期刊
BLOOD
卷 120, 期 24, 页码 4873-4881出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-06-436188
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资金
- Biotechnology and Biological Sciences Research Council Funding Source: Medline
- British Heart Foundation [RG/08/014/24067] Funding Source: Medline
- Intramural NIH HHS Funding Source: Medline
- Medical Research Council [G0700931, MC_U137686857] Funding Source: Medline
- NCATS NIH HHS [UL1 TR000124] Funding Source: Medline
- NCRR NIH HHS [UL1-RR-025005, RR-024156, M01 RR00052, RR018787] Funding Source: Medline
- NHGRI NIH HHS [U01-HG-004402, HHSN268200782096C] Funding Source: Medline
- NHLBI NIH HHS [1U01 HL072518, R01HL071258, R01HL071250, N01-HC-85084, N01-HC-95167, N01-HC-95168, N01-HC-55016, R01 HL095603, R01-HL-087641, N01-HC-95163, N01-HC-95159, N01-HC-95166, N01-HC-55018, N01-HC-95165, HL087652, R01HL071251, N01-HC-55021, R01HL071252, N01-HC-85086, R01HL071205, N01-HC-85239, R01HL071259, N01-HC-85082, R01-HL-59367, HL080295, N01-HC-95161, N01-HC-85079, N01-HC-35129, N01 HC-55222, N01-HC-55019, N01-HC-55015, N01-HC-95169, N01-HC-95164, N01-HC-45133, N01-HC-85083, N01-HC-55020, N01-HC-85080, N01-HC-75150, HL105756, N01-HC-85081, N01-HC-55022, HL65234, R01-HL59367, R01-HL-086694, N01-HC-95162, N01-HC-25195, HL67466, N02-HL-6-4278, R01HL071051, R01 HL59684, HHSN268201200036C, N01-HC-85085, N01-HC-95160, N01 HC-15103, U01 HL072518] Funding Source: Medline
- NIA NIH HHS [N01AG62106, N01AG62103, AG-027058, AG-20098, N01AG62101, AG-023629, AG-15928, 1R01AG032098-01A1] Funding Source: Medline
- NIDDK NIH HHS [K24 DK080140, DK063491] Funding Source: Medline
- NIGMS NIH HHS [P20 GM103534, T32 GM080178] Funding Source: Medline
- NLM NIH HHS [LM010098, R01 LM010098] Funding Source: Medline
- PHS HHS [HHSN268200625226C] Funding Source: Medline
- Wellcome Trust [090532] Funding Source: Medline
- Department of Health Funding Source: Medline
- MRC [G0700931, MC_U137686857] Funding Source: UKRI
- British Heart Foundation [RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [MC_U137686857, G0700931, G0801056B] Funding Source: researchfish
We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 x 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. (Blood. 2012;120(24):4873-4881)
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