The Soluble Guanylate Cyclase Genetic Variant rs13139571 Is Associated with an “Unfavorable” Metabolic Phenotype in an US General Community

Abstract

Metabolic syndrome and dyslipidemia are important risk factors for heart failure. Nitric oxide (NO) induces vasodilation and also exerts a metabolic action by stimulating lipogenesis. In rodents, 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 that are knock-out for the inducible NO synthase gene are also protected from high-fat diet 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). 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 lower blood pressure and odds of hypertension in a recent genome wide association study. To date, no studies have investigated the metabolic phenotype associated with rs13139571. In accordance with lipogenic properties of NO, the genetic variant rs13139571 will be associated with a metabolic penotype characterized by increased lipid plasma levels and visceral adiposity. We investigated the metabolic phenotype associated with rs13139571 in a random sample (n= 1854) of the general population from Olmsted County, MN. Frequencies of rs13139571 genotypes were CC: 59%, AC: 36%, AA: 5%. In a multivariate analysis adjusted for age, sex, BMI and antilipemic treatment, carriers of the A minor allele had significantly larger waist circumference (CC: 91±14, AC: 92±15, AA: 94±14 cm, p value= 0.01), higher plasma values of total cholesterol (CC: 202 ± 36, AC: 204±36, AA: 208 ±35 mg/dl, p value= 0.02) and triglycerides (CC: 146±87, AC: 151±86, AA: 173±104 mg/dl, p value= 0.02). Prevalence of metabolic syndrome was significantly higher among the carriers of the A minor allele (CC: 21%, AC: 24%, AA: 29%, p value= 0.04). Genotypes did not differ in terms of systolic blood pressure (CC: 132 ± 22, AC: 134 ± 21, AA: 132 ± 21 mmHg, p value= 0. 5), diastolic blood pressure (CC: 73 ± 10, AC: 73 ± 10, AA: 73 ± 12 mmHg, p value= 0.71), BMI (CC: 28 ± 5, AC: 29 ± 5, AA: 28 ± 5 Kg/m2, p value= 0.43) and percentage of subjects on antilipemic therapy (CC: 17%, AC: 19%, AA: 18%, p value= 0.56). The A minor allele of rs13139571 is associated with higher values of waist circumference, plasma levels of total cholesterol and tryglicerides. Metabolic syndrome is more prevalent among carriers of the A allele. The genetic variant rs13139571 may be associated with increased NO activity and influence lipid metabolism by favoring lipogenesis. Additional studies are warranted to confirm our findings and further investigate the metabolic phenotype associated with rs13139571.