New genetic variant discovered in Old Order Amish provides increased cardioprotection

Whole-exome sequencing and association analysis in nearly 7,000 Old Order Amish reveals a genetic variant that may confer protective effects against cardiovascular disease (CVD), researchers report. The findings could be used to inform novel therapeutic approaches to decreasing or preventing CVD. CVD is a leading cause of sickness and death worldwide. Increased blood levels of low-density lipoprotein cholesterol (LDL-C) and fibrinogen – a blood clotting protein – are independent risk factors for CVD. While variations in both LDL-C and fibrinogen are known to be governed in part by rare and common genetic variants, few gene variants have been found that have pleiotropic effects on more than one CVD risk factor. Through exome sequencing of an Old Order Amish population, May Montasser and colleagues discovered a missense variant of the protein coding B4GALT1 gene, which was correlated with lower levels of CVD. In a knock-in study involving a mouse model of CVD, the authors show that this variant produced a 38% decrease in blood LDL-C levels as well as decreases of fibrinogen. According to Montasser et al., targeted modulation of this protein may represent a therapeutic approach to decreasing CVD risk.