The Epidemiology and Genetics of Hyperuricemia and Gout Across Major Racial Groups: A literature Review and Population Genetics Secondary Data Analysis

Background Gout is an inammatory 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.


Introduction
Gout is an in ammatory arthritic condition caused by the deposition of monosodium crystals (MSU) into the distal joints and peripheral tissues. Elevated serum urate (SU) levels, a condition known as hyperuricemia (HU), generally precedes the formation of MSU. Developing HU could be caused by increased consumption of high fructose corn syrup, a purine-rich diet, and high alcohol intake. (1) Additionally, certain medications, such as diuretics and low-dose salicylates, can decrease urate excretion, increasing SU levels, and the risk of developing HU and gout. (2) Other risk factors for developing HU or gout include renal impairment, cardiovascular diseases, obesity, diabetes, and genetic factors affecting urate production, excretion, and reabsorption. Urate concentration greater than 6.8 mg/dL exceeds urate solubility, leading to the formation of MSU crystals. The deposition of MSU crystals in the synovial uid could trigger an in ammatory response in local joints. Gouty arthritis may present as recurrent painful ares in the monoarticular joints, usually in the rst metatarsophalangeal joint of the lower extremities. Further, the development of HU and gout is signi cantly associated with the development of cardiovascular diseases and all-cause cardiovascular mortality. (3)(4)(5) The 2007-2016 National Health and Nutrition Examination Survey (NHANES) estimated the prevalence of gout in the United States (U.S.) to be 3.9%, which corresponds to approximately 9.2 million people. (6) Strati ed by race, the 2007-2016 NHANES data estimated the prevalence of gout in African Americans, Caucasians, and Hispanics to be 4.8%, 4%, and 2%, respectively. (6) It is important to note that the gout incidence and prevalence across indigenous populations is different from the incidence and prevalence in the U.S. In the U.S., however, Asians are 2.7 times more likely to have a gout diagnosis compared with Caucasians.(7) Consistent with Asian subgroups being at a higher gout risk, a study of hospital charts for gout diagnosis found a 2.5% incidence of gouty arthritis in Filipino males versus 0.13% incidence in non-Filipino males (p<0.001). (8) Similar to the hospitalization reports of gout incidence in Filipino men, other studies have also suggested that Filipinos could be genetically predisposed to a higher HU and gout risk, especially Filipinos living in the United States compared with the Philippines. (9)(10)(11) Moreover, studies in the Hmong population, a group commonly ascribed as Han-Chinese residing in Minnesota, showed that gout prevalence could range from 5.1-6.5%. (12,13) In addition to the gender difference in disease risk, these epidemiological data suggest that acculturation to a Western lifestyle, a high-purine diet, and other socioeconomic factors, such as access to healthcare, may have a signi cant effect on the development of HU and gout. (14,15) Differential gout prevalence across racial populations have suggested that developing gout is compounded by genetics, signi cantly modulating the individual's risk for HU or gout when exposed to environmental or dietary factors. (16,17) Indeed, genetic variations in urate-related genes could lead to an increased or a decreased activity of urate transporters, decreasing or increasing the disposition of SU. (18) Numerous studies have characterized the effect of speci c single nucleotide polymorphisms (SNPs) on SU levels and gout risk within different populations. (19)(20)(21)(22) However, no studies have yet compared the epidemiology of HU and gout across ethnic populations and their relationship with the risk allele occurrence in the same populations. Therefore, the objective of this genetic analysis was to assess the frequency of elevated SU and gout-related risk alleles in select racial groups relative to Europeans. The goal of this study is to interrogate the role of genetics as a contributing factor to the racial health disparities of gout prevalence among the U.S. populations.

