Our genetic analysis identified that the CHS and JPT populations as having the highest prevalence of validated HU and gout risk alleles compared with EUR. Specifically, all the nine significantly different alleles in CHS were considered HU or gout risk alleles. The eleven of the significantly different alleles in JPT were considered HU or gout risk alleles. (Table 4). These results suggest a possible genetic basis of the document higher prevalence of HU and gout in Asian populations compared to EUR.(7)
The ABCG2 gene is strongly associated with SU levels, early-onset gout, and the progression from HU to gout.(41-43) The encoded protein, ATP-binding cassette superfamily G member 2 (ABCG2), is expressed in both the kidney and liver and functions as a urate efflux transporter. The genetic polymorphism rs2231142 (G>T) in ABCG2 leads to Glu141Lys amino acid change, which results in a reduced ABCG2-mediated urate efflux activity and inflammation dysregulation via augmented IL-8 release (Table 1). (44, 45) Individuals with this polymorphism are at a higher risk for HU and gout. A genomic meta-analysis of SU levels in over 28,000 European individuals showed that the rs2231142 (G>T), with the risk allele T, was present in only 10.8% and was significantly associated with increased SU levels (Effect size = 0.173, p= 3.10x10-26).(23) In our study, the risk allele T of rs2231142 (G>T) was present in 9.4% of Europeans, 25% in CHS, and 32% in JPT (Table 2).
The genetic polymorphism rs2231142 (G>T) in ABCG2 is strongly associated with increased risk for HU and gout across different populations. A study of 1206 Chinese individuals found that the rs2231142 (G>T) polymorphism was associated with HU risk (OR =1.63, 95% CI: 1.27;2.11) and increased SU levels (Effect size = 0.16, p= 6.75x10-9).(46) Additionally, a population-based study showed that the rs2231142 (G>T) is a causal variant for gout in Whites and Blacks with OR =1.68 per risk allele. Across the four major populations in the United States, the association between the rs2231142 (G>T) and prevalent gout was significantly stronger in men (OR = 2.03, p=1.53×10-13) than in women (OR =1.37, p = 0.03). Among women, the association was statistically significant only in postmenopausal women (OR = 1.45, p= 0.03) compared with premenopausal women (OR = 0.96, p = 0.94).(17) Collectively, the genetic polymorphism rs2231142 (G>T) in ABCG2 is believed to be the most significant gene variant associated with HU and gout compared to other risk alleles. These results support that the genetic polymorphism rs2231142 (G>T) in ABCG2 may not only lead to a higher risk for developing HU and gout in Asian populations compared to EUR, but it may also explain early-onset gout in select Asian subgroups.
SLC2A9 encodes the GLUT9, a high-capacity transporter for fructose, glucose, and SU.(16, 47) GLUT9 is not only expressed in the kidney and liver, but it is also expressed in the chondrocyte of human articular cartilage.(48) The rs734553 (G>T) in SLC2A9 is an intronic polymorphism that could result in an increased susceptibility to develop HU, gout, and diabetes due to altered transporter affinity.(23, 49, 50) Particularly, this genetic polymorphism has one the largest effect size on SU levels in EUR and could have a greater effect on SU in women (Effect size = 0.315, p=5.22x10-201).(23) Our analysis showed that the prevalence of the risk allele T in ASW and MXL (53.3% and 61.7%, respectively) was significantly lower than EUR (75.5%). On the other hand, the frequency of risk allele T was significantly higher in CHS and JPT (95.5% and 98.6%, respectively) than EUR (75.5%). With such distinct differential prevalence and large effect size on SU levels, our data suggest that CHS and JPT population are at greater risk for developing HU or gout compared to other populations.
SLC16A9 encodes for monocarboxylic acid transporter, a significant urate transporter (Table 1).(24) The genetic polymorphism rs1171614 (C>T) in SLC16A9 was reported to influence SU levels and the risk of gout.(24) Genome-wide association analysis showed that effect allele T of rs1171614 C>T was associated with lower SU levels and with a frequency of 22% in EUR (Effect size = -0.079, p= 2.3x10-28). Our analysis showed that the frequency of the risk allele C in the rs1171614 (C>T) within SLC16A9 was 100% in CHS and JPT, and 89.9% in MXL compared to 75.7% in EUR. However, the risk allele frequency between ASW and EUR was not significant (77% vs. 75.7%, p=0.75, Table 2). This finding suggests that the polymorphism rs1171614 (C>T) in SLC16A9 may be significantly contributing to the high gout prevalence among Asians and the increased risk among CHS and JPT.
