa A, et al. A case of acute renal failure after exercise with renal hypouricemia demonstrated compound heterozygous mutations of uric acid transporter 1. Clin Exp Nephrol 2012; 16(2): 316-9.
23
Hirashio S, Yamada K, Naito T, Masaki T. A case of renal hypouricemia and a G774A gene mutation causing acute renal injury that was improved by hemodialysis. CEN Case Rep 2012; 1(1): 24-8.
24
Kaito H, Ishimori S, Nozu K, et al. Molecular background of urate transporter genes in patients with exercise-induced acute kidney injury. Am J Nephrol 2013; 38(4): 316-20.
25
Kamei K, Ogura M, Ishimori S, Kaito H, Iijima K, Ito S. Acute kidney injury after acute gastroenteritis in an infant with hereditary hypouricemia. Eur J Pediatr 2014; 173(2): 247-9.
26
Sugihara S, Hisatome I, Kuwabara M, et al. Depletion of uric acid Due to SLC22A12 (URAT1) loss-of-function mutation causes endothelial dysfunction in hypouricemia. Circ J 2015; 79(5): 1125-32.
27
Fujita K, Ichida K. A novel compound heterozygous mutation in the SLC22A12 (URAT1) gene in a Japanese patient associated with renal hypouricemia. Clin Chim Acta 2016; 463: 119-21.
28
Cheong HI, Kang JH, Lee JH, et al. Mutational analysis of idiopathic renal hypouricemia in Korea. Pediatr Nephrol 2005; 20(7): 886-90.
29
Kim YH, Cho JT. A case of exercise-induced acute renal failure with G774A mutation in SCL22A12 causing renal hypouricemia. J Korean Med Sci 2011; 26(9): 1238-40.
30
Kim HO, Ihm CG, Jeong KH, et al. A case report of familial renal hypouricemia confirmed by genotyping of SLC22A12, and a literature review. Electrolyte Blood Press 2015; 13(2): 52-7.
31
Dinour D, Bahn A, Ganon L, et al. URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. Nephrol Dial Transplant 2011; 26(7): 2175-81.
32
Li Z, Ding H, Chen C, Chen Y, Wang DW, Lv Y. Novel URAT1 mutations caused acute renal failure after exercise in two Chinese families with renal hypouricemia. Gene 2013; 512(1): 97-101.
33
Stiburkova B, Sebesta I, Ichida K, et al. Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis. Eur J Hum Genet 2013; 21(10): 1067-73.
34
Mancikova A, Krylov V, Hurba O, et al. Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clin Exp Nephrol 2016; 20(4): 578-84.
35
Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.
36
Sakiyama M, Matsuo H, Shimizu S, et al. The effects of URAT1/SLC22A12 nonfunctional variants, R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression. Sci Rep 2016; 6: 20148.
37
Torres RJ, de Miguel E, Bailén R, Banegas JR, Puig JG. Tubular urate transporter gene polymorphisms differentiate patients with gout who have normal and decreased urinary uric acid excretion. J Rheumatol 2014; 41(9): 1863-70.
38
Tu HP, Chen CJ, Lee CH, et al. The SLC22A12 gene is associated with gout in han Chinese and Solomon Islanders. Ann Rheum Dis 2010; 69(6): 1252-4.
39
Flynn TJ, Phipps-Green A, Hollis-Moffatt JE, et al. Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects. Arthritis Res Ther 2013; 15(6): R220.
40
Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.
41
Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.
42
Augustin R, Carayannopoulos MO, Dowd LO, Phay JE, Moley JF, Moley KH. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): Alternative splicing alters trafficking. J Biol Chem 2004; 279(16): 16229-36.
43
Kimura T, Takahashi M, Yan K, Sakurai H. Expression of SLC2A9 isoforms in the kidney and their localization in polarized epithelial cells. PLoS One 2014; 9(1): e84996.
44
Anzai N, Ichida K, Jutabha P, et al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 2008; 283(40): 26834-8.
45
Matsuo H, Chiba T, Nagamori S, et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 2008; 83(6): 744-51.
46
Dinour D, Gray NK, Campbell S, et al. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol 2010; 21(1): 64-72.
