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Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.
Tuesday,2013-11-19 15:30 America/Los_Angeles — poolea2
| Title | Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Lin, H, Sinner, MF, Brody, JA, Arking, DE, Lunetta, KL, Rienstra, M, Lubitz, SA, Magnani, JW, Sotoodehnia, N, McKnight, B, McManus, DD, Boerwinkle, E, Psaty, BM, Rotter, JI, Bis, JC, Gibbs, RA, Muzny, D, Kovar, CL, Morrison, AC, Gupta, M, Folsom, AR, Kääb, S, Heckbert, SR, Alonso, A, Ellinor, PT, Benjamin, EJ |
| Corporate/Institutional Authors | CHARGE Atrial Fibrillation Working Group |
| Journal | Heart Rhythm |
| Volume | 11 |
| Issue | 3 |
| Pagination | 452-7 |
| Date Published | 2014 Mar |
| ISSN | 1556-3871 |
| Keywords | Aged, Atrial Fibrillation, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-6 |
| Abstract | <p><b>BACKGROUND: </b>Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.</p><p><b>OBJECTIVE: </b>To study the association of genetic variants with AF at GWAS top loci.</p><p><b>METHODS: </b>In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.</p><p><b>RESULTS: </b>One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).</p><p><b>CONCLUSIONS: </b>We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.</p> |
| DOI | 10.1016/j.hrthm.2013.11.012 |
| Alternate Journal | Heart Rhythm |
| PubMed ID | 24239840 |
| PubMed Central ID | PMC3943920 |
| Grant List | N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States R21 DA027021 / DA / NIDA NIH HHS / United States 1R01HL104156 / HL / NHLBI NIH HHS / United States 1RC1HL099452 / HL / NHLBI NIH HHS / United States 5RC2HL102419 / HL / NHLBI NIH HHS / United States 1RC1HL101056 / HL / NHLBI NIH HHS / United States K24 HL105780 / HL / NHLBI NIH HHS / United States U54HG003273 / HG / NHGRI NIH HHS / United States HHSN2682011000010C / / PHS HHS / United States R01 HL104156 / HL / NHLBI NIH HHS / United States R01 HL092577 / HL / NHLBI NIH HHS / United States N01-HC-85081 / HC / NHLBI NIH HHS / United States HHSN268201100005C / / PHS HHS / United States HL105756 / HL / NHLBI NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States HHSN268201100009C / / PHS HHS / United States UL1 TR000161 / TR / NCATS NIH HHS / United States RC1 HL099452 / HL / NHLBI NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States N01-HC-85082 / HC / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States HHSN268201100008C / / PHS HHS / United States 1K24HL105780 / HL / NHLBI NIH HHS / United States N01-HC-85083 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-85080 / HC / NHLBI NIH HHS / United States HHSN2682011000012C / / PHS HHS / United States HHSN268201100007C / / PHS HHS / United States 6R01-NS 17950 / NS / NINDS NIH HHS / United States N01HC-15103 / HC / NHLBI NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States HHSN268201200036C / / PHS HHS / United States HL080295 / HL / NHLBI NIH HHS / United States 1R01HL102214 / HL / NHLBI NIH HHS / United States N01-HC25195 / HC / NHLBI NIH HHS / United States N01-HC-85239 / HC / NHLBI NIH HHS / United States AG-023629 / AG / NIA NIH HHS / United States HHSN268201100006C / / PHS HHS / United States 1R01HL092577 / HL / NHLBI NIH HHS / United States 5R21DA027021 / DA / NIDA NIH HHS / United States HHSN2682011000011C / / PHS HHS / United States |