Genetic Markers Associated with an Intermediate Phenotype of the Metabolic Syndrome

Abstract

Background and Significance: The metabolic syndrome is a heterogeneous disorder leading to increased morbidity and mortality. Components of the metabolic syndrome are known to be inherited, however efforts to identify genomic markers in humans have been unsuccessful and a candidate-gene/intermediate phenotype approach may be useful. Evidence supports a relationship between altered metabolic function and three candidate genes, caveolin-1 (CAV1), peroxisome proliferator receptor-activated gamma, and angiotensinogen (AGT). These genes may serve as markers for the co-aggregation of insulin resistance and hypertension. Research Question: To examine whether single nucleotide polymorphisms (SNPs) in the CAV1, PPARg and AGT genes are associated with the co-aggregation of insulin resistance and hypertension. Methods: Three gene association studies were conducted in a Caucasian hypertensive cohort (HyperPATH). The homeostasis assessment model (HOMA-IR), hyperinsulinemic euglycemic clamp, and salt sensitive blood pressure were determined in each subject. Statistical analyses were conducted using a general linear model accounting for relatedness and adjusting for the following covariates: age, gender, body mass index, study site. Replication was assessed in a hypertensive Mexican-American cohort (HTN-IR) for the CAV1 gene and a hypertensive African American cohort (HyperPATH) for the PPARg gene. Results: SNPs of the CAV1 gene were significantly associated with insulin resistance in Caucasians from HyperPATH. These results were replicated in the HTN-IR cohort. A SNP of the PPARg gene was associated with salt sensitive blood pressure and increased plasma renin levels in Caucasians and African Americans from HyperPATH. SNPs of the AGT gene were associated with insulin sensitivity in Caucasians from HyperPATH. Conclusion: CAV1 and AGT are genomic markers for the co-aggregation of insulin resistance and hypertension. The PPARg gene is a potential genomic marker for vascular dysfunction in hypertension. Clinical Perspective: Genomic markers for insulin resistance exist in human populations with hypertension. These markers explain the inter-individual variability of insulin resistance and hypertension and help identify potential underlying mechanisms. Use of these bio-markers in clinical practice may improve individualized prevention and treatment strategies, decreasing the incidence of and improving outcomes for this chronic disease. Promoting health through individualized care makes the incorporation of genomic markers into nursing practice essential.