SNP Selection
The candidate gene approach was employed to select the gene/SNP pairs in this genetic analysis. The gene/SNP pairs are known to be physiologically and signi cantly associated with urate disposition, MSUinduced in ammatory response, and the risk of developing gout (Table 1). All gene/SNP pairs were previously validated across different populations and with directionally consistent effect on urate levels or gout risk. Our targeted SNPs were predominantly identi ed from a meta-analysis study done in over 28,000 individuals of European descent and large genome-wide association analysis in over 440,000 individuals of European descent with cross-validation in other ethnic groups. (23,24) When presented with multiple SNPs within the same locus, polymorphism with the largest effect size was prioritized for inclusion in the genetic analysis.

Statistical Analysis
In this genetic analysis, the risk allele was de ned as the allele that is associated with increased risks for HU or gout. The risk allele was noted for each SNP and then compared across the following populations: EUR, ASW, CHS, JPT, and MXL. Chi-square or Fisher's exact test was used to test for differences in allele and genotype frequencies of the population of interest, compared with EUR. A Bonferroni adjustment for multiple comparisons was used, with p <0.005 for statistical signi cance. The risk allele index was then estimated as the count of possible risk alleles that had signi cantly different frequencies between the target population and EUR. The risk allele index for a given population, in our genetic analysis, could range from 0-11.

Epidemiology of Hyperuricemia and Gout
A literature review was conducted to gather the most recent global HU and gout prevalence in non-US populations. These populations included Africans living in Africa, Asians living in Asia, Europeans living in Europe, and Hispanics living in Mexico. Also, we used the 2007-2016 NHANES to extract HU and gout prevalence across the United States for non-Hispanic whites, non-Hispanic Blacks, and Hispanics.

Results
Hyperuricemia and Gout Risk Alleles Frequencies: Risk allele and genotype frequencies of the eleven SNPs in our targeted population are summarized in Tables 2 and 3, respectively. In the African American (ASW) population, seven out of the eleven SNPs were signi cantly different compared with EUR (Table 4). Among those seven signi cantly different SNPs, ASW had ve risk alleles that were signi cantly more prevalent (71.4%) than EUR. These alleles include: rs1183201 (T>A) in SLC17A1, rs2078267 (C>T) in SLC22A11, rs505802 (C>T) in SLC22A12, and rs675209 (C>T) in RREB1, and rs478607 (G>A) in NRXN2.
Among all studied populations, Asian subgroups, JPT and CHS, had the highest risk allele indices, 11 and 9, respectively. The percentage of risk alleles was 100% in JPT and CHS, followed by MXL and ASW populations at 75% and 71.4%, respectively ( Table 4).

