Interactions Between the Genes of Vasodilatation Pathways Influence Blood Pressure and Nitric Oxide Level in Hypertension

BACKGROUND: This study investigates the contribution of genetic interactions between the β-2 adrenergic receptor (ADRB2) and nitric oxide synthase (NOS3) genes to the complex etiology of hypertension. METHODS: Using single nucleotide polymorphism (SNP) markers, we studied potential interactions between ADRB2 and NOS3 variants and their correlation with clinical, biochemical, and expression levels in 546 individuals with hypertension and 884 age-, sex-, and ethnicity-matched unrelated control subjects. Generalized multifactor dimensionality reduction (GMDR) analysis identified the models for genotype interaction. RESULTS: The best models to represent association of genotypes with augmented hypertension susceptibility were the 4- and 5-locus interacting GMDR models of ADRB2 and NOS3 compared with within-gene 6-locus ADRB2 and 2-locus NOS3 (odds ratio (OR) = 4.8, P = 0.04; OR = 5.6, P = 0.02, respectively). Stratification of 4- and 5-locus GMDR models on the basis of risk alleles (in increasing order) increased the ORs from 1.26 to 14.17 and from 0.81 to 14.18, respectively, and correlated linearly with increased systolic blood pressure, diastolic blood pressure, and mean arterial pressure and decreased nitric oxide level (P ≤ 0.0004). We performed various analyses, such as single-locus, genetic interactions, sliding-window, and comparative analysis. Each analysis consistently revealed the 46A allele of ADRB2 46G/A SNP and 4a allele of NOS3 4b/4a SNP to be associated with risk of hypertension. These risk-conferring markers were associated with decreased ADRB2 and NOS3 expression and decreased nitric oxide level in the patients (P ≤ 0.04). CONCLUSIONS: Evidence of interaction between the genetic loci of ADRB2 and NOS3 points to varied clinical, biochemical, and expression levels and a role in hypertension susceptibility.