title: The effects of sex and method of blood pressure measurement on genetic associations with blood pressure in the PAMELA study.
abstract: BACKGROUND
  Phenotypic accuracy and specificity are essential for a successful genetic association study. Blood pressure (BP) measurements show heterogeneity depending on the method and time of measurement, sexual dimorphism and measurement errors, making genetic dissection difficult.
  
  
  RESULTS
  We studied 1550 adults aged 25-74 years, not on any antihypertensive treatment, resident in Monza, Italy (PAMELA study) all of whom had home, clinic and ambulatory BPs measured. We analysed 3705 single nucleotide polymorphisms (SNPs) (1324 typed and 2381 imputed) across 168 genes for association with these traits. No SNP achieved an experiment wide significance level of P less than 3 x 10 for any of the phenotypes studied. We selected 28 top candidate SNPs for further analysis of phenotypic heterogeneity and sexual dimorphism using a gene-centric strategy calculating empirical P values by permutations within each gene by including genic SNPs with an r less than 0.5. The association signals were not consistent across all the BP phenotypes, whether compared by genes or by physiological pathways. The top SNPs in WNK1, ADRA1A, ADRA1B, DRD1, NOS1 and PON3 showed significant sex interaction for BP and when analysed separately by sex showed evidence of dimorphism with opposite direction of effect for the same allele in the two sexes.
  
  
  CONCLUSIONS
  In the largest study of its kind, we show that sex and BP measurement methods have a significant impact on association signals. These findings might explain previous inconsistencies in studies on cardiovascular candidate genes and should have major implications for the design and interpretation of association studies.
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.forename: Wai K
authors.initials: WK
authors.lastname: Lee
authors.forename: Stewart
authors.initials: S
authors.lastname: Laing
authors.forename: Paola
authors.initials: P
authors.lastname: Brambilla
authors.forename: Roberto
authors.initials: R
authors.lastname: Sega
authors.forename: Roberto
authors.initials: R
authors.lastname: Perego
authors.forename: Guido
authors.initials: G
authors.lastname: Grassi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Cesana
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mancia
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors