👤 Rohit Tandon

Adipocytokines, including leptin, adiponectin, and resistin, are key mediators linking adiposity, insulin resistance, and inflammation. We present the first genome-wide association study (GWAS; N = 5258) and exome-wide association study (ExWAS; N = 4578) on leptin, adiponectin, and resistin in South Asian population. We identified novel associations in genes ZNF467, and LEPREL2 for leptin; ZNF467, LEPREL2, CRLF3, ZNF732, SOX30, XIRP1, ATP8B3, SPATA2L, TMCO4, TLN2, ABCA12, and SHB for adiponectin; and D2HGDH for resistin. Additionally, we confirmed known associations of FTO, MC4R, and HOXB3 with leptin and ADIPOQ with adiponectin. Notably, ADIPOQ variants were consistently significant across GWAS, ExWAS, and gene-based analyses, reinforcing their central role in regulating adiponectin levels. Most of these novel associations identified were population-specific, highlighting the importance of studying diverse populations to uncover unique genetic signals. After adjusting for BMI, the associations with adiponectin and resistin remained significant, whereas most associations for leptin weakened in both effect size and significance. Functional annotation revealed that the identified variants were enriched for expression in adipose tissue, the brain (cerebellar hemisphere and cerebral cortex), and the pituitary gland. These variants act as eQTLs and splice-QTLs in adipose, brain, and pancreas, suggesting cross-tissue regulatory mechanisms. ExWAS further implicated rare variant burden in genes such as LONP1, ZNF335, and TTC16 for adiponectin and resistin. These findings enhance our understanding of adipocytokine biology, emphasises the need for population-specific genetic research, and lays foundation for future functional studies. Show less

Childhood obesity (OB) is influenced by complex gene-environmental interaction. While genetics of adult OB have been extensively studied, polygenic childhood OB in non-European populations is still underexplored. Furthermore, in a developing nation such as India, how the environmental component strongly modulated by the socioeconomic status (SES) shapes the genetic susceptibility is crucial to understand. A two-staged genome-wide association study (GWAS; N = 5673) and an independent exome-wide association study (ExWAS; N = 4963) were performed using a generalized linear model assuming additive effect to identify the common and rare genetic variants respectively associated with childhood OB. Rare-variant burden testing was also performed. We used the gene expression profiles and regulatory data from public databases to explain the novel associations. The implications of SES as a potential modifier of genetic susceptibility were evaluated. GWAS identified novel associations in TCF7L2, IMMP2L, IPMK, CDC5L, SNTG1, and MX1, whereas ExWAS uncovered CNTN4, COQ4, TNFRSF10D, FLG-AS1, and BMP3. Both GWAS and ExWAS validated known associations in FTO and MC4R. Furthermore, rare-variant testing highlighted the role of 101 genes. We also observed that SES can modulate the inherent susceptibility to OB. Our study identified genetic variants associated with childhood OB and highlighted the gene-environmental interaction in childhood OB. Show less

Elucidating the genetic basis of lipid metabolism in children is essential for early intervention in dyslipidemia and cardiovascular diseases. We performed a two-staged genome-wide association study (GWAS; N = 5412) and an independent exome-wide association study (ExWAS; N = 4750) on lipid parameters-HDL, LDL, Triglycerides (TG), Total Cholesterol (TC) in Indian school-going children - the largest single-cohort paediatric lipid study till date. GWAS identified robust associations at established loci, including CETP for HDL; CELSR2, and PSRC1 for LDL and TC, and GCKR, ZNF259, and TBL2 for TG. We also validated known associations at sub-GWAS significance in FADS2, GATAD2A, PRKCA, and QKI. Exome-based analyses further refined functional variants within these loci and revealed additional known loci in ALDH1A2 for HDL; APOE, APOC1, TM6SF2, CILP2, TOMM40, for LDL and TC; and APOA5, BUD13 for TG and novel loci in ATP8B3, MYH7B, GYS2, and RNF8 for TG. Conditional analysis revealed multiple independent signals at key loci. Gene-based GWAS pinpointed CETP and APOC1 as significant for HDL and LDL, respectively. Rare variant analysis identified significant contribution of loss-of-function missense variants in CETP, TM6SF2, and APOE, in regulating lipid profiles. Associations replicated with consistent directionality in European datasets and Indian adults, reinforcing conserved biology across ancestries and age groups. Functional enrichment analyses emphasized lipid-related pathways and differential expression in liver. These findings lay the foundation for ancestry-informed genetic risk prediction models to identify children at early risk for cardiovascular diseases. Show less

