Gender Differences in Genetic Risk Profiles for Cardiovascular Disease

Abstract

BackgroundCardiovascular 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.Methodology/Principal FindingsWe 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/SignificanceA 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.

Combined effect of C-reactive protein gene SNP +2147 A/G and interleukin-6 receptor gene SNP rs2229238 C/T on anthropometric characteristics among school children in Taiwan

“…33 In two Finnish cohort studies, a strong association between CRP gene variants and CRP levels was found only in men. 31,32 Our data indicate that a relationship between the CRP polymorphism and anthropometric characteristics is only present in boys. This may be due to sex hormones, which have previously been reported to be associated with the CRP gene 33 and body composition.…”

“…It seems that the CRP gene has gender-specific effects. [31][32][33] In an animal model, testosterone and IL-6 have been found to be required for human CRP gene expression in transgenic mice. 33 In two Finnish cohort studies, a strong association between CRP gene variants and CRP levels was found only in men.…”

Extracellular heat shock protein 70 (HSPA1A) and classical vascular risk factors in a general population

“…Additionally, low levels of serum Hsp70 (HSPA1A) have been shown in patients with metabolic syndrome (Armutcu et al 2008) and with type 2 diabetes (Hooper and Hooper 2009). The lower concentration of circulating Hsp70 (HSPA1A) in women confirms epidemiological data showing worse prognosis of cardiovascular accidents for women (Silander et al 2008). The unanswered question, asked by Hooper and Hoopet 2004, remains: are low levels of Hsp70 the cause or the consequence of atherosclerosis?…”

Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression

“…Sex differences in gene expression may contribute to differences between men and women in the prevalence, extent, and progression of disease, including autoimmune diseases (54), kidney disease (37), cardiovascular disease (45), and liver diseases, such as hepatocellular carcinoma (9,58). In addition, sex-related differences in pharmacokinetics and pharmacodynamics are common and may affect drug response (52).…”