SLC17A1 encodes for voltage-gated cotransporter protein NPT1, which is expressed on the apical side of the proximal tubule.29 The genetic polymorphism rs1183201 (T>A) in SLC17A1 was found to be associated with decreased SU levels (Effect size = -0.062, 95% CI: -0.078; -0.459) with the effect allele A being the protective allele in European descent.(23) For the intronic SNP rs1183201 (T>A), the A allele, associated with lower SU levels, had a 48.2% prevalence in individuals of European descent.(23) Our analysis showed a similar prevalence of the effect A allele to be 46.1% in EUR. In contrast, the A allele was significantly lower in all our targeted populations, with 12.3% in ASW, 11.9% in CHS, and 16.3% in JPT (p<0.005, Table 2). This data suggest that specific populations could be genetically predisposed to elevated SU levels. Specifically, ASW, CHS, and JPT populations could garner less protection against HU or gout because of the lower frequency of the A allele of the rs1183201 (T>A) in SLC17A1 compared to the European population.
SLC22A11 and SLC22A12 encode for organic anion transporter 4 (OAT4) and urate transporter 1 (URAT1), respectively. These transporters are responsible for the majority of urate reabsorption in the kidneys and the primary targets for urate-lowering therapies. GWAS in different populations identified that genetic polymorphisms rs2078267 (C>T) in SLC22A11 and rs505802 (C>T) in SLC22A12 could significantly modulate SU levels (Table 1).(23, 24). Particularly, the T allele of rs2078267 (C>T) in SLC22A11 was associated with reduced SU levels (effect size=-0.073, p= 9.4 × 10-38) in EUR with a prevalence of 53.1%. Additionally, the T allele of the rs505802 (C>T) in SLC22A12 was found to be associated with lower SU levels (effect size=-0.056, p=2.04X10-9) in EUR with a prevalence of 70.7%. Consistent with previous GWAS, population studies reported that the rs505802 (C>T) within SLC22A12 was associated with lower SU levels in Chinese and Japanese populations.(21, 51) Our study showed that the frequency of risk allele C in both loci-SLC22A11 and SLC22A12 was significantly higher in all targeted populations (ASW, CHS, JPT, MXL) compared to EUR (Table 2). Specifically, the frequencies of the risk allele C of both polymorphisms, rs505802 (C>T) and rs2078267 (C>T) were highest in Asian subgroups CHS and JPT compared with the rest of other populations.
GCKR encodes for a glucokinase regulatory protein (GCKR), which modulates the metabolic syndrome-related traits, such as triglyceride regulation, blood pressure, and type-2 diabetes.(52, 53) Several mechanisms may explain the association between urate levels and metabolic diseases, such as insulin resistance leading to impaired oxidative phosphorylation in hepatic cells and subsequent urate retention.(23) Furthermore, the GCKR polymorphism rs1260326 (C>T) was associated with a 14% increased gout risk (OR = 1.39, 95%CI 1.23;1.57) and increased SU levels (Effect size = 0.074, p= 1.2x10-44) in individuals of European ancestry.(24) In our analysis, the risk allele T was higher in JPT compared to EUR (58.2% vs. 41.1%, p<0.0001) and lower in ASW compared to EUR (9.8% vs. 41.1%, p<0.0001) (Table 2).
