title: Gender differences in genetic risk profiles for cardiovascular disease.
abstract: BACKGROUND
  Cardiovascular disease (CVD) incidence, complications and burden differ markedly between women and men. Although there is variation in the distribution of lifestyle factors between the genders, they do not fully explain the differences in CVD incidence and suggest the existence of gender-specific genetic risk factors. We aimed to estimate whether the genetic risk profiles of coronary heart disease (CHD), ischemic stroke and the composite end-point of CVD differ between the genders.
  
  
  RESULTS
  We studied in two Finnish population cohorts, using the case-cohort design the association between common variation in 46 candidate genes and CHD, ischemic stroke, CVD, and CVD-related quantitative risk factors. We analyzed men and women jointly and also conducted genotype-gender interaction analysis. Several allelic variants conferred disease risk for men and women jointly, including rs1801020 in coagulation factor XII (HR = 1.31 (1.08-1.60) for CVD, uncorrected p = 0.006 multiplicative model). Variant rs11673407 in the fucosyltransferase 3 gene was strongly associated with waist/hip ratio (uncorrected p = 0.00005) in joint analysis. In interaction analysis we found statistical evidence of variant-gender interaction conferring risk of CHD and CVD: rs3742264 in the carboxypeptidase B2 gene, p(interaction) = 0.009 for CHD, and rs2774279 in the upstream stimulatory factor 1 gene, p(interaction) = 0.007 for CHD and CVD, showed strong association in women but not in men, while rs2069840 in interleukin 6 gene, p(interaction) = 0.004 for CVD, showed strong association in men but not in women (uncorrected p-values). Also, two variants in the selenoprotein S gene conferred risk for ischemic stroke in women, p(interaction) = 0.003 and 0.007. Importantly, we identified a larger number of gender-specific effects for women than for men.
  
  
  CONCLUSIONS
  A false discovery rate analysis suggests that we may expect half of the reported findings for combined gender analysis to be true positives, while at least third of the reported genotype-gender interaction results are true positives. The asymmetry in positive findings between the genders could imply that genetic risk loci for CVD are more readily detectable in women, while for men they are more confounded by environmental/lifestyle risk factors. The possible differences in genetic risk profiles between the genders should be addressed in more detail in genetic studies of CVD, and more focus on female CVD risk is also warranted in genome-wide association studies.
authors.affiliation: Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland. kaisa.silander@ktl.fi
authors.forename: Kaisa
authors.initials: K
authors.lastname: Silander
authors.forename: Mervi
authors.initials: M
authors.lastname: Alanne
authors.forename: Kati
authors.initials: K
authors.lastname: Kristiansson
authors.forename: Olli
authors.initials: O
authors.lastname: Saarela
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Kirsi
authors.initials: K
authors.lastname: Auro
authors.forename: Juha
authors.initials: J
authors.lastname: Karvanen
authors.forename: Sangita
authors.initials: S
authors.lastname: Kulathinal
authors.forename: Matti
authors.initials: M
authors.lastname: Niemelä
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Erkki
authors.initials: E
authors.lastname: Vartiainen
authors.forename: Pekka
authors.initials: P
authors.lastname: Jousilahti
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Kari
authors.initials: K
authors.lastname: Kuulasmaa
authors.forename: Alun
authors.initials: A
authors.lastname: Evans
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012307:Risk Factors; D012727:Sex Characteristics