47
Stiburkova B, Ichida K, Sebesta I. Novel homozygous insertion in SLC2A9 gene caused renal hypouricemia. Mol Genet Metab 2011; 102(4): 430-5.
48
Shima Y, Nozu K, Nozu Y, et al. Recurrent EIARF and PRES with severe renal hypouricemia by compound heterozygous SLC2A9 mutation. Pediatrics 2011; 127(6): e1621-5.
49
Kawamura Y, Matsuo H, Chiba T, et al. Pathogenic GLUT9 mutations causing renal hypouricemia type 2 (RHUC2). Nucleosides Nucleotides Nucleic Acids 2011; 30(12): 1105-11.
50
Dinour D, Gray NK, Ganon L, et al. Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2. Nephrol Dial Transplant 2012; 27(3): 1035-41.
51
Stiburkova B, Taylor J, Marinaki AM, Sebesta I. Acute kidney injury in two children caused by renal hypouricaemia type 2. Pediatr Nephrol 2012; 27(8): 1411-5.
52
Jeannin G, Chiarelli N, Gaggiotti M, et al. Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9 compound heterozygosity. BMC Med Genet 2014; 15: 3.
53
Chiba T, Matsuo H, Nagamori S, et al. Identification of a hypouricemia patient with SLC2A9 R380W, a pathogenic mutation for renal hypouricemia type 2. Nucleosides Nucleotides Nucleic Acids 2014; 33(4-6): 261-5.
54
Shen H, Feng C, Jin X, et al. Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review. BMC Pediatr 2014; 14: 73.
55
Mou LJ, Jiang LP, Hu Y. A novel homozygous GLUT9 mutation cause recurrent exercise-induced acute renal failure and posterior reversible encephalopathy syndrome. J Nephrol 2015; 28(3): 387-92.
56
Windpessl M, Ritelli M, Wallner M, Colombi M. A novel homozygous SLC2A9 mutation associated with renal-induced hypouricemia. Am J Nephrol 2016; 43(4): 245-50.
57
Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: A genome-wide association study. Lancet 2008; 372(9654): 1953-61.
58
Hollis-Moffatt JE, Xu X, Dalbeth N, et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets. Arthritis Rheum 2009; 60(11): 3485-92.
59
Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7: 43614.
60
Kim YS, Kim Y, Park G, et al. Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population. Korean J Intern Med (Korean Assoc Intern Med) 2015; 30(6): 913-20.
61
Urano W, Taniguchi A, Anzai N, et al. Association between GLUT9 and gout in Japanese men. Ann Rheum Dis 2010; 69(5): 932-3.
62
Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.
63
Hurba O, Mancikova A, Krylov V, Pavlikova M, Pavelka K, Stibůrková B. Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout. PLoS One 2014; 9(9): e107902.
64
Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40(4): 437-42.
65
Tu HP, Chen CJ, Tovosia S, et al. Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders. Ann Rheum Dis 2010; 69(5): 887-90.
66
Stark K, Reinhard W, Neureuther K, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One 2008; 3(4): e1948.
67
Hollis-Moffatt JE, Gow PJ, Harrison AA, et al. The SLC2A9 nonsynonymous Arg265His variant and gout: Evidence for a population-specific effect on severity. Arthritis Res Ther 2011; 13(3): R85.
68
Wan W, Xu X, Zhao DB, Pang YF, Wang YX. Polymorphisms of uric transporter proteins in the pathogenesis of gout in a Chinese Han population. Genet Mol Res 2015; 14(1): 2546-50.
69
Zheng C, Yang H, Wang Q, Rao H, Diao Y. Association analysis of five SNP variants with gout in the Minnan population in China. Turk J Med Sci 2016; 46(2): 361-7.
70
Das Gupta E, Sakthiswary R, Lee SL, Wong SF, Hussein H, Gun SC. Clinical significance of SLC2A9/GLUT9 rs11722228 polymorphisms in gout. Int J Rheum Dis 2018; 21(3): 705-9.
71
Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis 2016; 75(4): 652-9.
72
Tin A, Woodward OM, Kao WH, et al. Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Hum Mol Genet 2011; 20(20): 4056-68.
73
He W, Phipps-Green A, Stamp LK, Merriman TR, Dalbeth N. Population-specific association between ABCG2 variants and tophaceous disease in people with gout. Arthritis Res Ther 2017; 19(1): 43.