Epidemiology of Hyperuricemia and Gout:
Global gout epidemiology Recent reports of the prevalence and incidence of gout vary widely due to the population demographics, regional differences, and methods employed. Nonetheless, these reports could range from a prevalence of <1% to 10% and an incidence of 0.58-2.89 per 1,000 person years. (25,26) The burden of gout is generally highest in developed regions and countries. Countries with the highest age-standardized point prevalence estimates of gout in 2017 were New Zealand, Australia, and the US. The countries with the highest increases in age-standardized point prevalence estimates of gout from 1990 to 2017 were the US, Canada, and Oman. Globally, the annual percent change in age-standardized prevalence (males, 0.22%; females, 0.38%) of gout increased every year from 1990 to 2017. (27,28) U.S. populations.
The prevalence of HU and gout across racial groups in the United States are summarized in Table 6.
According to NHANES 2007-2016, gout prevalence is 4.8% in African-Americans and 4% in Caucasians. (6) The most recent data (2015-2016) collected on Hispanics, which may include Mexican-Americans reported a 2.1% gout prevalence. (29)This has increased from the 1.0-1.1% reported in 2008 from the Population Architecture using Genomics and Epidemiology (PAGE) study in over 3500 Mexican-Americans as well as previous prevalence data from NHANES 2009NHANES -2010. (17,29) African populations Epidemiological studies of HU and gout prevalence in Africa is limited. However, these studies suggest that while the trends and the patterns of gout remain similar to other populations, the incidence and prevalence of HU and gout is low. (30,31) Furthermore, a study found that the prevalence of gout was 14.1% among 85 African patients in Southeast Gabon (Table 5).(32) This prevalence of gout was likely high due to the study's inclusion criteria of participants who were requesting urate level tests, leading to a biased and underrepresented sample of the African population. Another cross-sectional study prescribed anti-gout medications to 4.0% in 400 African patient enrollees seeking treatment for joint pain in Madagascar. (33) Another study done to characterize the prevalence of rheumatic disorders in Africans found no cases of gout out of 450 respondents in four South African populations. (31) Asian populations Gout prevalence among Asians living in oriental countries (Table 5) tends to be lower compared to Asians in the U.S., except for the aborigines living in Taiwan (Table 6). (34,35) The Community Oriented Program for Control of Rheumatic Diseases (COPCORD) reported that gout prevalence in some Asian countries, including Bangladesh, China, India, Philippines, and Thailand remains low (<0.5%). (26) In 2014, a database of health insurance claims in Japan reported that gout prevalence to be 1.6% for men aged 20-64 and remains constant for Japanese women at 0.09% in 2010-2014. (36) Gout prevalence could also vary by region within the same population. For example, a study of approximately 5,000 Chinese subjects estimated HU and gout prevalence at 13.2% and 1.1%, respectively in the Shandong coastal cities of Eastern China, which is higher compared to the rest of China. (26,37) Furthermore, the prevalence of either condition was signi cantly higher in Chinese men compared to women (18.3% vs 8.6% for hyperuricemia and 1.9% vs 0.4% for gout). (37) Other Asian countries, such as Indonesia and Kuwait, were reported to have gout prevalence of 1.7% and 0.8%, respectively. (26) Hispanic populations The gout prevalence in Mexicans was lower versus other targeted populations in our analysis (Table 5). For example, a 2015 cross-sectional community-based study conducted in the Chontal and Mixtec indigenous communities of Oaxaca, Mexico, reported one gout case out of 1061 participants (0.09%). (38) Another study used the COPCORD questionnaires estimated gout prevalence to be 0.3-0.4% in suburban communities located in Mexico. (39) European populations Gout prevalence appears to be lower in European countries (Table 5) compared to Caucasians living in the U.S. (Table 6). For example, European countries such as Germany, France, Portugal, Sweden, and the Czech Republic, reported gout prevalence ranging from 0.3%-1.8%. (26,40) The highest prevalence of gout recorded in Europe was in Greece and the United Kingdom at 4.8% and 2.5%, respectively. (26,40)

Discussion
Our genetic analysis identi ed that the CHS and JPT populations as having the highest prevalence of validated HU and gout risk alleles compared with EUR. Speci cally, all the nine signi cantly different alleles in CHS were considered HU or gout risk alleles. The eleven of the signi cantly 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)(42)(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 e ux transporter. The genetic polymorphism rs2231142 (G>T) in ABCG2 leads to Glu141Lys amino acid change, which results in a reduced ABCG2mediated urate e ux activity and in ammation 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 signi cantly 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 signi cantly 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 signi cant 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 signi cant 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 a nity. (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 signi cantly lower than EUR (75.5%). On the other hand, the frequency of risk allele T was signi cantly 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 signi cant urate transporter (Table 1). (24) The genetic polymorphism rs1171614 (C>T) in SLC16A9 was reported to in uence 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 signi cant (77% vs. 75.7%, p=0.75, Table 2). This nding suggests that the polymorphism rs1171614 (C>T) in SLC16A9 may be signi cantly 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 signi cantly 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 speci c populations could be genetically predisposed to elevated SU levels. Speci cally, 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 identi ed that genetic polymorphisms rs2078267 (C>T) in SLC22A11 and rs505802 (C>T) in SLC22A12 could signi cantly 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 signi cantly higher in all targeted populations (ASW, CHS, JPT, MXL) compared to EUR (Table 2). Speci cally, 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.
The CHARGE meta-analysis along with multiple GWAS have identi ed RREB1 and INHBC loci as having genome-wide signi cance with SU levels.(24, 52, 54) RREB1 encodes for zinc nger 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 signi cantly 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 signi cantly higher risk allele frequencies compared to both of the previously mentioned polymorphisms. Speci cally, 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 signi cantly 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 signi cantly 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 signi cantly 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 signi cantly 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 signi cantly different between the rest of our selected populations and EUR.
The rising of HU and gout prevalence in speci c 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 (overintake 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 strati cation for disease risk. Additionally, this genetic information could be used for gout risk strati cation and potentially guide prescribers in choosing the most optimal drug therapy for patients at risk for developing gout.

