A genetic variant of soluble guanylate cyclase is associated with higher plasma cholesterol and triglycerides in the general population

Abstract

Nitric oxide (NO) is a vasodilator that also possesses lipogenic properties. In rats, lipid accumulation and lipogenic enzymes are induced by NO and insulin-stimulated glucose uptake is dependent on intact NO synthesis in white adipose tissue. Mice in which the gene encoding inducible NO synthase was disrupted are protected from high-fat induced insulin resistance and NO inhibition in rodents on a high fat diet reduces hepatic lipid accumulation. These biological actions of NO are mediated by soluble guanylate cyclase (sGC) and importantly human adipocytes express the genes GUCY1A2, GUCY1A3, GUCY1B3 encoding for the alpha and beta subunits of sGC. The single nucleotide polymorphism rs13139571 is located within an intron of GUCY1A3 and its minor allele is associated with higher blood pressure and odds of hypertension in a recent genome wide association study. For the first time, we investigated the metabolic phenotype associated with rs13139571 in a random sample (n1⁄4 2007) of the general population from Olmsted County, MN. Frequencies of rs13139571 genotypes were CC: 59%, AC: 36%, AA: 5%. In age and gender adjusted analysis, carriers of the A minor allele had significantly higher plasma values of total cholesterol (CC: 202 36, AC: 204 36, AA: 208 34 mg/dl, p value1⁄4 0.04) and triglycerides (CC: 145 85, AC: 150 86, CC: 169 101 mg/dl, p value1⁄4 0.01). Metabolic syndrome trended toward increased prevalence in carriers of the minor allele (CC: 21%, AC: 23%, AA: 28%, p value1⁄4 0.06). Genotypes did not differ in terms of systolic blood pressure (CC: 132 22, AC: 134 21, CC: 132 21 mmHg, p value1⁄4 0.45), diastolic blood pressure (CC: 74 10, AC: 74 10, CC: 73 12 mmHg, p value1⁄4 0.77), BMI (CC: 28 5, 29 5, 28 5 Kg/m, p value1⁄4 0.43) and percentage of subjects on antilipemic therapy (CC: 17%, AC: 19%, AA: 18%, p value1⁄4 0.56). These studies suggest that the minor allele of rs13139571 may be associated with increased NO activity and influence lipid metabolism by favoring lipid accumulation and insulin resistance. Alternatively, rs13139571 may be in linkage disequilibrium with another genetic locus that affects cardiometabolic phenotype. Additional studies are warranted to confirm our findings and further investigate the metabolic phenotype associated with this genetic variant.