74
Li C, Chu N, Wang B, et al. Polymorphisms in the presumptive promoter region of the SLC2A9 gene are associated with gout in a Chinese male population. PLoS One 2012; 7(2): e24561.
75
Hagos Y, Stein D, Ugele B, Burckhardt G, Bahn A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol 2007; 18(2): 430-9.
76
Sakiyama M, Matsuo H, Shimizu S, et al. A common variant of organic anion transporter 4 (OAT4/SLC22A11) gene is associated with renal underexcretion type gout. Drug Metab Pharmacokinet 2014; 29(2): 208-10.
77
Miyaji T, Kawasaki T, Togawa N, Omote H, Moriyama Y. Type 1 sodium-dependent phosphate transporter acts as a membrane potential-driven urate exporter. Curr Mol Pharmacol 2013; 6(2): 88-94.
78
Iharada M, Miyaji T, Fujimoto T, et al. Type 1 sodium-dependent phosphate transporter (SLC17A1 Protein) is a Cl(-)-dependent urate exporter. J Biol Chem 2010; 285(34): 26107-13.
79
Sakiyama M, Matsuo H, Nagamori S, et al. Expression of a human NPT1/SLC17A1 missense variant which increases urate export. Nucleosides Nucleotides Nucleic Acids 2016; 35(10-12): 536-42.
80
Hollis-Moffatt JE, Phipps-Green AJ, Chapman B, et al. The renal urate transporter SLC17A1 locus: Confirmation of association with gout. Arthritis Res Ther 2012; 14(2): R92.
81
Urano W, Taniguchi A, Anzai N, et al. Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann Rheum Dis 2010; 69(6): 1232-4.
82
Chiba T, Matsuo H, Kawamura Y, et al. NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout. Arthritis Rheumatol 2015; 67(1): 281-7.
83
Jutabha P, Anzai N, Kitamura K, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem 2010; 285(45): 35123-32.
84
Togawa N, Miyaji T, Izawa S, Omote H, Moriyama Y. A Na+-phosphate cotransporter homologue (SLC17A4 protein) is an intestinal organic anion exporter. Am J Physiol Cell Physiol 2012; 302(11): C1652-60.
85
Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation. Biochem J 1999; 343(Pt 2): 281-99.
86
Nakayama A, Matsuo H, Shimizu T, et al. Common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility. Hum Cell 2013; 26(4): 133-6.
87
Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport--an update. AAPS J 2015; 17(1): 65-82.
88
Woodward OM, Köttgen A, Coresh J, Boerwinkle E, Guggino WB, Köttgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA 2009; 106(25): 10338-42.
89
Meyer zu Schwabedissen HE, Kroemer HK. In vitro and in vivo evidence for the importance of breast cancer resistance protein transporters (BCRP/MXR/ABCP/ABCG2). Handb Exp Pharmacol 2011; (201): 325-71.
90
Hosomi A, Nakanishi T, Fujita T, Tamai I. Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2. PLoS One 2012; 7(2): e30456.
91
Zhou D, Liu Y, Zhang X, et al. Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population. Int J Mol Sci 2014; 15(5): 9149-59.
92
Yu KH, Chang PY, Chang SC, et al. A comprehensive analysis of the association of common variants of ABCG2 with gout. Sci Rep 2017; 7(1): 9988.
93
Jiri M, Zhang L, Lan B, et al. Genetic variation in the ABCG2 gene is associated with gout risk in the Chinese Han population. Clin Rheumatol 2016; 35(1): 159-63.
94
Matsuo H, Takada T, Ichida K, et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: A function-based genetic analysis in a Japanese population. Sci Transl Med 2009; 1(5): 5ra11.
95
Higashino T, Takada T, Nakaoka H, et al. Multiple common and rare variants of ABCG2 cause gout. RMD Open 2017; 3(2): e000464.
96
Yamagishi K, Tanigawa T, Kitamura A, Köttgen A, Folsom AR, Iso H. The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people. Rheumatology (Oxford) 2010; 49(8): 1461-5.
97
Phipps-Green AJ, Hollis-Moffatt JE, Dalbeth N, et al. A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Māori, case and control sample sets. Hum Mol Genet 2010; 19(24): 4813-9.
