Browsing by Author "Goyal, Shiwali"

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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).
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    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).