Browsing by Author "Singh, Jai Rup"

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APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups
(BioMed Central Ltd, 2021-09-21T00:00:00) Goyal, Shiwali; Tanigawa, Yosuke; Zhang, Weihua; Chai, Jin-Fang; Almeida, Marcio; Sim, Xueling; Lerner, Megan; Chainakul, Juliane; Ramiu, Jonathan Garcia; Seraphin, Chanel; Apple, Blair; Vaughan, April; Muniu, James; Peralta, Juan; Lehman, Donna M.; Ralhan, Sarju; Wander, Gurpreet S.; Singh, Jai Rup; Mehra, Narinder K.; Sidorov, Evgeny; Peyton, Marvin D.; Blackett, Piers R.; Curran, Joanne E.; Tai, E. Shyong; van Dam, Rob; Cheng, Ching-Yu; Duggirala, Ravindranath; Blangero, John; Chambers, John C.; Sabanayagam, Charumathi; Kooner, Jaspal S.; Rivas, Manuel A.; Aston, Christopher E.; Sanghera, Dharambir K.
Background: 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. Methods: 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. Results: 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? 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p�= 0.042). Conclusions: 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. � 2021, The Author(s).
A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans
(BioMed Central Ltd, 2021-07-27T00:00:00) Bejar, Cynthia A.; Goyal, Shiwali; Afzal, Shoaib; Mangino, Massimo; Zhou, Ang; van der Most, Peter J.; Bao, Yanchun; Gupta, Vipin; Smart, Melissa C.; Walia, Gagandeep K.; Verweij, Niek; Power, Christine; Prabhakaran, Dorairaj; Singh, Jai Rup; Mehra, Narinder K.; Wander, Gurpreet S.; Ralhan, Sarju; Kinra, Sanjay; Kumari, Meena; de Borst, Martin H.; Hypp�nen, Elina; Spector, Tim D.; Nordestgaard, B�rge G.; Blackett, Piers R.; Sanghera, Dharambir K.
Context: Multiple observational studies have reported aninverse relationship between 25-hydroxyvitaminD concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results ofshort- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have beeninconsistent. Objectives and methods: To evaluate the causal role of reduced blood25(OH)D in T2D, here we have performed a bidirectional Mendelian randomizationstudy using 59,890 individuals (5,862 T2D cases and 54,028 controls) fromEuropean and Asian Indian ancestries. We used six known SNPs, including threeT2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluatethe causality and direction of the association between T2D and circulating25(OH)D concentration. Results: Results of the combined meta-analysis of eightparticipating studies showed that a composite score of three T2D SNPs wouldsignificantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 � 10�32; Z score 11.86, which, however, hadno significant association with 25(OH)D status (Beta -0.02nmol/L � SE0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the geneticallyinstrumented composite score of 25(OH)D lowering alleles significantlydecreased 25(OH)D concentrations (-2.1nmol/L � SE 0.1nmol/L,p = 7.92 � 10�78; Z score -18.68) but was notassociated with increased risk for T2D (OR 1.00, p = 0.12;Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as anindividual genetic instrument, a per allele reduction of 25(OH)D concentration(-4.2nmol/L � SE 0.3nmol/L)was predicted to increase T2D risk by 5%, p = 0.004;Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GCrs2282679, CYP2R1 rs12794714) when used as an individual instrument. Conclusion: Our new data on this bidirectional Mendelianrandomization study suggests that genetically instrumented T2D risk does notcause changes in 25(OH)D levels. However, genetically regulated 25(OH)Ddeficiency due to vitamin D synthesis gene (DHCR7) may influence the risk ofT2D. � 2021, The Author(s).
Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium
(Frontiers Media S.A., 2022-04-14T00:00:00) Venkatesan, Vettriselvi; Lopez-Alvarenga, Juan Carlos; Arya, Rector; Ramu, Deepika; Koshy, Teena; Ravichandran, Umarani; Ponnala, Amaresh Reddy; Sharma, Surendra K.; Lodha, Sailesh; Sharma, Krishna K.; Shaik, Mahaboob Vali; Resendez, Roy G.; Venugopal, Priyanka; Parthasarathy, R.; Saju, Noelta; Ezeilo, Juliet A.; Bejar, Cynthia; Wander, Gurpreet S.; Ralhan, Sarju; Singh, Jai Rup; Mehra, Narinder K.; Vadlamudi, Raghavendra Rao; Almeida, Marcio; Mummidi, Srinivas; Natesan, Chidambaram; Blangero, John; Medicherla, Krishna M.; Thanikachalam, Sadagopan; Panchatcharam, Thyagarajan Sadras; Kandregula, Dileep Kumar; Gupta, Rajeev; Sanghera, Dharambir K.; Duggirala, Ravindranath; Paul, Solomon F. D.
To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ? 126 mg/dl or HbA1c ? 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ? 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits. Copyright � 2022 Venkatesan, Lopez-Alvarenga, Arya, Ramu, Koshy, Ravichandran, Ponnala, Sharma, Lodha, Sharma, Shaik, Resendez, Venugopal, R, Saju, Ezeilo, Bejar, Wander, Ralhan, Singh, Mehra, Vadlamudi, Almeida, Mummidi, Natesan, Blangero, Medicherla, Thanikachalam, Panchatcharam, Kandregula, Gupta, Sanghera, Duggirala and Paul.