98
Zhang L, Spencer KL, Voruganti VS, et al. Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. Am J Epidemiol 2013; 177(9): 923-32.
99
Tomlinson B, Hu M, Lee VW, et al. ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther 2010; 87(5): 558-62.
100
Ghafouri H, Ghaderi B, Amini S, Nikkhoo B, Abdi M, Hoseini A. Association of ABCB1 and ABCG2 single nucleotide polymorphisms with clinical findings and response to chemotherapy treatments in Kurdish patients with breast cancer. Tumour Biol 2016; 37(6): 7901-6.
101
Wen CC, Yee SW, Liang X, et al. Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther 2015; 97(5): 518-25.
102
Roberts RL, Wallace MC, Phipps-Green AJ, et al. ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout. Pharmacogenomics J 2017; 17(2): 201-3.
103
Van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Renal Physiol 2005; 288(2): F327-33.
104
Tanner C, Boocock J, Stahl EA, et al. Population-specific resequencing associates the ATP-binding cassette subfamily C member 4 gene with gout in New Zealand Māori and pacific men. Arthritis Rheumatol 2017; 69(7): 1461-9.
105
Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996; 384(6604): 80-3.
106
Yamagata K, Senokuchi T, Lu M, et al. Voltage-gated K+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line. Biochem Biophys Res Commun 2011; 407(3): 620-5.
107
Li C, Li Z, Liu S, et al. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese. Nat Commun 2015; 6: 7041.
108
Anzai N, Jutabha P, Amonpatumrat-Takahashi S, Sakurai H. Recent advances in renal urate transport: Characterization of candidate transporters indicated by genome-wide association studies. Clin Exp Nephrol 2012; 16(1): 89-95.
109
Li M, Li Q, Li CG, et al. Genetic polymorphisms in the PDZK1 gene and susceptibility to gout in male Han Chinese: A case-control study. Int J Clin Exp Med 2015; 8(8): 13911-8.
110
Phipps-Green AJ, Merriman ME, Topless R, et al. Twenty-eight loci that influence serum urate levels: analysis of association with gout. Ann Rheum Dis 2016; 75(1): 124-30.
111
Reynolds RJ, Vazquez AI, Srinivasasainagendra V, et al. Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index. Rheumatol Int 2016; 36(2): 263-70.
112
Yang Q, Köttgen A, Dehghan A, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet 2010; 3(6): 523-30.
113
Higashino T, Matsuo H, Sakiyama M, et al. Common variant of PDZ domain containing 1 (PDZK1) gene is associated with gout susceptibility: A replication study and meta-analysis in Japanese population. Drug Metab Pharmacokinet 2016; 31(6): 464-6.
114
Takada Y, Matsuo H, Nakayama A, et al. Common variant of PDZK1, adaptor protein gene of urate transporters, is not associated with gout. J Rheumatol 2014; 41(11): 2330-1.
115
Goytain A, Hines RM, Quamme GA. Functional characterization of NIPA2, a selective Mg2+ transporter. Am J Physiol Cell Physiol 2008; 295(4): C944-53.
116
Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. The P2X7 receptor-interleukin-1 Liaison. Front Pharmacol 2017; 8: 123.
117
da Silva TA, Zorzetto-Fernandes ALV, Cecílio NT, Sardinha-Silva A, Fernandes FF, Roque-Barreira MC. CD14 is critical for TLR2-mediated M1 macrophage activation triggered by N-glycan recognition. Sci Rep 2017; 7(1): 7083.
118
McKinney C, Stamp LK, Dalbeth N, et al. Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout. Arthritis Res Ther 2015; 17: 288.
119
Chen H, Wilkins LM, Aziz N, et al. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet 2006; 15(4): 519-29.
120
LeVan TD, Bloom JW, Bailey TJ, et al. A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 2001; 167(10): 5838-44.
121
Liu S, Yin C, Chu N, Han L, Li C. IL-8 -251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population. Scand J Rheumatol 2013; 42(2): 150-8.
122
Cui YX, Zhao H, Guo HQ. Role of IL-8 rs4073 and rs2227306 polymorphisms in the development of primary gouty arthritis in a Chinese population. Genet Mol Res 2016; 15(4)
123
Ohyauchi M, Imatani A, Yonechi M, et al. The polymorphism interleukin 8 -251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 2005; 54(3): 330-5.
