Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder with elevated LDL-C levels which can ultimately lead to premature Coronary Artery Disease (CAD). In presence of limited gen Show more
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder with elevated LDL-C levels which can ultimately lead to premature Coronary Artery Disease (CAD). In presence of limited genetic data on FH in India, the present study was aimed to determine the mutation spectrum in Indian FH patients using a targeted exome sequencing. 54 FH cases (31 index cases + 23 extended family members) were categorized according to Dutch Lipid Clinic Network Criteria (DLCNC). Targeted exome sequencing was performed using 23 gene panel associated with lipid metabolism. All subjects showed the presence of family history of CAD, 38(70%) patients had corneal arcus whereas only 06(11%) subjects had xanthomas. As per the DLCNC, definite, probable, possible and unlikely FH were 48%, 30%, 11% and 11% respectively. Mutations were observed in 12 of the 23 gene panel with CETP, APOA5, EPHX2 and SREBP2 genes were identified for the first time in Indian FH patients. All 19 mutations including a novel frame-shift mutation in LDLR gene were reported for the first time in Indian FH patients. These mutations were identified in 28(52%) subjects and interestingly ∼73% of the clinically identified FH patients didn't harbour mutations in FH classical genes (LDLR, ApoB, PCSK9). This is the first study in the South Indian FH patients to perform targeted exome sequencing. Absence of mutations in the FH classical genes strongly indicates the polygenic nature of FH, further underscoring the importance of targeted exome sequencing for identifying mutations in genetically diverse Indian population. Show less
Asian Indians who have settled overseas and those in urban India have increased risk of coronary events. Reasons for this increased risk are thought to be genetic but are yet unclear. Advances in mole Show more
Asian Indians who have settled overseas and those in urban India have increased risk of coronary events. Reasons for this increased risk are thought to be genetic but are yet unclear. Advances in molecular cardiology have revealed a number of single nucleotide polymorphisms associated with atherosclerosis. In this review, gene polymorphisms that have been associated with coronary diseases among Indians are discussed. Topics include the genes involved in hyperlipidemia, hypertension, and homocysteine. Mutations in the low-density lipoprotein receptor (LDLR) gene resulting in familial hypercholesterolemia have strong association with premature atherosclerosis. Common polymorphism of the apolipoproteins (apo) B-100 and E genes have been associated with variation in lipid and lipoprotein levels. Recently identified polymorphisms in the apoC3 (T-455C, C-482T), and cholesteryl ester transfer protein (CETP) (B1/B2 allele) genes are associated with increased triglycerides and reduced high-density lipoprotein (HDL)-levels, a feature now also common among Asian Indians. Angiotensin-converting enzyme-deletion (DD) polymorphism has been shown to influence beta-blocker therapy in heart failure. Mutations in methylenetetrahydrofolate reductase (C667T), cystathionine beta-synthase (T833C), and methionine synthase (A2756G) genes cause hyperhomocysteinemia, an independent risk factor for atherothrombosis. As the genetics of atherosclerosis continues to evolve, these factors along with the newer emerging factors may become a part of the routine assessment, aiding prediction of future coronary events. Show less