The CHARGE meta-analysis along with multiple GWAS have identified RREB1 and INHBC loci as having genome-wide significance with SU levels.(24, 52, 54) RREB1 encodes for zinc finger transcription factor and is responsible for binding to RAS-responsive elements of gene promoters and regulating the androgen receptor and calcitonin gene. INHBC encodes for a member of the transforming growth factor β family.(24, 54). The polymorphism rs675209 (C>T) in RREB1 was associated with increased SU (Effect size = 0.061, p=1.3x10-23) and increased risk for gout (OR = 1.09, p=1.1x10-2) in individuals of European ancestry.(24) In contrast, rs3741414 (C>T) within INHBC was associated with lower SU concentrations in individuals of European ancestry (Effect size = -0.072, p=2.2x10-25) and decreased risk for gout (OR = 0.87, p=2.7x10-4).(24) Though the exact biological mechanism underlying the association of the forementioned SNPs and the risk of HU or gout is inconclusive, it is presumed that these genetic polymorphisms may reduce the repressor activity functions of RREB1 and INHBC.(54, 55)
Compared to EUR, the CHS population had significantly higher frequencies of both risk alleles of rs675209 (C>T) in RREB1 (91.4% vs. 26.9%, p<0.0001) and rs3741414 (C>T) within INHBC (91.4% vs. 80.5%, p=0.0002) (Table 2). Compared to ERU, the JPT population also had significantly higher risk allele frequencies compared to both of the previously mentioned polymorphisms. Specifically, the frequency of the risk allele T of rs675209 (C>T) in RREB1 was 92.3% in JPT compared to 26.9% in EUR (p<0.0001) (Table 2). The frequency of the risk allele C of rs3741414 (C>T) in INHBC was 94.2% in JPT compared to 80.5% in EUR (p<0.0001) (Table 2). However, the MXL population had mixed results of allele frequencies of the forementioned polymorphisms. Compared to EUR, the MXL had a higher frequency of the risk allele T of rs675209 (C>T) in RREB1 compared with EUR (47.7% vs. 26.9%, p<0.0001), while having a lower frequency of the risk allele of C of rs3741414 (C>T) in INHBC compared with EUR (53.1% vs 85.5, p<0.0001) (Table 2).
PDZK1 is expressed in the kidney and encodes PDZ domain-containing molecules, which act as a scaffolding protein for a variety of subcellular transport proteins.(56) The results of a case-control study suggest that PDZK1 genetic polymorphism rs12129861 (C>T) is associated with reduced gout risk in male Han Chinese (OR = 0.727, 95% CI: 0.562;0.940).(56) A similar observation was reported in GWAS where the T allele was significantly associated with lower SU levels compared with the C allele (Effect size = -0.062, 95% CI: -0.083; -0.042). In our analysis, CHS had a significantly higher frequency of the risk allele C compared to EUR (78.1% vs. 54.1%, p<0.0001) (Table2). In the JPT population, however, the risk allele C was markedly higher compared to EUR (91.3% vs. 54.1%, p<0.0001). In contrast, the risk allele frequencies were not significantly different between ASW or MXL and EUR (Table 2). Collectively, these results suggest that CHS and JPT populations are enriched with the HU and gout risk alleles, contributing to a higher prevalence of gout among Asians compared with EUR.
NRXN2 encodes a member of the neurexin gene family, which produces cell adhesion molecules and receptors in the nervous system. Nonetheless, the same gene family was linked to urate levels in multiple populations.(24) Although the mechanism remains elusive, a GWAS showed that the intronic genetic polymorphism rs478607 (G>A) in NRXN2 could affect SU levels and the fractional excretion of urate (FEUA). Particularly, the A allele was associated with reduced SU levels (Effect size= −0.047, p=4.4 × 10-11) and increased FEUA (Effect size=0.046, p=0.046). Notably, except for the ASW population, the interrogated genetic polymorphism rs478607 (G>A) was in strong linkage disequilibrium with the missense rs12273892 (A>T). In our study, ASW and JPT populations had a significantly higher frequency of the risk allele G compared to EUR (46.7% vs. 15.4, p <0.0001; 24.5% vs. 15.4%, p=0.0014, respectively) (Table 2). The risk allele frequency was not significantly different between the rest of our selected populations and EUR.
The rising of HU and gout prevalence in specific populations in recent decades suggest substantial changes in the lifestyle and the global rising of gout risk factors.(40, 57) Moreover, gout prevalence could also differ between rural, urban, and coastal regions, reinforcing the interaction between social determinants of health, lifestyle factors, and existing comorbidities in gout development.(37) Indeed, nongenetic factors such as diet, obesity, physical activity, and other environmental factors could further modulate the risk of developing gout.(58-61) Developed countries accustomed to westernized diets (over-intake of purine-rich foods and alcohol), such as the U.S., have been shown to have higher gout prevalence (Table 5) compared to non-U.S. countries (Table 6). Additionally, this might explain the health consequences of immigration and or acculturation to a high purine diet in the U.S., among population subgroups. While we recognize the critical role of nongenetic factors in the development of gouty arthritis, we believe our study provides evidence to support that the population enrichment of HU or gout risk alleles could lead to a higher gout incidence, especially when exposed and acculturated to a western diet.(15, 37) Therefore, a polygenic assessment approach for gout risk may provide a precise and reliable tool rather than relying on racial stratification for disease risk. Additionally, this genetic information could be used for gout risk stratification and potentially guide prescribers in choosing the most optimal drug therapy for patients at risk for developing gout.