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

Defining lipid goals solely on low-density lipoprotein-cholesterol (LDL-C) levels in Indian population may cause misclassification due to high prevalence of hypertriglyceridemia and small dense LDL-C particles. International guidelines now recommend Apoliporotein-B (Apo-B) and non-high-density lipoprotein-cholesterol (non-HDL-C) levels as alternative targets. In this study, we used a cross-sectional representative population database to determine Apo-B and non-HDL-C cut-offs corresponding to identified LDL-C targets and compared them to international guidelines. A community-based survey carried out in urban Delhi and adjacent rural Ballabhgarh provided lipid values for 3047 individuals. The Spearman correlation coefficient was used to evaluate the degree of relationship between Apo-B and LDL-C and non-HDL-C. Cut-off values for Apo-B and non-HDL-C were established using receiver operator curve analysis correlating with guideline-recommended LDL-C targets. Spearman's rank correlations between Apo-B and LDL-C (0.82) and non-HDL-C and LDL-C (0.93) were significant (p < 0.05). Proposed corresponding cut-off values for LDL-C of 55, 70,100,130 and 160 mg/dl for Apo-B and non-HDL-C in our population were 75.3, 75.5, 91.3, 107.6, 119.4 mg/dL and 92.5,96.5, 123.5, 154.5, 179.5 mg/dL respectively. However, in those with triglycerides >150 mg/dl the corresponding Apo-B and non-HDL-C values were 85.1, 92.7, 103.5, 117.5 and 135 mg/dL and 124.5, 126.5, 147.5, 167.5 and 190.5 mg/L respectively. Based on this study we provide Apo-B and non-HDL cut-offs corresponding to target LDL-C values in Indian patients with and without high triglycerides. It is noted that in individuals with triglycerides ≥ 150 mg/dl, the Apo-B levels are much higher than the values recommended by guidelines. Show less

Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6,617 MetS and 3,476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages-discovery phase ( Show less

Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation. Show less

Vascular hyperproliferative disorders are characterized by excessive smooth muscle cell (SMC) proliferation leading to vessel remodeling and occlusion. In pulmonary arterial hypertension (PAH), SMC phenotype switching from a terminally differentiated contractile to synthetic state is gaining traction as our understanding of the disease progression improves. While maintenance of SMC contractile phenotype is reportedly orchestrated by a MEF2C-myocardin (MYOCD) interplay, little is known regarding molecular control at this nexus. Moreover, the burgeoning interest in microRNAs (miRs) provides the basis for exploring their modulation of MEF2C-MYOCD signaling, and in turn, a pro-proliferative, synthetic SMC phenotype. We hypothesized that suppression of SMC contractile phenotype in pulmonary hypertension is mediated by miR-214 via repression of the MEF2C-MYOCD-leiomodin1 (LMOD1) signaling axis. In SMCs isolated from a PAH patient cohort and commercially obtained hPASMCs exposed to hypoxia, miR-214 expression was monitored by qRT-PCR. miR-214 was upregulated in PAH- vs. control subject hPASMCs as well as in commercially obtained hPASMCs exposed to hypoxia. These increases in miR-214 were paralleled by MEF2C, MYOCD and SMC contractile protein downregulation. Of these, LMOD1 and MEF2C were directly targeted by the miR. Mir-214 overexpression mimicked the PAH profile, downregulating MEF2C and LMOD1. AntagomiR-214 abrogated hypoxia-induced suppression of the contractile phenotype and its attendant proliferation. Anti-miR-214 also restored PAH-PASMCs to a contractile phenotype seen during vascular homeostasis. Our findings illustrate a key role for miR-214 in modulation of MEF2C-MYOCD-LMOD1 signaling and suggest that an antagonist of miR-214 could mitigate SMC phenotype changes and proliferation in vascular hyperproliferative disorders including PAH. Show less