title: Interactions between the genes of vasodilatation pathways influence blood pressure and nitric oxide level in hypertension.
abstract: 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.
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Present address: Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Denver, Colorado (R.K.); Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, California (T.S.); Research Center for Molecular Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran (A.N.).
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Academy of Scientific and Innovative Research, New Delhi, India;
authors.forename: Samantha
authors.initials: S
authors.lastname: Kohli
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India;
authors.forename: Aastha
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India;
authors.forename: Ritu
authors.initials: R
authors.lastname: Garg
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India;
authors.forename: Perwez
authors.initials: P
authors.lastname: Alam
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Present address: Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Denver, Colorado (R.K.); Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, California (T.S.); Research Center for Molecular Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran (A.N.).
authors.forename: Tsering
authors.initials: T
authors.lastname: Stobdan
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Present address: Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Denver, Colorado (R.K.); Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, California (T.S.); Research Center for Molecular Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran (A.N.).
authors.forename: Azim
authors.initials: A
authors.lastname: Nejatizadeh
authors.affiliation: Department of Cardiology, Govind Ballabh Pant Hospital, New Delhi, India.
authors.forename: Mohit
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Department of Cardiology, Govind Ballabh Pant Hospital, New Delhi, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Tyagi
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Academy of Scientific and Innovative Research, New Delhi, India; qpasha@igib.res.in.
authors.forename: M A Qadar
authors.initials: MA
authors.lastname: Pasha
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics*
chemical_list: C553443:ADRB2 protein, human; D018343:Receptors, Adrenergic, beta-2; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: association study; blood pressure; epistasis; haplotype; hypertension; single nucleotide polymorphism.