Limitations
Our analysis is not without limitations. While genetics could play a signi cant role in the development of elevated SU and gout, nongenetic factors such as diet, obesity, physical activity, and other environmental factors may also affect the risk of developing HU and gout. Nonetheless, nongenetic factors have yet explained little variability in SU levels to date. Also, our study lacked robust epidemiological data for HU and gout prevalence in the Asian American population. Currently, NHANES 2007-2016 does not report HU and gout prevalence for Asian Americans, which may have limited our ability to corroborate HU and gout prevalence with gout risk alleles in the US. We also focused on Southern Han-Chinese and Japanese populations in our risk allele analyses. Genetic information on gout and HU from other major Asian subgroups, such as Vietnamese, Korean, Filipinos, and others were not assessed. Therefore, future studies in Asian subgroups are needed to validate our ndings. Also, we limited our genetic analyses to 11 gene/SNP pairs. Both HU and gout are polygenic disorders and may involve other genes beyond what was studied in our genetic analysis. These limited genes may alter the risk allele index for each racial group. Finally, though the risk allele index approach may provide insights on the directionality of disease risk, it may not explain the racial disparities of gout prevalence, partly due to the variation in the effect sizes associated with the different alleles. However, our genetic results remain directionally consistent with a greater genetic predisposition for HU and gout in Asian descent than Europeans.

Future Perspective
Genomic and personalized medicine is a growing eld in health care. Evaluating the individual's genetic information may guide the choice of the appropriate drugs and design personalized risk-mitigation strategies for individuals at high risk for developing HU or gout. Consequently, this will avert unnecessary drug therapy and reduce the risk of new disease onset. Not only does this approach have the potential to improve healthcare outcomes, but it could address the existing health disparities associated with HU and gout across different racial populations, thereby improving health equity. Ultimately, relying on genetic information such as those assessed in our study may allow us to make precise gout-related therapy recommendations leading to improved clinical outcomes, rather than employing imprecise demographic information such as self-reported race. Finally, while there is no present evidence to suggest that treating idiopathic HU is warranted, studies investigating the effect of lowering urate levels in populations genetically enriched with HU or gout risk alleles may be worth further investigations.

Conclusions
Our genetic analysis suggests that population enrichment with HU or gout risk alleles may result in a higher prevalence of HU and gout versus Europeans. Overall, our results showed that CHS and JPT to have the highest risk allele index compared to Europeans. Limited reports have suggested that Asian subgroups have higher HU and gout prevalence compared to non-Asians. Although NHANES 2015-2016 does not report HU or gout prevalence for Asian-Americans, patient claims study has shown that Asians are 2.7 times more likely to have a gout diagnosis versus Caucasians in ambulatory care settings. Validation of our SNP selections from multiple genome-wide association studies further supports our hypothesis that the differences in allele frequencies could be responsible for the differential HU and gout prevalence across distinct racial groups.

24
*Bolded letter allele indicates the risk allele, which is de ned as the allele that is associated with baseline or higher risk for HU or gout.     (11) 78.1 (50) Bold letter allele indicates the risk allele, which is de ned as the allele that is associated with baseline or higher risk for HU or gout.    (62), gout prevalence data derived from Germany, Italy, France, Portugal, UK, and Greece (26) b Based on a study population of 85 African men and women conducted in Southeast Gabon (32) c Based on the Shandong coastal cities of Eastern Chinese (37)