Background: Despite decades of research, the genetic basis of coronary heart disease and its metabolic risk factors is poorly understood. Few studies consider that sex may modify the effect of gene variants on disease. Investigation of gene by sex interaction may help to elucidate underlying genetic susceptibilities and explain the sexual dimorphism of these complex traits.
Aims: The aim of this review is to summarize evidence for gene by sex interaction in the etiology of coronary heart disease and the metabolic syndrome.
Data synthesis: Published literature was examined in the areas of familial aggregation of coronary heart disease; heritability of body mass, insulin resistance, hypertension and dyslipidemia; genome-wide linkage analysis in humans and rodents; and large-scale genetic association studies. Possible mechanisms of gene by sex interaction are discussed including X-linked inheritance, confounding by risk factors and the effect of sex hormones.
Conclusions: The strongest evidence for gene by sex interaction in relation to coronary heart disease and the metabolic syndrome is in the etiology of body mass, insulin resistance and possibly dyslipidemia. Genetic studies of these traits would benefit from taking sex differences into account. Alternative mechanisms underlying gene by sex interaction, besides obvious sex hormone differences, should be considered.