Abstract
While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25–44%; P < 3 × 10−14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p < 3 × 10−9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6× 10−6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p < 7.1 × 10−10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation.
Highlights
Hyperuricemia or elevated concentration of urate in serum (SU) is a risk factor for gout, hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD)[1,2,3,4]
Genetic analysis was conducted using rank-inverse-normal transformed SU concentrations, which were regressed on covariates such as age, sex, and their interactions, diabetes status, and medications[27,28]
Metabochip genotyping was conducted in a subset of 2000 Strong Heart Family Study (SHFS) (Arizona = 300, Dakotas = 850, Oklahoma = 850) participants who were free of diabetes at visit 1
Summary
Hyperuricemia or elevated concentration of urate in serum (SU) is a risk factor for gout, hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD)[1,2,3,4]. The renal transport of urate involves several genes including solute carrier family 2, member 9 (SLC2A9), ATP-binding cassette ABC, subfamily G, member 2 (ABCG2), solute carrier family 22, members 11 and 12 (SLC22A11 and SLC22A12), solute carrier family 17, members 1, 3 and 4 (SLC17A1, SLC17A3 and SLC17A4), and solute carrier family 16, member 9 (SLC16A9) Most of these genes have been associated with hyperuricemia[1,2,3,4,5,6]. While a recent review by Li et al.[9] found no clear role for uric acid in metabolic diseases other than gout and nephrolithiasis, many studies including ours, have shown that gout patients and asymptomatic hyperuricemic individuals tend to be at high risk for CVD and CKD (Table 1)[10,11]. The Strong Heart Family Study (SHFS) is a multigenerational family-based study of CVD in American Indians This cohort has high rates of obesity, diabetes, CKD and CVD24–26. We aimed to identify American Indian-specific SNPs in SLC2A9, the gene most strongly associated with SU in this study
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