Our study found that the population of Asian ancestry had a higher prevalence of HU and/or gout risk alleles compared with the EUR population. Uric acid associated alleles found in the Asian subgroup were significantly different from the EUR population and were all considered HU and/or gout risk allele. These results could partially explain the differential prevalence of hyperuricemia and gout across different ethnic and racial groups based on their genetic makeup. Therefore, a discussion on the role of these various genes/alleles in developing HU and/gout is warranted.
ABCG2 gene encodes the ATP-Binding Cassette G-protein transporter located in the apical membrane in the proximal renal tubule, and it is also expressed in the gastrointestinal tract and liver. ABCG2 is a major urate excretion transporter. Genetic polymorphisms in the ABCG2 gene were reported to contribute to elevated urate levels leading to hyperuricemia and gout. The SNP rs2231142 G > T (Q131K) in ABCG2 is associated with increased urate levels in the presence of the T-allele. Therefore, individuals with the TT genotype are at high risk of HU and gout than GG counterparts. A recent study reported that T-allele presence is 3- times higher in East Asians than EUR. This suggests that East Asian populations are at higher risk for developing HU and gout.
Similarly, our findings showed that the prevalence of the T allele of the rs2231142 (G > T) was 9.4% in EUR, 45.8% in Filipinos, 27.7% in Koreans, and 25.6% in Japanese (Table 5). In our Korean cohort, however, the rs2231142 (G > T) deviated from the HWE (p = 0.0407) (Table 6). In the Native Hawaiian and Pacific Islander (NHPI) subgroups, the frequencies of the T allele of the rs2231142 (G > T) were 31.1%, 17.6%, and 12.7% in Samoan, Marshallese, and Native Hawaiian subgroups, respectively. The genetic polymorphism rs22131142 (G > T) in ABCG2 is significantly associated with urate levels and increased risk for HU and gout among different populations.[20–22] A study conducted in the Korean population showed that the rs22131142 G > T is strongly associated with gout risk (Odds ratio [OR] 3.32; 95% confidence interval [CI]: 2.11 to 5.20).Also, in a study of 6881 Koreans identified that the genetic polymorphism rs2231142 (G > T) was associated with increased SU levels (Effect size = 0.220, p = 2.06E-29). Consistent with our results, a previous study reported that the minor allele frequency (MAF) of the T risk allele of the genetic variant rs2231142 in ABCG2 was high in Japanese and Koreans compared to Caucasians (0.29, 0.28, vs. 0.11). Additionally, a meta-analysis conducted on a multi-ethnic cohort reported that the T allele of rs22131142 G > T in ABCG2 was strongly associated with HU and gout across populations, and the severity is affected by gender and ethnicity.
Overall, the genetic polymorphism rs2231142 (G > T) of the ABCG2 gene is considered the most significant gene polymorphism related to the increased risk of HU and/or gout in selected minorities compared with other risk alleles. Sun et al. studied the association between 11 genetic loci of which ABCG2 rs2231142 (G > T) was one of the genes associated with serum urate concentrations in the Chinese population. Also, Zhang et al. reported that the SNP rs2231142 of the ABCG2 gene was associated with hyperuricemia in the American population consisting of EUR Americans, African Americans, Mexican Americans, and Indian Americans. Our finding provides that the genetic variants in ABCG2 rs2231142 (G > T) may increase urate levels and gout risk in Asian, Native Hawaiian, and Pacific Islander subgroups compared to EUR.
SLC2A9 encodes the GLUT9 transporter, which has a high-capacity transporter for urate, fructose, and glucose. SLC2A9 is known to be strongly associated with urate regulation in the human body. It is mainly expressed in the kidneys and liver, but it is also expressed in human articular cartilage. The intronic polymorphism rs734553 (G > T) in SLC2A9 is associated with increased HU risk and gout resulting from a change in transporter affinity for urate. This genetic variation strongly affects SU levels in EUR ancestry and could significantly affect SU in women (Effect size = 0.315, p = 5.22x10-201). Reginato Am et al. have identified that polymorphism rs734553 of the SLC2A9 gene is linked to SU levels and gout in the Islandic Polynesian population. Our analysis has shown that the T-allele's prevalence in Asian and Pacific Islander populations was higher than in the EUR population. Specifically, the frequency of rs734553 (G > T) was 99.5% in Japanese, 98.9% in Filipinos, and 98.3% in Koreans compared to 75.5% in EUR (p < 00.006). Additionally, the frequency of rs734553 (G > T) was 100% in Marshallese, 98.3% in Samoans, and 90.9% in Hawaiians compared to 75.5% in EUR (p < 0.006) (Table 3). Our results suggest that carrying the T -allele will likely increase the risk of elevated SU in both the Asian and NHPI subgroups.
