Elisabeth A Rosenthal1, David R Crosslin2, Adam S Gordon3, David S Carrell4, Ian B Stanaway2, Eric B Larson4, Jane Grafton4, Wei-Qi Wei5, Joshua C Denny5,6, Qi-Ping Feng6, Amy S Shah7, Amy C Sturm8, Marylyn D Ritchie9, Jennifer A Pacheco3, Hakon Hakonarson10, Laura J Rasmussen-Torvik11, John J Connolly10, Xiao Fan12, Maya Safarova12, Iftikhar J Kullo12,13, Gail P Jarvik14,15. 1. Division of Medical Genetics, School of Medicine, University of Washington Medical Center, 1705 NE Pacific St, Box 357720, Seattle, WA, 98195, USA. erosen@uw.edu. 2. Department of Biomedical Informatics Medical Education, School of Medicine, University of Washington, Seattle, WA, USA. 3. Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 4. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA. 5. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. 6. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 7. Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital and the University of Cincinnati, Cincinnati, OH, USA. 8. Genomic Medicine Institute, Geisinger, Danville, PA, 17822, USA. 9. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. 10. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 11. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 12. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA. 13. Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA. 14. Division of Medical Genetics, School of Medicine, University of Washington Medical Center, 1705 NE Pacific St, Box 357720, Seattle, WA, 98195, USA. 15. Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Abstract
BACKGROUND: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. METHODS: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. RESULTS: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. CONCLUSIONS: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
BACKGROUND: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. METHODS: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. RESULTS: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. CONCLUSIONS: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
Entities:
Keywords:
Cardiovascular disease; Electronic health records; Genetics; Triglycerides
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