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Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study.

ABSTRACT: 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.

SUBMITTER: Malarstig A

PROVIDER: S-EPMC2727417 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study.

Mälarstig Anders A Buil Alfonso A Souto Juan Carolos JC Clarke Robert R Blanco-Vaca Francisco F Fontcuberta Jordi J Peden John J Andersen Malin M Silveira Angela A Barlera Simona S Seedorf Udo U Watkins Hugh H Almasy Laura L Hamsten Anders A Soria José Manuel JM

Blood 20090612 7

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 fami ...[more]

PMID: 19525478

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Project description:BackgroundHuman genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data. In silico tools such as candidate gene prediction systems allow rapid identification of disease genes by identifying the most probable candidate genes linked to genetic markers of the disease or phenotype under investigation. Integration of drug-target data with candidate gene prediction systems can identify novel phenotypes which may benefit from current therapeutics. Such a drug repositioning tool can save valuable time and money spent on preclinical studies and phase I clinical trials.MethodsWe previously used Gentrepid (http://www.gentrepid.org) as a platform to predict 1,497 candidate genes for the seven complex diseases considered in the Wellcome Trust Case-Control Consortium genome-wide association study; namely Type 2 Diabetes, Bipolar Disorder, Crohn's Disease, Hypertension, Type 1 Diabetes, Coronary Artery Disease and Rheumatoid Arthritis. Here, we adopted a simple approach to integrate drug data from three publicly available drug databases: the Therapeutic Target Database, the Pharmacogenomics Knowledgebase and DrugBank; with candidate gene predictions from Gentrepid at the systems level.ResultsUsing the publicly available drug databases as sources of drug-target association data, we identified a total of 428 candidate genes as novel therapeutic targets for the seven phenotypes of interest, and 2,130 drugs feasible for repositioning against the predicted novel targets.ConclusionsBy integrating genetic, bioinformatic and drug data, we have demonstrated that currently available drugs may be repositioned as novel therapeutics for the seven diseases studied here, quickly taking advantage of prior work in pharmaceutics to translate ground-breaking results in genetics to clinical treatments.

Project description:Migraine is associated with an increased risk for cardiovascular disease (CVD). Both migraine and CVD are highly heritable. However, the genetic liability for CVD among migraineurs is unclear.We performed a genome-wide association study for incident CVD events during 12 years of follow-up among 5,122 migraineurs participating in the population-based Women's Genome Health Study. Migraine was self-reported and CVD events were confirmed after medical records review. We calculated odds ratios (OR) and 95% confidence intervals (CI) and considered a genome-wide p-value <5×10(-8) as significant.Among the 5,122 women with migraine 164 incident CVD events occurred during follow-up. No SNP was associated with major CVD, ischemic stroke, myocardial infarction, or CVD death at the genome-wide level; however, five SNPs showed association with p<5×10(-6). Among migraineurs with aura rs7698623 in MEPE (OR?=?6.37; 95% CI 3.15-12.90; p?=?2.7×10(-7)) and rs4975709 in IRX4 (OR?=?5.06; 95% CI 2.66-9.62; p?=?7.7×10(-7)) appeared to be associated with ischemic stroke, rs2143678 located close to MDF1 with major CVD (OR?=?3.05; 95% CI 1.98-4.69; p?=?4.3×10(-7)), and the intergenic rs1406961 with CVD death (OR?=?12.33; 95% CI 4.62-32.87; p?=?5.2×10(-7)). Further, rs1047964 in BACE1 appeared to be associated with CVD death among women with any migraine (OR?=?4.67; 95% CI 2.53-8.62; p?=?8.0×10(-7)).Our results provide some suggestion for an association of five SNPs with CVD events among women with migraine; none of the results was genome-wide significant. Four associations appeared among migraineurs with aura, two of those with ischemic stroke. Although our population is among the largest with migraine and incident CVD information, these results must be treated with caution, given the limited number of CVD events among women with migraine and the low minor allele frequencies for three of the SNPs. Our results await independent replication and should be considered hypothesis generating for future research.

Dataset Information

Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study.

Publications

Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study.

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