SLC17A1 encodes the voltage-gated human sodium-dependent phosphate co-transporter type 1 protein (NPT1), located in the proximal tubule's apical side in the kidney and works as renal urate efflux transporter. Decreased SU Levels were found to be associated with the genetic polymorphism rs1183201 (T > A) in SLC17A1 (Effect size = -0.062, 95% CI: -0.078; -0.459) with the effect of allele A as the protective allele of EUR descent. In the intronic SNP rs1183201 (T > A) of SLC17A1, the A allele was associated with decreased SU level with a prevalence of 48.2% in EUR descent. The polymorphism rs1165205 of SLC17A3 has strong linkage disequilibrium r2 = 0.966 with rs1183201of SLC17A1 and has shown an association with gout and SU in Korean population with a MAF of T allele of 0.137.
Our analysis found that the prevalence of A allele in both Asian and Pacific Islander populations was lower than EUR descent except in Marshallese, where it was 57.2% vs. 46.1% (p < 0.006). Amongst the Asian population, the frequency of A allele for rs1183201 (T > A) was 2-3-folds lower than that observed in EUR (14.6%, 16.1%, and 20,7% for Koreans, Japanese, and Filipinos respectively vs. 46.1% p < 0.006)) (Table 3). The significant differences in A allele frequency across minorities covered in our study suggest that some ethnicities could be genetically predisposed to high urate levels.
SLC22A12 encodes for URAT1, a protein found on the kidney's apical side of the proximal tubules. This transporter is responsible for the majority of the urate reabsorption from the kidneys and a primary target for urate-lowering therapies. A previous study reported that the loss of activity in URAT1 had been found to cause hypouricemia in Japanese populations, suggesting that URAT1 plays an essential role in regulating the renal tubular reabsorption of urate. The intergenic polymorphism rs505802 (C > T) in SLC22A12 was observed to reduce urate levels in EUR ancestry. Specifically, the T- allele correlates with lower SU levels in women and men (Beta effect − 0.073, -0.047, respectively) in EURs. Jang et al. reported that the T6092C genetic variant of SLC22A12 was also significantly associated with SU concentration amongst the male Korean population. The T6092C at rs1529909 of SLC22A12 was found in linkage disequilibrium (LD = 1, r2 = 1) with rs505802 of SLC22A12. However, the prevalence of the T-allele in our population subgroups was lower than EUR population (p < 0.006). Our results found that the prevalence of T-alleles was 3-4-folds lower in both Asian and NHPI populations (Table 3), which suggests a higher baseline line urate levels in the Asian and NHPI population subgroups compared with EURs. Furthermore, our findings showed that the C-allele frequency was higher in both subgroups of targeted populations compared with EUR. Particularly, the frequency of the C allele in Marshallese was more than three times than EUR (95% vs. 29.3%, p < 0.006). These results propose a higher risk for HU and/or gout in our studied populations and suggest a possible implication in the response to treatments targeting URAT1 transporter in Asian and NHPI subgroups.
