Adaptive genetic variation and heart disease risk

Abstract

Purpose of review Obesity, dyslipidemia and cardiovascular disease are complex and determined by both genetic and environmental factors and their inter-relationships. Many associations from genome-wide association studies and candidate gene approaches have described a multitude of polymorphisms associating with lipid and obesity phenotypes but identified genetic variants account for only a small fraction of phenotypic variation. Recent findings That many genotype–phenotype associations involve variants under positive selection and that those variants respond to environmental cues together suggest prominent roles for both genetic adaptation and their interactions with the environment. Adaptive genetic variations interacting with environment modulate disease susceptibility but the level to which those variants contribute to dyslipidemia and obesity and how environmental factors, especially diet, alter the genetic association is not yet completely known. Summary It is evident that genetic variants under positive selection make important contributions to obesity and heart disease risk. Advances in resequencing the entire human genome will enable accurate identification of adaptive variants. Considering interactions between environmental factors and genotypes will empower both genome-wide association studies and characterization of the relationship between positive selection and the obese and dyslipidemic conditions.

Gene regulation underlies environmental adaptation in house mice

“…In humans, many candidate genes for metabolic disorders, such as obesity, also show evidence of climatic adaptation (Hancock et al 2008). In humans, both ADAM17 and BCAT2 have been implicated in metabolic disease (Arribas and Esselens 2009;Newgard et al 2009;Junyent et al 2010;Menghini et al 2013), and variation at ADAM17 has been identified in genome scans for selection (Pickrell et al 2009;Parnell et al 2010;Fumagalli et al 2011) in addition to its association with body weight and obesity risk (Junyent et al 2010).…”

“…ADAM17 and its physiological inhibitor, TIMP3, have also been reported to be involved in glucose homeostasis and adipose, hepatic, and vascular inflammation in both genetic and nutritional models of obesity in mice (Fiorentino et al 2010;Menghini et al 2012;Matsui et al 2014). In addition to its association with body mass and metabolism in mice, in humans variation at ADAM17 has been linked to differences in body weight, BMI, waist circumference, and obesity risk (Junyent et al 2010) and shows signatures of selection (Pickrell et al 2009;Parnell et al 2010;Fumagalli et al 2011).…”

Genetics of Myocardial Infarction

“…Molecular genetics data enlarge our understanding of this problem and we learned a lot. In addition, further progress of whole gene scan might be useful to understand an adaptation of human genes to substantial change of the environmental long-lasting effects [30]. Still we lack a useful tool of molecular genetics for medical practice in MI predisposition.…”

Gene-environment interaction: The causes of high obesity incidence

“…Environmental factors can include climate, diet, dietary components such as saturated fatty acids, physical activity, sedentary behavior, alcohol, or sleep, among many others. Such GxE interactions can serve to modulate the adverse effects of a risk allele, or can exacerbate the genotype-phenotype relationship and increase risk [8].…”