Abstract
Increased serum uric acid (SUA) is a risk factor for gout and renal and cardiovascular disease (CVD). The purpose of this study was to identify genetic factors that affect the variation in SUA in 632 Mexican Americans participants of the San Antonio Family Heart Study (SAFHS). A genome-wide association (GWA) analysis was performed using the Illumina Human Hap 550K single nucleotide polymorphism (SNP) microarray. We used a linear regression-based association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. All analyses were performed in the software package SOLAR. SNPs rs6832439, rs13131257, and rs737267 in solute carrier protein 2 family, member 9 (SLC2A9) were associated with SUA at genome-wide significance (p < 1.3 × 10−7). The minor alleles of these SNPs had frequencies of 36.2, 36.2, and 38.2%, respectively, and were associated with decreasing SUA levels. All of these SNPs were located in introns 3–7 of SLC2A9, the location of the previously reported associations in European populations. When analyzed for association with cardiovascular-renal disease risk factors, conditional on SLC2A9 SNPs strongly associated with SUA, significant associations were found for SLC2A9 SNPs with BMI, body weight, and waist circumference (p < 1.4 × 10−3) and suggestive associations with albumin-creatinine ratio and total antioxidant status (TAS). The SLC2A9 gene encodes an urate transporter that has considerable influence on variation in SUA. In addition to the primary association locus, suggestive evidence (p < 1.9 × 10−6) for joint linkage/association (JLA) was found at a previously-reported urate quantitative trait locus (Logarithm of odds score = 3.6) on 3p26.3. In summary, our GWAS extends and confirms the association of SLC2A9 with SUA for the first time in a Mexican American cohort and also shows for the first time its association with cardiovascular-renal disease risk factors.
Highlights
Hyperuricemia is a risk factor for gout, renal disease, and cardiovascular disease (CVD) (Cirillo et al, 2006; Nakagawa et al, 2006) and is known to aggregate in families (Dixon, 1960; Friedlander et al, 1988; Cameron and Simmonds, 2005)
Our GWAS found polymorphisms in SLC2A9 to be significantly associated with serum uric acid (SUA) levels in Mexican Americans
AProportion of the residual phenotypic variance that is explained by the minor allele of the single nucleotide polymorphism (SNP). b1 – major allele; 2 – minor allele. c genotype-specific mean of serum uric acid levels
Summary
Hyperuricemia is a risk factor for gout, renal disease, and cardiovascular disease (CVD) (Cirillo et al, 2006; Nakagawa et al, 2006) and is known to aggregate in families (Dixon, 1960; Friedlander et al, 1988; Cameron and Simmonds, 2005). Family-based studies have reported significant heritabilities for SUA levels with estimates ranging from 25 to 73% (Rao et al, 1982; Rice et al, 1990; Wilk et al, 2000; Tang et al, 2003; Yang et al, 2005; Nath et al, 2007; Voruganti et al, 2009a,b). Genome-wide studies conducted to identify significant linkages for the variation in SUA have found quantitative trait loci (QTL) on several chromosomes for different populations; a QTL on chromosome 15 in Framingham Heart Study (Yang et al, 2005); on chromosome 8 in the Genetic Epidemiology Network of Arteriopathy (GENOA) (Rule et al, 2009); on chromosome 4p15 in an Australian Cohort (Cummings et al, 2010). Genome-wide association (GWA) and candidate gene studies have found several genes to be associated with SUA, mainly solute carrier protein 2 family, member 9 (SLC2A9)
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