124
Kim HS, Chung DH. TLR4-mediated IL-12 production enhances IFN-γ and IL-1β production, which inhibits TGF-β production and promotes antibody-induced joint inflammation. Arthritis Res Ther 2012; 14(5): R210.
125
Seegers D, Zwiers A, Strober W, Peña AS, Bouma G. A TaqI polymorphism in the 3'UTR of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 2002; 3(7): 419-23.
126
Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: A key cytokine in inflammatory diseases. Ann Med 2011; 43(7): 503-11.
127
Liu S, He H, Yu R, et al. The rs7517847 polymorphism in the IL-23R gene is associated with gout in a Chinese Han male population. Mod Rheumatol 2015; 25(3): 449-52.
128
Liu S, Zhou Z, Wang C, Guo M, Chu N, Li C. Associations between interleukin and interleukin receptor gene polymorphisms and risk of gout. Sci Rep 2015; 5: 13887.
129
Yokose K, Sato S, Asano T, et al. TNF-ɑ potentiates uric acid-induced interleukin-1β (IL-1β) secretion in human neutrophils. Mod Rheumatol 2017; 1-5.
130
Chang SJ, Tsai PC, Chen CJ, Lai HM, Ko YC. The polymorphism -863C/A in tumour necrosis factor-alpha gene contributes an independent association to gout. Rheumatology (Oxford) 2007; 46(11): 1662-6.
131
Sun R, Zhang K, Zhang X, et al. The CC chemokine ligand 2 (CCL2) polymorphism -2518A/G is associated with gout in the Chinese Han male population. Rheumatol Int 2015; 35(3): 479-84.
132
Karrer S, Bosserhoff AK, Weiderer P, et al. The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis. J Invest Dermatol 2005; 124(1): 92-8.
133
Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases. Clin Exp Rheumatol 2016; 34(4)(Suppl. 98): 12-6.
134
So AK, Martinon F. Inflammation in gout: Mechanisms and therapeutic targets. Nat Rev Rheumatol 2017; 13(11): 639-47.
135
Deng J, Lin W, Chen Y, et al. rs3806268 of NLRP3 gene polymorphism is associated with the development of primary gout. Int J Clin Exp Pathol 2015; 8(10): 13747-52.
136
Vats D, Mukundan L, Odegaard JI, et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 2006; 4(1): 13-24.
137
Chang WC, Jan Wu YJ, Chung WH, et al. Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis. Rheumatology (Oxford) 2017; 56(3): 457-66.
138
Qing YF, Zhang QB, Zhou JG, Jiang L. Changes in toll-like receptor (TLR)4-NFκB-IL1β signaling in male gout patients might be involved in the pathogenesis of primary gouty arthritis. Rheumatol Int 2014; 34(2): 213-20.
139
Xiao J, Zhang XL, Fu C, et al. Soluble uric acid increases NALP3 inflammasome and interleukin-1β expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway. Int J Mol Med 2015; 35(5): 1347-54.
140
Qing YF, Zhou JG, Zhang QB, et al. Association of TLR4 Gene rs2149356 polymorphism with primary gouty arthritis in a case-control study. PLoS One 2013; 8(5): e64845.
141
Rasheed H, McKinney C, Stamp LK, et al. The Toll-Like receptor 4 (TLR4) variant rs2149356 and risk of gout in European and Polynesian sample sets. PLoS One 2016; 11(1): e0147939.
142
Fontalba A, Martinez-Taboada V, Gutierrez O, et al. Deficiency of the NF-kappaB inhibitor caspase activating and recruitment domain 8 in patients with rheumatoid arthritis is associated with disease severity. J Immunol 2007; 179(7): 4867-73.
143
Paramel GV, Folkersen L, Strawbridge RJ, et al. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation. Clin Sci (Lond) 2013; 125(8): 401-7.
144
Chen Y, Ren X, Li C, et al. CARD8 rs2043211 polymorphism is associated with gout in a Chinese male population. Cell Physiol Biochem 2015; 35(4): 1394-400.
145
Lee SW, Lee SS, Oh DH, et al. Genetic association for P2X7R rs3751142 and CARD8 rs2043211 polymorphisms for susceptibility of gout in Korean men: Multi-center study. J Korean Med Sci 2016; 31(10): 1566-70.
