Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study
Por:
Malarstig, A, Buil, A, Souto, JC, Clarke, R, Blanco-Vaca, F, Fontcuberta, J, Peden, J, Andersen, M, Silveira, A, Barlera, S, Seedorf, U, Watkins, H, Almasy, L, Hamsten, A, Soria, JM
Publicada:
13 ago 2009
Resumen:
Total plasma homocysteine concentration (tHcy) is a biomarker for atherothrombotic disease, but causality remains uncertain. Polymorphisms in the genes involved in methionine metabolism explain only a small fraction of the heritability of tHcy levels. In a genome-wide association study, we examined the genetic determinants of tHcy using a 2-stage design. First, 283 437 single nucleotide polymorphisms (SNPs) were tested for association with tHcy in 387 persons recruited from 21 large Spanish families. Of those, 17 SNPs showed equal or stronger association with tHcy level compared with the MTHFR 677C > T SNP (beta = 0.10, P = .0001). Second, a replication analysis of these 17 SNPs was performed in patients with premature myocardial infarction (n = 1238). Novel associations were found for SNPs near the ZNF366 gene (lead SNP rs7445013; discovery stage: adjusted beta = -0.12, P = 5.30 x 10(-6), replication stage: adjusted beta = -0.13, P = .004) and the PTPRD gene (lead SNP rs973117; discovery stage: adjusted beta = 0.11, P = 5.5 x 10(-6), replication stage: adjusted beta = 0.10, P = .005). These associations were independent of known confounders, including creatinine clearance and plasma fibrinogen concentration. Our findings implicate novel pathways in homocysteine metabolism, and highlight the need for investigation of the associated genes in the etiology of vascular diseases. (Blood.2009;114:1417-1422)
Filiaciones:
Malarstig, A:
Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden
Buil, A:
Res Inst, Unit Genom Complex Dis, Barcelona, Spain
Souto, JC:
Hosp Santa Creu & Sant Pau, Dept Hematol, Barcelona, Spain
Clarke, R:
Univ Oxford, Clin Trials Serv, Oxford, England
Univ Oxford, Epidemiol Studies Unit CTSU, Oxford, England
Blanco-Vaca, F:
Hosp Santa Creu & Sant Pau, Dept Biochem, Barcelona, Spain
Fontcuberta, J:
Hosp Santa Creu & Sant Pau, Dept Hematol, Barcelona, Spain
Peden, J:
Univ Oxford, Dept Cardiovasc Med, Oxford, England
Andersen, M:
Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden
Silveira, A:
Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden
Barlera, S:
Mario Negri Inst Pharmacol Res, Dept Cardiovasc Res, I-20157 Milan, Italy
Seedorf, U:
Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany
Watkins, H:
Hosp Santa Creu & Sant Pau, Dept Biochem, Barcelona, Spain
Almasy, L:
SW Fdn Biomed Res, Dept Populat Genet, San Antonio, TX 78284 USA
Hamsten, A:
Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden
Soria, JM:
Res Inst, Unit Genom Complex Dis, Barcelona, Spain
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