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Genet Epidemiol. 2017 Jul;41(5):455-466. doi: 10.1002/gepi.22049. Epub 2017 Apr 18.

Leveraging cell type specific regulatory regions to detect SNPs associated with tissue factor pathway inhibitor plasma levels.

Author information

1
Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
2
Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Canada.
3
Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México.
4
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
5
Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
6
Ottawa Hospital Research Institute, Ottawa, Canada.
7
Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
8
INSERM, UMR_S 1166, Paris, France.
9
ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
10
INSERM, UMR_S 1062, Marseille, France.
11
Inra, UMR_INRA 1260, Marseille, France.
12
Aix Marseille Université, Marseille, France.
13
Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Canada.

Abstract

Tissue factor pathway inhibitor (TFPI) regulates the formation of intravascular blood clots, which manifest clinically as ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). TFPI plasma levels are heritable, but the genetics underlying TFPI plasma level variability are poorly understood. Herein we report the first genome-wide association scan (GWAS) of TFPI plasma levels, conducted in 251 individuals from five extended French-Canadian Families ascertained on VTE. To improve discovery, we also applied a hypothesis-driven (HD) GWAS approach that prioritized single nucleotide polymorphisms (SNPs) in (1) hemostasis pathway genes, and (2) vascular endothelial cell (EC) regulatory regions, which are among the highest expressers of TFPI. Our GWAS identified 131 SNPs with suggestive evidence of association (P-value < 5 × 10-8 ), but no SNPs reached the genome-wide threshold for statistical significance. Hemostasis pathway genes were not enriched for TFPI plasma level associated SNPs (global hypothesis test P-value = 0.147), but EC regulatory regions contained more TFPI plasma level associated SNPs than expected by chance (global hypothesis test P-value = 0.046). We therefore stratified our genome-wide SNPs, prioritizing those in EC regulatory regions via stratified false discovery rate (sFDR) control, and reranked the SNPs by q-value. The minimum q-value was 0.27, and the top-ranked SNPs did not show association evidence in the MARTHA replication sample of 1,033 unrelated VTE cases. Although this study did not result in new loci for TFPI, our work lays out a strategy to utilize epigenomic data in prioritization schemes for future GWAS studies.

KEYWORDS:

epigenetics; genetic association studies; multiple hypothesis testing; thrombosis; tissue factor pathway inhibitor

PMID:
28421636
DOI:
10.1002/gepi.22049
[Indexed for MEDLINE]

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