146
Gicquel T, Robert S, Loyer P, et al. IL-1β production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages. FASEB J 2015; 29(10): 4162-73.
147
Tao JH, Cheng M, Tang JP, et al. Single nucleotide polymorphisms associated with P2X7R function regulate the onset of gouty arthritis. PLoS One 2017; 12(8): e0181685.
148
Zeng F, Harris RC. Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol 2014; 28: 2-11.
149
Yan X, Li Q, Ni D, et al. Apobec-1 complementation factor regulates cell migration and apoptosis through Dickkopf1 by acting on its 3′ untranslated region in MCF7 cells. Tumour Biol 2017; 39(6): 1010428317706218.
150
Drewes T, Senkel S, Holewa B, Ryffel GU. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol 1996; 16(3): 925-31.
151
Sun H, Tian J, Xian W, Xie T, Yang X. miR-34a inhibits proliferation and invasion of bladder cancer cells by targeting orphan nuclear receptor HNF4G. Dis Markers 2015; 2015: 879254.
152
McNab FW, Rajsbaum R, Stoye JP, O’Garra A. Tripartite-motif proteins and innate immune regulation. Curr Opin Immunol 2011; 23(1): 46-56.
153
Han L, Cao C, Jia Z, et al. Epidermal growth factor gene is a newly identified candidate gene for gout. Sci Rep 2016; 6: 31082.
154
Christensen EI, Birn H. Megalin and cubilin: Multifunctional endocytic receptors. Nat Rev Mol Cell Biol 2002; 3(4): 256-66.
155
Dong Z, Zhao D, Yang C, et al. Common variants in LRP2 and COMT genes affect the susceptibility of gout in a chinese population. PLoS One 2015; 10(7): e0131302.
156
Rasheed H, Phipps-Green A, Topless R, et al. Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption. Arthritis Res Ther 2013; 15(6): R177.
157
Nakayama A, Matsuo H, Shimizu T, et al. Common variants of a urate-associated gene LRP2 are not associated with gout susceptibility. Rheumatol Int 2014; 34(4): 473-6.
158
Raimondo A, Rees MG, Gloyn AL. Glucokinase regulatory protein: Complexity at the crossroads of triglyceride and glucose metabolism. Curr Opin Lipidol 2015; 26(2): 88-95.
159
Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease. Metabolism 2016; 65(8): 1026-37.
160
Wang J, Liu S, Wang B, et al. Association between gout and polymorphisms in GCKR in male Han Chinese. Hum Genet 2012; 131(7): 1261-5.
161
Strosberg AD. Structure and function of the beta 3-adrenergic receptor. Annu Rev Pharmacol Toxicol 1997; 37: 421-50.
162
Wang B, Meng D, Wang J, et al. Positive correlation between Beta-3-Adrenergic Receptor (ADRB3) gene and gout in a Chinese male population. J Rheumatol 2011; 38(4): 738-40.
163
Fatima T, Altaf S, Phipps-Green A, et al. Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout. Rheumatol Int 2016; 36(2): 255-61.
164
Sakiyama M, Matsuo H, Nakaoka H, et al. Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus. Sci Rep 2016; 6: 25360.
165
Sakiyama M, Matsuo H, Akashi A, et al. Independent effects of ADH1B and ALDH2 common dysfunctional variants on gout risk. Sci Rep 2017; 7(1): 2500.
166
Wang C, Li C, Ding C, et al. The polymorphisms of aldehyde dehydrogenase 2 gene are associated with gout disease in male Han Chinese. Gout and Hyperuricemia 2016; 3: 40-5.
167
Pestana M, Jardim H, Correia F, Vieira-Coelho MA, Soares-da-Silva P. Renal dopaminergic mechanisms in renal parenchymal diseases and hypertension. Nephrol Dial Transplant 2001; 16(Suppl. 1): 53-9.
168
Zeng C, Zhang M, Asico LD, Eisner GM, Jose PA. The dopaminergic system in hypertension. Clin Sci (Lond) 2007; 112(12): 583-97.