SLC22A11 is predominantly expressed in the proximal tubule's apical side in the kidney and encodes the organic anion transporter 4 (OAT4). The Organic anion transporter 4 (OAT4) is associated with regulating UA reabsorption, like URAT1, and a target for urate-lowering therapy. The intronic variant rs17300741 (A > G) in the SLC22A11 gene was associated with renal urate underexcretion type gout in the Japanese population (p = 0.049). Kolz et al. have reported a significant association between the polymorphism in OAT4/SLC22A11 rs17300741 A > G and UA levels in individuals of Caucasian descent (p = 6.7×10 − 14). Our analysis found that the A-allele prevalence was higher across selected minorities than EUR. The A allele frequency in the Asian subgroups of Koreans, Filipinos, and Japanese, was about 2-fold higher than EUR (89.5%, 85.3%, and 84.7%, respectively vs. 46.2% in EUR (p < 0.006). Furthermore, the A allele frequency was higher in Samoan, Native Hawaiian, and Marshallese compared with EUR (78.7%, 72.3%, and 70%, respectively, vs. 46.2% in EUR (p < 0.006). Our analysis of the rs17300741 A > G in SLC22A11 suggests a higher genetic risk for higher baseline urate levels or gout in Asian and NHPI compared with EUR. Hence, our results are consistent with the previous literature confirming the association of rs17300741 A > G with the prevalence of gout, which is two-fold higher in non-EURs relative to EURs. Collectively, our study shows that the frequencies of risk alleles C and A in both loci-SLC22A12 and SLC22A11, respectively, were significantly higher in Filipino, Korean, Japanese, Samoan, Marshallese, and Native Hawaiian relative to EUR (Table 3). Notably, the prevalence of risk alleles rs505802 (C > T) of SLC22A12 and rs17300741 (A > G) of SLC22A11 genes were highest in Asian subgroups compared with the NHPI population.
SLC16A9 encodes for monocarboxylic acid transporter protein across the cell membrane (MCT9). It is located on the proximal tubule's apical side of the kidney and responsible for urate excretion. A missense variant rs2242206 (G > T) in the SLC16A9 has been reported to dysregulate urate level. The exact function of the MCT9 transporter is still unclear. Nonetheless, Nakayama et al. have found a significant relationship between the rs2242206 G > T (K258T) in SLC16A9, and gout (p = 0.012), with an odds ratio (OR) of 1.28 in a Japanese population. Our cohort analysis showed that the frequency of T allele across minority subgroups was significantly higher than that of EUR ancestry (Table 3). Remarkably, the Asian subgroup (Koreans, Japanese, and Filipinos) had the highest prevalence of T allele, which is approximately two times higher vs. EUR (59.5%, 55.5%, and 54%, respectively, vs.26.6%, p < 0.006). Additionally, the prevalence of risk allele T in Native Hawaiians (45.1%), Marshallese (44.5%), and Samoans (39.3%) were significantly higher compared with EUR (26.6%) (p < 0.006). However, the polymorphism rs2242206 (G > T) in the SLC16A9 was not in HWE in Samoans and Hawaiians (Table 6). These findings suggest that individuals of Asian descent, carrying the polymorphism in rs2242206 (G > T) in SLC16A9 could be at higher risk for and an increase the susceptibility to gout, especially in individuals of Japanese, Korean, and Filipino descent.
GCKR is a protein that encodes glucokinase regulatory protein (GCKR), which has a role in developing the metabolic syndrome, involving triglyceride regulation and glucose metabolism.[41, 42] Several studies have shown the relationship between urate levels and metabolic syndrome-related traits such as insulin resistance and hypertension through oxidative stress and inflammatory pathway. The intronic variant rs780094 (C > T) of the GCKR gene has shown a strong association with gout in the male Han-Chinese population. Furthermore, the T- allele of Intronic polymorphism of rs780094 C > T has been associated with UA concentration regulation in EUR ancestry. Meanwhile, the MAF of the C allele was higher in the Korean group compared with Caucasian ancestry (0.47, vs. 0.42). In our analysis, the frequency of T-allele was higher in the Japanese subgroup than EUR (58% vs. 41.1%, p < 0.006) and lower in Samoans than EUR (30.6 vs. 41.1%, p < 0.006) (Table 3). This signifies that allele is associated with less risk for HU and/or gout. There was no significant difference between Filipinos and Koreans compared to EUR, although the T-allele frequency was higher in Asian subgroup ancestry. Overall, these results found that the Japanese subgroup could be predisposed to developing HU and gout compared with other subgroups in the study. Noteworthy, GCKR protein is associated with modulating the metabolic activities; hence, this finding might partially suggest a biological mechanism between genetic variations and the development of cardiometabolic disorders, including HU and gout, which may contribute to the health disparities seen in gestational diabetes and hypertension in pregnant women.
