Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort
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/...
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doaj-6017526f88914f8fb0934870332439bf2021-04-02T16:27:36ZengBMCBMC Medical Genomics1755-87942021-01-0114111110.1186/s12920-020-00854-2Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohortElisabeth A. Rosenthal0David R. Crosslin1Adam S. Gordon2David S. Carrell3Ian B. Stanaway4Eric B. Larson5Jane Grafton6Wei-Qi Wei7Joshua C. Denny8Qi-Ping Feng9Amy S. Shah10Amy C. Sturm11Marylyn D. Ritchie12Jennifer A. Pacheco13Hakon Hakonarson14Laura J. Rasmussen-Torvik15John J. Connolly16Xiao Fan17Maya Safarova18Iftikhar J. Kullo19Gail P. Jarvik20Division of Medical Genetics, School of Medicine, University of Washington Medical CenterDepartment of Biomedical Informatics Medical Education, School of Medicine, University of WashingtonCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern UniversityKaiser Permanente Washington Health Research InstituteDepartment of Biomedical Informatics Medical Education, School of Medicine, University of WashingtonKaiser Permanente Washington Health Research InstituteKaiser Permanente Washington Health Research InstituteDepartment of Biomedical Informatics, Vanderbilt University Medical CenterDepartment of Biomedical Informatics, Vanderbilt University Medical CenterDepartment of Medicine, Vanderbilt University Medical CenterDivision of Endocrinology, Department of Pediatrics, Cincinnati Children’s Hospital and the University of CincinnatiGenomic Medicine Institute, GeisingerDepartment of Genetics, University of PennsylvaniaCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern UniversityCenter for Applied Genomics, The Children’s Hospital of PhiladelphiaDepartment of Preventive Medicine, Northwestern University Feinberg School of MedicineCenter for Applied Genomics, The Children’s Hospital of PhiladelphiaDepartment of Cardiovascular Medicine, Mayo ClinicDepartment of Cardiovascular Medicine, Mayo ClinicDepartment of Cardiovascular Medicine, Mayo ClinicDivision of Medical Genetics, School of Medicine, University of Washington Medical CenterAbstract 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.https://doi.org/10.1186/s12920-020-00854-2GeneticsCardiovascular diseaseTriglyceridesElectronic health records |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Elisabeth A. Rosenthal David R. Crosslin Adam S. Gordon David S. Carrell Ian B. Stanaway Eric B. Larson Jane Grafton Wei-Qi Wei Joshua C. Denny Qi-Ping Feng Amy S. Shah Amy C. Sturm Marylyn D. Ritchie Jennifer A. Pacheco Hakon Hakonarson Laura J. Rasmussen-Torvik John J. Connolly Xiao Fan Maya Safarova Iftikhar J. Kullo Gail P. Jarvik |
spellingShingle |
Elisabeth A. Rosenthal David R. Crosslin Adam S. Gordon David S. Carrell Ian B. Stanaway Eric B. Larson Jane Grafton Wei-Qi Wei Joshua C. Denny Qi-Ping Feng Amy S. Shah Amy C. Sturm Marylyn D. Ritchie Jennifer A. Pacheco Hakon Hakonarson Laura J. Rasmussen-Torvik John J. Connolly Xiao Fan Maya Safarova Iftikhar J. Kullo Gail P. Jarvik Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort BMC Medical Genomics Genetics Cardiovascular disease Triglycerides Electronic health records |
author_facet |
Elisabeth A. Rosenthal David R. Crosslin Adam S. Gordon David S. Carrell Ian B. Stanaway Eric B. Larson Jane Grafton Wei-Qi Wei Joshua C. Denny Qi-Ping Feng Amy S. Shah Amy C. Sturm Marylyn D. Ritchie Jennifer A. Pacheco Hakon Hakonarson Laura J. Rasmussen-Torvik John J. Connolly Xiao Fan Maya Safarova Iftikhar J. Kullo Gail P. Jarvik |
author_sort |
Elisabeth A. Rosenthal |
title |
Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort |
title_short |
Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort |
title_full |
Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort |
title_fullStr |
Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort |
title_full_unstemmed |
Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort |
title_sort |
association between triglycerides, known risk snvs and conserved rare variation in slc25a40 in a multi-ancestry cohort |
publisher |
BMC |
series |
BMC Medical Genomics |
issn |
1755-8794 |
publishDate |
2021-01-01 |
description |
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. |
topic |
Genetics Cardiovascular disease Triglycerides Electronic health records |
url |
https://doi.org/10.1186/s12920-020-00854-2 |
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