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Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

Wednesday,2015-03-04 11:56 America/Los_Angeles — zdrager
TitleSequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
Publication TypeJournal Article
Year of Publication2014
AuthorsBis, JC, White, CC, Franceschini, N, Brody, J, Zhang, X, Muzny, D, Santibanez, J, Gibbs, R, Liu, X, Lin, H, Boerwinkle, E, Psaty, BM, North, KE, Cupples, AL, O'Donnell, CJ
Corporate/Institutional AuthorsCHARGE Subclinical Atherosclerosis Working Group
JournalCirc Cardiovasc Genet
Volume7
Issue3
Pagination359-64
Date Published2014 Jun
ISSN1942-3268
KeywordsAged, Aged, 80 and over, Aging, Atherosclerosis, Class Ib Phosphatidylinositol 3-Kinase, Cohort Studies, European Continental Ancestry Group, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Sodium-Phosphate Cotransporter Proteins, Type I
Abstract<p><b>BACKGROUND: </b>Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).</p><p><b>METHODS AND RESULTS: </b>We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).</p><p><b>CONCLUSIONS: </b>Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.</p>
DOI10.1161/CIRCGENETICS.113.000116
Alternate JournalCirc Cardiovasc Genet
PubMed ID24951662
PubMed Central IDPMC4112104
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
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HHSN268201000010C / HL / NHLBI NIH HHS / United States
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UL1 TR000124 / TR / NCATS NIH HHS / United States
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U54 HG003273 / HG / NHGRI NIH HHS / United States
HL120393 / HL / NHLBI NIH HHS / United States
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R01 HL105756 / HL / NHLBI NIH HHS / United States
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HHSN268201100008C / / PHS HHS / United States
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HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
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N01HC25195 / HL / NHLBI NIH HHS / United States
Z99 HL999999 / / Intramural NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
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HHSN268201000012C / HL / NHLBI NIH HHS / United States
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HHSN268201100006C / / PHS HHS / United States
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HL103612 / HL / NHLBI NIH HHS / United States
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AG023629 / AG / NIA NIH HHS / United States
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HHSN268201100001C / WH / WHI NIH HHS / United States
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HHSN2682011000011C / / PHS HHS / United States

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