PDZK1 has been identified in the kidney and acts as a scaffolding protein for different transporter proteins associated with SU levels baseline. The Intergenic variants rs12129861 (C > T) of PDZK1 protein have shown an association with reducing the risk of gout in the male Han-Chinese population (OR = 0.727, P = 0.015) . Kolz et al. have identified the role of scaffolding PDZK1 protein in SU baseline regulation. Our analysis pointed that only the Korean minority had a higher frequency of the C- allele than EUR but was not statistically significant (56.7% vs. 54.1%, p > 0.006). In addition, other Asian subgroups, Filipinos and Japanese, had a lower prevalence of C-allele than EUR and were not statistically significant, with Japanese (48.9% vs. 54.1%, p > 0.006). Only the Filipino population in Asian minorities had a significant difference compared with EUR but had a lower prevalence of the C- allele (44.7% vs. 46.4% p < 0.006). In contrast, Pacific Islander sub-groups- Native Hawaiians, Marshallese, and Samoans had a significantly lower prevalence of the C-allele relative to European (39.3%, 39.4%, 46.4% vs. 54.1%, p < 0.006). It should be noted that we found a deviation when we conducted the Hardy-Weinberg equilibrium investigation PDZK1 rs12129861 (C > T) genotypes across all minorities addressed in the study (p < 0.05) (Table 6). In this case, further studies having a larger sample size and different ethnic backgrounds are needed to investigate the prevalence of risk alleles to validate our results. Hence, we excluded this protein from the results of this study to avoid any conflicts in our findings.
LRR16A is expressed in the apical side of proximal tubules in the kidneys, which encodes a protein called capping protein ARP2/3 and myosin-I linker (CARMIL). This protein has a role in urate transportome formation, which mediates urate reabsorption.[32, 45] Hiraka Ogata et al. have found a significant association between intergenic variant homozygote AA in rs742132 A > G of LRRC16A and risk of gout disease among Japanese males. Moreover, a genetic variant rs742132 in LRRC16A is associated with increased SU in EUR ancestry. Notably, a GWAS study conducted on East Asian minorities, including Koreans, showed that rs742132 in LRRC16A is associated with elevated urate levels. Our analysis shows that the Asian subgroup (Japanese) had a significant difference and the highest frequency of the A-allele compared to EUR (78.2%, vs. 69%, p < 0.006). However, the frequency of the A-allele in the Filipino subgroup was indifferent compared with EUR (69.7% vs. 69, p > 0.006). In addition, the Korean sub-minority had an insignificant A-allele prevalence than EUR (78%, vs. 69, p > 0.006). On the other hand, in NHPI minorities, there was a deviation from Hardy-Weinberg equilibrium in the Hawaiian population p < 0.05 (Table 6). Also, although the prevalence of A-allele in Marshallese was higher than EUR, no significant difference was found (70%, vs. 69%, p > 0.006) (Table 3). Moreover, the Samoan subgroup had a lower frequency of A-allele compared with EUR (51.7%, vs. 69%, p < 0.006) (Table 3). Asian subgroups of Japanese and Koreans had the highest A-allele frequency as compared to the other subgroups in this study, and this is consistent with other results in the literature. Our findings suggest that the genetic polymorphism in rs742132 of LRRC16A may explain the differential prevalence of HU/gout across different populations subgroups.
Our results have collectively shown that the frequency of HU and/or gout risk alleles in several population subgroups significantly differs from EUR (p < 0.006). We found out that the Asian subgroups had the highest prevalence of HU and/or gout risk alleles as compared to the NHPI populations. These results are consistent with the patient claims data in the ambulatory care clinics that gout diagnosis in the Asian population living in the U.S. is about three times more than EUR. Consistent with the previously published reports, our results provide more evidence that populations of Asian descent have a higher risk of developing HU and/or gout than EUR.[21, 49, 50] We believe that other genes/SNPs are also involved in urate disposition and other factors that may influence urate levels (i.e., older age, smoking, diuretic use, and dietary habits). However, we provide primary knowledge that could help clinical practitioners understand the pathophysiology of diseases in some understudied population subgroups. Further replication in different ethnic subgroups with larger population samples is needed.