Gout is an inflammatory condition caused by elevated serum urate (SU), a condition known as hyperuricemia (HU). Genetic variations, including single nucleotide polymorphisms (SNPs), can alter the function of urate transporters, leading to differential HU and gout prevalence across different populations. In the United States (U.S.), gout prevalence differentially affects certain racial groups. The objective of this proposed analysis is to compare the frequency of urate-related genetic risk alleles between Europeans (EUR) and the following major racial groups: Africans in Southwest U.S. (ASW), Han-Chinese (CHS), Japanese (JPT), and Mexican (MXL) from the 1000 Genomes Project. The Ensembl genome browser of the 1000 Genomes Project was used to conduct cross-population allele frequency comparisons of 11 SNPs across 11 genes, physiologically involved and significantly associated with SU levels and gout risk. Gene/SNP pairs included: ABCG2 (rs2231142), SLC2A9 (rs734553), SLC17A1 (rs1183201), SLC16A9 (rs1171614), GCKR (rs1260326), SLC22A11 (rs2078267), SLC22A12 (rs505802), INHBC (rs3741414), RREB1 (rs675209), PDZK1 (rs12129861), and NRXN2 (rs478607). Allele frequencies were compared to EUR using Chi-Square or Fisher’s Exact test, when appropriate. Bonferroni correction for multiple comparisons was used, with p < 0.0045 for statistical significance. Risk alleles were defined as the allele that is associated with baseline or higher HU and gout risks. The cumulative HU or gout risk allele index of the 11 SNPs was estimated for each population. The prevalence of HU and gout in U.S. and non-US populations was evaluated using published epidemiological data and literature review. Compared with EUR, the SNP frequencies of 7/11 in ASW, 9/11 in MXL, 9/11 JPT, and 11/11 CHS were significantly different. HU or gout risk allele indices were 5, 6, 9, and 11 in ASW, MXL, CHS, and JPT, respectively. Out of the 11 SNPs, the percentage of risk alleles in CHS and JPT was 100%. Compared to non-US populations, the prevalence of HU and gout appear to be higher in western world countries. Compared with EUR, CHS and JPT populations had the highest HU or gout risk allele frequencies, followed by MXL and ASW. These results suggest that individuals of Asian descent are at higher HU and gout risk, which may partly explain the nearly three-fold higher gout prevalence among Asians versus Caucasians in ambulatory care settings. Furthermore, gout remains a disease of developed countries with a marked global rising.

Uric acid is the final product of purine metabolism and is converted to allantoin in most mammals via the uricase enzyme. The accumulation of loss of function mutations in the uricase gene rendered hominoids (apes and humans) to have higher urate concentrations compared to other mammals. The loss of human uricase activity may have allowed humans to survive environmental stressors, evolution bottlenecks, and life-threatening pathogens. While high urate levels may contribute to developing gout and cardiometabolic disorders such as hypertension and insulin resistance, low urate levels may increase the risk for neurodegenerative diseases. The double-edged sword effect of uric acid has resurrected a growing interest in urate’s antioxidant role and the uricase enzyme’s role in modulating the risk of obesity. Characterizing both the effect of uric acid levels and the uricase enzyme in different animal models may provide new insights into the potential therapeutic benefits of uric acid and novel uricase-based therapy.

Background: Gout, an inflammatory condition, is characterized by the precipitation of monosodium urate crystals (MSU) in or around distal joints. The latter is caused by chronic hyperuricemia (HU)—high urate levels in the blood. Genetic variations in urate transporters play a significant role in determining urate levels within the human body, rendering some racial and ethnic groups more or less susceptible to developing either HU or gout. This study aims to estimate the frequencies of HU and gout risk alleles in Asian, Native Hawaiian, and Pacific Islander subgroups, using biorepository DNA samples. Methods: The biospecimens repository at the University of Hawai’i provided DNA samples of consented post-partum women of Japanese, Filipino, Korean, Native Hawaiian, Samoan, and Marshallese descent. The DNA was previously extracted from maternal blood and genotyped at the Genomics and Bioinformatics Shared Resource, Cancer Center (Honolulu, HI). Nine urate genes: ABCG2, SLC2A9, SLC16A9, GCKR, SLC22A11, SLC22A12, LRR16A, PDZK1, and SLC17A1, were selected due to their significant association with HU and gout risk. Hardy–Weinberg Equilibrium (HWE) for genotype frequencies was assessed, using the Chi-Square test with p < 0.006 for statistical significance. Allele frequencies in our study were then compared to EUR from the 1000 Genomes Project Database Phase III, using Chi-square or Fisher's exact test, when appropriate. Bonferroni correction for multiple comparisons was used, with p < 0.006 for statistical significance. Results: Our study involved 1059 post-partum women 18-year-old or older who self-reported their respective race and ethnicity, including Asian, Native Hawaiian, and Pacific Islander ancestry. The Asian subgroups included Japanese, Filipino, and Korean. The Pacific Islander subgroups included Marshallese and Samoan. None of the study participants had a history of gout. We excluded the PDZK1 gene from the final analysis due to its deviation from HWE (p < 0.006) across all the population subgroups, with eight loci remaining for cross-subgroup comparisons. Compared to EUR, the genetic polymorphism frequencies were significantly different-8/8 in Japanese, 6/8 in Korean, 6/8 in Filipino, 8/8 in Samoan, 6/8 in Native Hawaiian, and 6/8 in Marshallese. HU and gout risk alleles indices were 8, 6, 5, 5, 4, and 4 in Japanese, Filipino, Korean, Samoan, Marshallese, and Native Hawaiian, respectively. The percentage of cumulative risk alleles was 100% in both Japanese and Filipino, followed by 83.5% in Korean. Conclusions: Compared to EUR, Asian subgroups, particularly Japanese, Filipino, and Korean, had the highest percentage of the cumulative uric acid risk alleles. These results could partly explain the increased risk of developing gout among some Asian ancestral subgroups compared to EUR.

Gout is a metabolic disorder, and one of the most common inflammatory arthritic conditions, caused by elevated serum urate (SU). Gout is globally rising, partly due to global dietary changes and the growing older adult population. Gout was known to affect people of high socioeconomic status. Currently, gout disproportionately affects specific population subgroups that share distinct racial and ethnic backgrounds. While genetics may predict SU levels, nongenetic factors, including diet, cultural traditions, and social determinants of health (SDOH), need to be evaluated to optimize patient treatment outcomes. This approach would allow clinicians to assess whether certain cultural norms, or some SDOH, could be contributing to their patient’s risk of developing gout or recurrent gout flares. A cultural assessment may inform the development of culturally tailored dietary recommendations for patients with gout. Causal and association studies investigating the interaction between diet, genetics, and gout, should be cautiously interpreted due to the lack of reproducibility in different racial groups. Optimal gout management could benefit from a multidisciplinary approach, involving pharmacists and nurses. While data on the effect of specific dietary recommendations on managing hyperuricemia and gout may be limited, counseling patients with gout on the role of a healthy diet to optimally control their gout flares and other comorbidities should be part of patient education. Future research investigating the role of a gene–diet interaction in the context of hyperuricemia and gout is needed. Optimal care for patients with gout needs to include a holistic assessment for gout and gout-related comorbidities. Additionally, addressing health beliefs and culture-specific lifestyle factors among patients with gout may reduce their risk of gout flare, improve adherence to urate-lowering therapy (ULT), and achieve health equity in gout management.