👤 Gurpreet S Wander

Hypertrophic cardiomyopathy (HCM), associated with left ventricular hypertrophy, can lead to significant morbidity. Given the hereditary association, identifying population-specific genetic markers and gender disparities could enable better screening and management strategies. The study aimed to observe the genetic patterns of HCM and investigate its gender associations among the Indian population. A prospective analysis was performed based on the medical records of patients with HCM. Genetic testing was conducted among those with a family history of HCM or sudden cardiac death. Genetic testing results, echocardiography, and clinical outcomes were documented. The prevalence of HCM types and genetic abnormalities were estimated in the study population and were compared between the two genders. The study included 103 patients with a mean age of 56.3 ± 13.9 years. Genetic analysis was conducted in 48/103 individuals based on the hereditary linkage. Only 50% of the 48 individuals had known genes associated with HCM. About 48% had apical or midapical HCM, and 31.1% had reverse curvature HCM. About 38% of apical and 60% of neutral or reverse curvature were associated with genetic abnormalities. The more commonly associated genes were MYBPC3 and MYH7. The current study also identified genetic variants in several emerging genes in Indian HCM patients. Our study findings indicate that the prevalence of different types of HCM is different in the Indian population. With only 50% of the hereditary HCM linked to known genes, the study calls for further screening of genes associated with HCM in the Indian population. Show less

Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10 Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk. Show less

Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p = 2.03×10(-26)). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p = 1.74×10(-17); rs12286037: p = 1.58×10(-2)). We further explored 45 SNPs in a ∼195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: p = 1.06×10(-39)). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD. Show less

Recent genome-wide association studies (GWAS) in Asian Indians reported strong associations of variants near melanocortin-4 receptor (MC4R) and MLX interacting protein-like (MLXIPL) genes with insulin resistance and several obesity-related quantitative traits (QTs). Here, we evaluated the association of two variants (rs12970134 and rs4450508) near MC4R and a nonsynonymous (Gln241His) variant (rs3812316) in MLXIPL gene with type 2 diabetes (T2D) and obesity-related QTs in our case-control cohort (n = 1,528; 745 T2D cases and 783 controls) from a Sikh population from North India. We have successfully replicated the association of MC4R (rs12970134) with BMI (P = 0.0005), total weight (WT) (P = 0.001), and waist circumference (WC) (P = 0.001). These associations remained significant after controlling for multiple testing by applying Bonferroni's correction. However, our data did not confirm the association of rs3812316 in the MLXIPL gene with triglyceride (TG) levels. These observations demonstrate that the genetic variation in MC4R locus can have a moderate contribution in the regional fat deposition and development of central obesity in Asian Indians. Show less