AIMS: Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI). METHODS AND RESULTS: We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25-2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32-2.68) compared with a causal genetic odds ratio of 1.94 (1.40-1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38-2.02) observational and 2.23(1.48-3.35) causal (P for comparison = 0.21). CONCLUSION: These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters.
AIMS: Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI). METHODS AND RESULTS: We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25-2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32-2.68) compared with a causal genetic odds ratio of 1.94 (1.40-1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38-2.02) observational and 2.23(1.48-3.35) causal (P for comparison = 0.21). CONCLUSION: These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters.
Authors: Frederick E Dewey; Viktoria Gusarova; Richard L Dunbar; Colm O'Dushlaine; Claudia Schurmann; Omri Gottesman; Shane McCarthy; Cristopher V Van Hout; Shannon Bruse; Hayes M Dansky; Joseph B Leader; Michael F Murray; Marylyn D Ritchie; H Lester Kirchner; Lukas Habegger; Alex Lopez; John Penn; An Zhao; Weiping Shao; Neil Stahl; Andrew J Murphy; Sara Hamon; Aurelie Bouzelmat; Rick Zhang; Brad Shumel; Robert Pordy; Daniel Gipe; Gary A Herman; Wayne H H Sheu; I-Te Lee; Kae-Woei Liang; Xiuqing Guo; Jerome I Rotter; Yii-Der I Chen; William E Kraus; Svati H Shah; Scott Damrauer; Aeron Small; Daniel J Rader; Anders Berg Wulff; Børge G Nordestgaard; Anne Tybjærg-Hansen; Anita M van den Hoek; Hans M G Princen; David H Ledbetter; David J Carey; John D Overton; Jeffrey G Reid; William J Sasiela; Poulabi Banerjee; Alan R Shuldiner; Ingrid B Borecki; Tanya M Teslovich; George D Yancopoulos; Scott J Mellis; Jesper Gromada; Aris Baras Journal: N Engl J Med Date: 2017-05-24 Impact factor: 91.245
Authors: Mark A Sarzynski; Peter K Davidsen; Yun Ju Sung; Matthijs K C Hesselink; Patrick Schrauwen; Treva K Rice; D C Rao; Francesco Falciani; Claude Bouchard Journal: Br J Sports Med Date: 2015-10-21 Impact factor: 13.800
Authors: Allan D Sniderman; Patrick Couture; Seth S Martin; Jacqueline DeGraaf; Patrick R Lawler; William C Cromwell; John T Wilkins; George Thanassoulis Journal: J Lipid Res Date: 2018-05-16 Impact factor: 5.922