169
Sulikowska B, Manitius J, Odrowaz-Sypniewska G, Łysiak-Szydłowska W, Rutkowski B. Uric acid excretion and dopamine-induced glomerular filtration response in patients with IgA glomerulonephritis. Am J Nephrol 2008; 28(3): 391-6.
170
Tu HP, Ko AM, Wang SJ, et al. Monoamine oxidase A gene polymorphisms and enzyme activity associated with risk of gout in Taiwan aborigines. Hum Genet 2010; 127(2): 223-9.
171
Liao WT, You HL, Li C, Chang JG, Chang SJ, Chen CJ. Cyclic GMP-dependent protein kinase II is necessary for macrophage M1 polarization and phagocytosis via toll-like receptor 2. J Mol Med (Berl) 2015; 93(5): 523-33.
172
Chang SJ, Tsai MH, Ko YC, Tsai PC, Chen CJ, Lai HM. The cyclic GMP-dependent protein kinase II gene associates with gout disease: identified by genome-wide analysis and case-control study. Ann Rheum Dis 2009; 68(7): 1213-9.
173
Guo M, Cheng Z, Li C, et al. Polymorphism of rs7688672 and rs10033237 in cGKII/PRKG2 and gout susceptibility of Han population in northern China. Gene 2015; 562(1): 50-4.
174
Sakiyama M, Matsuo H, Chiba T, et al. Common variants of cGKII/PRKG2 are not associated with gout susceptibility. J Rheumatol 2014; 41(7): 1395-7.
175
Ono S. Functions of actin-interacting protein 1 (AIP1)/WD repeat protein 1 (WDR1) in actin filament dynamics and cytoskeletal regulation. Biochem Biophys Res Commun 2017 Oct 19. pii: S0006-291X(17)32074-0.
176
Liu LJ, Zhang XY, He N, et al. Genetic variation in WDR1 is associated with gout risk and gout-related metabolic indices in the Han Chinese population. Genet Mol Res 2016; 15(2)
177
Heine M, Cramm-Behrens CI, Ansari A, et al. Alpha-kinase 1, a new component in apical protein transport. J Biol Chem 2005; 280(27): 25637-43.
178
Ko AM, Tu HP, Liu TT, et al. ALPK1 genetic regulation and risk in relation to gout. Int J Epidemiol 2013; 42(2): 466-74.
179
Chiba T, Matsuo H, Sakiyama M, et al. Common variant of ALPK1 is not associated with gout: A replication study. Hum Cell 2015; 28(1): 1-4.
180
Sakiyama M, Matsuo H, Shimizu S, et al. Common variant of leucine-rich repeat-containing 16A (LRRC16A) gene is associated with gout susceptibility. Hum Cell 2014; 27(1): 1-4.
181
Ogata H, Matsuo H, Sakiyama M, et al. Meta-analysis confirms an association between gout and a common variant of LRRC16A locus. Mod Rheumatol 2017; 27(3): 553-5.
182
Magnani D, Morlé L, Hasenpusch-Theil K, et al. The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating the patterning of prethalamus and ventral telencephalon. Hum Mol Genet 2015; 24(9): 2578-93.
183
Ait-Lounis A, Bonal C, Seguín-Estévez Q, et al. The transcription factor Rfx3 regulates beta-cell differentiation, function, and glucokinase expression. Diabetes 2010; 59(7): 1674-85.
184
Siva K, Venu P, Mahadevan A, S K S, Inamdar MS. Human BCAS3 expression in embryonic stem cells and vascular precursors suggests a role in human embryogenesis and tumor angiogenesis. PLoS One 2007; 2(11): e1202.
185
Gill MB, Kato AS, Wang H, Bredt DS. AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform. Eur J Neurosci 2012; 35(2): 182-94.
186
Herring BE, Shi Y, Suh YH, et al. Cornichon proteins determine the subunit composition of synaptic AMPA receptors. Neuron 2013; 77(6): 1083-96.
187
Sheikh F, Lyon RC, Chen J. Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease. Gene 2015; 569(1): 14-20.
188
Kim YJ, Go MJ, Hu C, et al. Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. Nat Genet 2011; 43(10): 990-5.
189
Pal R, Ramdzan ZM, Kaur S, et al. CUX2 protein functions as an accessory factor in the repair of oxidative DNA damage. J Biol Chem 2015; 290(37): 22520-31.