Goyal, ShiwaliTanigawa, YosukeZhang, WeihuaChai, Jin-FangAlmeida, MarcioSim, XuelingLerner, MeganChainakul, JulianeRamiu, Jonathan GarciaSeraphin, ChanelApple, BlairVaughan, AprilMuniu, JamesPeralta, JuanLehman, Donna M.Ralhan, SarjuWander, Gurpreet S.Singh, Jai RupMehra, Narinder K.Sidorov, EvgenyPeyton, Marvin D.Blackett, Piers R.Curran, Joanne E.Tai, E. Shyongvan Dam, RobCheng, Ching-YuDuggirala, RavindranathBlangero, JohnChambers, John C.Sabanayagam, CharumathiKooner, Jaspal S.Rivas, Manuel A.Aston, Christopher E.Sanghera, Dharambir K.2024-01-212024-08-142024-01-212024-08-142021-09-211476511X10.1186/s12944-021-01531-8https://kr.cup.edu.in/handle/32116/4192Background: 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).en-USApoC-IIIAsian IndiansCoronary artery disease riskMendelian randomizationRare and common variantsTriglycerideArticlehttps://lipidworld.biomedcentral.com/articles/10.1186/s12944-021-01531-8