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Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.
Tuesday,2015-10-06 13:38 America/Los_Angeles — zdrager
| Title | Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Auer, PL, Nalls, M, Meschia, JF, Worrall, BB, Longstreth, WT, Seshadri, S, Kooperberg, C, Burger, KM, Carlson, CS, Carty, CL, Chen, W-M, Cupples, AL, DeStefano, AL, Fornage, M, Hardy, J, Hsu, L, Jackson, RD, Jarvik, GP, Kim, DS, Lakshminarayan, K, Lange, LA, Manichaikul, A, Quinlan, AR, Singleton, AB, Thornton, TA, Nickerson, DA, Peters, U, Rich, SS |
| Corporate/Institutional Authors | National Heart, Lung, and Blood Institute Exome Sequencing Project |
| Journal | JAMA Neurol |
| Volume | 72 |
| Issue | 7 |
| Pagination | 781-8 |
| Date Published | 2015 Jul |
| ISSN | 2168-6157 |
| Keywords | Aged, Brain Ischemia, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Muscle Proteins, National Heart, Lung, and Blood Institute (U.S.), Nuclear Proteins, Open Reading Frames, Palmitoyl-CoA Hydrolase, Stroke, United States |
| Abstract | <p><b>IMPORTANCE: </b>Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.</p><p><b>OBJECTIVE: </b>To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.</p><p><b>DESIGN, SETTING, AND PARTICIPANTS: </b>The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.</p><p><b>MAIN OUTCOMES AND MEASURES: </b>Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).</p><p><b>RESULTS: </b>We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).</p><p><b>CONCLUSIONS AND RELEVANCE: </b>Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.</p> |
| DOI | 10.1001/jamaneurol.2015.0582 |
| Alternate Journal | JAMA Neurol |
| PubMed ID | 25961151 |
| PubMed Central ID | PMC4673986 |
| Grant List | 024156 / / PHS HHS / United States 5R00-HG004316 / HG / NHGRI NIH HHS / United States AG033193 / AG / NIA NIH HHS / United States AG08122 / AG / NIA NIH HHS / United States F32-HL083714 / HL / NHLBI NIH HHS / United States HHSN268200800007C / / PHS HHS / United States HHSN268201100001C / / PHS HHS / United States HHSN268201100002C / / PHS HHS / United States HHSN268201100003C / / PHS HHS / United States HHSN268201100004C / / PHS HHS / United States HHSN268201100046C / / PHS HHS / United States HHSN268201200036C / / PHS HHS / United States HHSN271201100004C / / PHS HHS / United States HL-69197 / HL / NHLBI NIH HHS / United States HL-76285 / HL / NHLBI NIH HHS / United States HL077916 / HL / NHLBI NIH HHS / United States HR-46002 / HR / NHLBI NIH HHS / United States K23-AR52742 / AR / NIAMS NIH HHS / United States M01-RR07122 / RR / NCRR NIH HHS / United States N01 HC-55015 / HC / NHLBI NIH HHS / United States N01 HC-55016 / HC / NHLBI NIH HHS / United States N01 HC-55018 / HC / NHLBI NIH HHS / United States N01 HC-55019 / HC / NHLBI NIH HHS / United States N01 HC-55020 / HC / NHLBI NIH HHS / United States N01 HC-55021 / HC / NHLBI NIH HHS / United States N01 HC-95170 / HC / NHLBI NIH HHS / United States N01 HC-95171 / HC / NHLBI NIH HHS / United States N01 HC-95172 / HC / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States N01-HC-95159 / HC / NHLBI NIH HHS / United States N01-HC-95160 / HC / NHLBI NIH HHS / United States N01-HC-95161 / HC / NHLBI NIH HHS / United States N01-HC-95162 / HC / NHLBI NIH HHS / United States N01-HC-95163 / HC / NHLBI NIH HHS / United States N01-HC-95164 / HC / NHLBI NIH HHS / United States N01-HC-95165 / HC / NHLBI NIH HHS / United States N01-HC-95166 / HC / NHLBI NIH HHS / United States N01-HC-95167 / HC / NHLBI NIH HHS / United States N01-HC-95168 / HC / NHLBI NIH HHS / United States N01-HC-95169 / HC / NHLBI NIH HHS / United States N01-HC48047 / HC / NHLBI NIH HHS / United States N01-HC48048 / HC / NHLBI NIH HHS / United States N01-HC48049 / HC / NHLBI NIH HHS / United States N01-HC48050 / HC / NHLBI NIH HHS / United States N01-HC95095 / HC / NHLBI NIH HHS / United States N01HC-55017 / HC / NHLBI NIH HHS / United States N01HC55222 / HC / NHLBI NIH HHS / United States N01HC85079 / HC / NHLBI NIH HHS / United States N01HC85080 / HC / NHLBI NIH HHS / United States N01HC85081 / HC / NHLBI NIH HHS / United States N01HC85082 / HC / NHLBI NIH HHS / United States N01HC85083 / HC / NHLBI NIH HHS / United States N01HC85086 / HC / NHLBI NIH HHS / United States NS17950 / NS / NINDS NIH HHS / United States P50-HL084946 / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R01-HG004738 / HG / NHGRI NIH HHS / United States R01-HL068890 / HL / NHLBI NIH HHS / United States R01-NS39987 / NS / NINDS NIH HHS / United States R01-NS42733 / NS / NINDS NIH HHS / United States R01AG023629 / AG / NIA NIH HHS / United States R01HL087652 / HL / NHLBI NIH HHS / United States R01HL103612 / HL / NHLBI NIH HHS / United States R01HL105756 / HL / NHLBI NIH HHS / United States R01HL120393 / HL / NHLBI NIH HHS / United States R02-HL095396 / HL / NHLBI NIH HHS / United States RC2 HL-102923 / HL / NHLBI NIH HHS / United States RC2 HL-102924 / HL / NHLBI NIH HHS / United States RC2 HL-102925 / HL / NHLBI NIH HHS / United States RC2 HL-102926 / HL / NHLBI NIH HHS / United States RC2 HL-103010 / HL / NHLBI NIH HHS / United States RC2 HL103010 / HL / NHLBI NIH HHS / United States RC2-HL066583 / HL / NHLBI NIH HHS / United States RC2-HL101651 / HL / NHLBI NIH HHS / United States RC2-HL101779 / HL / NHLBI NIH HHS / United States RC2-HL102924 / HL / NHLBI NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States U01-HL089856 / HL / NHLBI NIH HHS / United States U01-HL089897 / HL / NHLBI NIH HHS / United States U01HL080295 / HL / NHLBI NIH HHS / United States UL1 TR000423 / TR / NCATS NIH HHS / United States UL1-RR025014 / RR / NCRR NIH HHS / United States Z01-AG000954-7 / AG / NIA NIH HHS / United States / / Intramural NIH HHS / United States |