Molecular circuits of sex dimorphism in cardiometabolic traits and risk factors

Cardiometabolic traits including cardiovascular diseases (CVD), type 2 diabetes (T2D), and metabolic syndrome (MetS) are the leading cause of death worldwide. They are defined as complex traits and are believed to result from genetic variation within multiple genes and their interaction with behavioral and environmental factors.
Cardiometabolic traits also exhibit some degree of sex differences, including differences in incidence or prevalence, age of onset, severity, disease progression, susceptibility, response to treatment and pharmacological adverse events. For example, women have a lower incidence of cardiovascular disease, such as stroke, before menopause, after which the incidence surpasses that of men; women can manifest diabetes during pregnancy (gestational diabetes), which is a risk factor for CVD and T2D later in life. In general, men are more insulin resistant and have higher levels of fasting glucose, whereas women are more likely than men to have elevated 2-hr glucose concentrations.
Despite the crucial importance of sex as a biological variable in cardiometabolic traits, relatively few studies addressed the sex-specific mechanisms of disease pathogenesis or investigated appropriate treatment and prevention strategies. Methodological challenges related with the lack of appropriate approaches to analyze sex chromosomes as well as inadequate sample size for sex stratified analyses have impeded progresses in studying the genetic of sex differences in human populations. Only recently, with the advance of large population-based studies like the UK Biobank and Lifelines, potential natural targets to explore sex-dimorphic effect, some studies have reached sufficient sample sizes to be well powered for sex stratified analysis.
In this context, the importance of sex stratified genome-wide association studies (GWAS) is crucial to discover the effects of individual variants within each sex and to identify novel loci that may have been previously undetected in sex combined GWAS.