Genome-wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and Dyslipidemia

Abstract

Many common diseases are accompanied by disturbances in biochemical traits. Identifying the genetic determinants could provide novel insights into disease mechanisms and reveal avenues for developing new therapies. Here, we report a genome-wide association analysis for commonly measured serum and urine biochemical traits. As part of the WTCCC, 500,000 SNPs genome wide were genotyped in 1955 hypertensive individuals characterized for 25 serum and urine biochemical traits. For each trait, we assessed association with individual SNPs, adjusting for age, sex, and BMI. Lipid measurements were further examined in a meta-analysis of genome-wide data from a type 2 diabetes scan. The most promising associations were examined in two epidemiological cohorts. We discovered association between serum urate and SLC2A9, a glucose transporter (p = 2 x 10(-15)) and confirmed this in two independent cohorts, GRAPHIC study (p = 9 x 10(-15)) and TwinsUK (p = 8 x 10(-19)). The odds ratio for hyperuricaemia (defined as urate >0.4 mMol/l) is 1.89 (95% CI = 1.36-2.61) per copy of common allele. We also replicated many genes previously associated with serum lipids and found previously recognized association between LDL levels and SNPs close to genes encoding PSRC1 and CELSR2 (p = 1 x 10(-7)). The common allele was associated with a 6% increase in nonfasting serum LDL. This region showed increased association in the meta-analysis (p = 4 x 10(-14)). This finding provides a potential biological mechanism for the recent association of this same allele of the same SNP with increased risk of coronary disease.

Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians

“…Several twin and family-based studies have found SUA levels to be significantly heritable. [10][11][12] Genome-wide linkage scans [10][11][12][13] and association studies (GWAS) [14][15][16][17][18][19] in several populations have consistently pointed to the important role of uric acid transporters, particularly solute carrier protein 2 family, member 9 (SLC2A9), in the regulation of SUA. However, the relevance of these genetic variants to minority populations is largely unknown.…”

Genetic architecture of circulating lipid levels

“…[1][2][3][4] A number of genome-wide association studies (GWASs) successfully identified multiple genes influencing circulating lipid levels. [5][6][7][8][9][10][11][12] There are currently over 100 established loci that include both common variants with relatively small effects as well as a considerable number of rare variants with large effects. 13 Despite these successes, a substantial proportion of the heritability of each trait remains unexplained, suggesting that many determinants have yet to be identified.…”

The genetics of cardiovascular disease

“…This will include a translational 8 approach from rodent to human genetics and recent findings from large-scale genotyping 9 projects in man. 10 In recent years, we have witnessed substantial progress in unravelling the genetic determinants 11 of cardiovascular disease. Better understanding of pathophysiological principles and recent 12 genome-wide association studies (GWAS) have identified robust candidate genes involved in 13 cardiovascular disease.…”

“…Rapidly evolving tools such as chip-based genotyping technology [3,4] few years ago. This innovation has facilitated genetic studies in large cohorts in multicentre and 17 multinational collaborations [5][6][7][8][9][10][11]. These advances in human population genetics have been 18 complemented by a significant progress in our understanding of molecular genetics ranging from 19 design of animal models to discovery of key elements of gene regulation.…”

“…For example, assessing inflammatory markers at the 14 time of blood pressure measurement could help confirm the functional relevance of any 15 establishd genetic associations. Indeed, GWAS has been successful in identifying biomarkers 16 such as lipids [9][10][11] and urate levels [10] in patients with diabetes and cardiovascular disease. 17…”