Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial
Background Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease...
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| Format: | Article |
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PeerJ Inc.
2017-05-01
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| Online Access: | https://peerj.com/articles/3187.pdf |
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| author | Skylar W. Marvel Daniel M. Rotroff Michael J. Wagner John B. Buse Tammy M. Havener Howard L. McLeod Alison A. Motsinger-Reif The ACCORD/ACCORDion Investigators |
| author_facet | Skylar W. Marvel Daniel M. Rotroff Michael J. Wagner John B. Buse Tammy M. Havener Howard L. McLeod Alison A. Motsinger-Reif The ACCORD/ACCORDion Investigators |
| author_sort | Skylar W. Marvel |
| collection | DOAJ |
| description | Background Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. Methods DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV), defined as minor allele frequency (MAF) ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV) associations (MAF < 3%) were conducted using a suite of methods that collapse multiple RV within individual genes. Results Many statistically significant CV (p < 1 × 10−8) replicate findings in large meta-analyses in non-diabetic subjects. RV analyses also confirmed findings in other studies, whereas significant RV associations with CNOT2, HPN-AS1, and SIRPD appear to be novel (q < 0.1). Discussion Here we present findings for the largest GWAS of lipid levels in people with type 2 diabetes to date. We identified 17 statistically significant (p < 1 × 10−8) associations of CV with lipid levels in 11 genes or chromosomal regions, all of which were previously identified in meta-analyses of mostly non-diabetic cohorts. We also identified 13 associations in 11 genes based on RV, several of which represent novel findings. |
| first_indexed | 2024-03-09T06:38:01Z |
| format | Article |
| id | doaj.art-2f43bf3d4b6e4cd5985adbb5df2a301a |
| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T06:38:01Z |
| publishDate | 2017-05-01 |
| publisher | PeerJ Inc. |
| record_format | Article |
| series | PeerJ |
| spelling | doaj.art-2f43bf3d4b6e4cd5985adbb5df2a301a2023-12-03T10:55:11ZengPeerJ Inc.PeerJ2167-83592017-05-015e318710.7717/peerj.3187Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trialSkylar W. Marvel0Daniel M. Rotroff1Michael J. Wagner2John B. Buse3Tammy M. Havener4Howard L. McLeod5Alison A. Motsinger-Reif6 The ACCORD/ACCORDion InvestigatorsBioinformatics Research Center, North Carolina State University, Raleigh, NC, United States of AmericaBioinformatics Research Center, North Carolina State University, Raleigh, NC, United States of AmericaCenter for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of AmericaDivision of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of AmericaCenter for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of AmericaMoffitt Cancer Center, Tampa, FL, United States of AmericaBioinformatics Research Center, North Carolina State University, Raleigh, NC, United States of AmericaBackground Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. Methods DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV), defined as minor allele frequency (MAF) ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV) associations (MAF < 3%) were conducted using a suite of methods that collapse multiple RV within individual genes. Results Many statistically significant CV (p < 1 × 10−8) replicate findings in large meta-analyses in non-diabetic subjects. RV analyses also confirmed findings in other studies, whereas significant RV associations with CNOT2, HPN-AS1, and SIRPD appear to be novel (q < 0.1). Discussion Here we present findings for the largest GWAS of lipid levels in people with type 2 diabetes to date. We identified 17 statistically significant (p < 1 × 10−8) associations of CV with lipid levels in 11 genes or chromosomal regions, all of which were previously identified in meta-analyses of mostly non-diabetic cohorts. We also identified 13 associations in 11 genes based on RV, several of which represent novel findings.https://peerj.com/articles/3187.pdfExomeDiabetesGeneticsLipidsRare variantsGenomics |
| spellingShingle | Skylar W. Marvel Daniel M. Rotroff Michael J. Wagner John B. Buse Tammy M. Havener Howard L. McLeod Alison A. Motsinger-Reif The ACCORD/ACCORDion Investigators Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial PeerJ Exome Diabetes Genetics Lipids Rare variants Genomics |
| title | Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial |
| title_full | Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial |
| title_fullStr | Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial |
| title_full_unstemmed | Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial |
| title_short | Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial |
| title_sort | common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the accord clinical trial |
| topic | Exome Diabetes Genetics Lipids Rare variants Genomics |
| url | https://peerj.com/articles/3187.pdf |
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