Genetic Associations for Activated Partial Thromboplastin Time and Prothrombin Time, their Gene Expression Profiles, and Risk of Coronary Artery Disease

Abstract

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulationfactor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p ¼ 4.26 3 10 À24 ). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p ¼ 3.22 3 10 À9 ) and AGBL1 (rs2469184, p ¼ 3.61 3 10 À8 ). For PT, significant associations were identified and confirmed in F7 (rs561241, p ¼ 3.71 3 10 À56 ) and PROCR/EDEM2 (rs2295888, p ¼ 5.25 3 10 À13 ). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for~29% of the variance in aPTT and two loci that account for~14% of the variance in PT were detected and supported by functional data.

Influence of ABO type on global coagulation assay results: effect of coagulation factor VIII

“…These results suggest that the prolonged aPTT in those with type O is partly due to low FVIII levels. A genome-wide association study showed that aPTT is significantly associated with KNG1 , HRG , F11 , F12 , and ABO genes [27] . Although ABO type cannot account for all inter-individual variations in aPTT, some of the variations in aPTT can be explained by the ABO type.…”

Identification ofITGA2BandITGB3Single-Nucleotide Polymorphisms and Their Influences on the Platelet Function

“…In the other research, the GWAS for APTT and PT was conducted and replicated genome-wide significant associations at KNG1, HRG, F11, F12, and ABO for APTT and identified significant associations at the F7 and PROCR/EDEM2 regions for PT. Eight genetic loci accounted for ~29% of the variance in APTT, and two loci accounted for ~14% of the variance in PT [27]. In this study, the association of APTT, PT, FIB, and TT with ITGA2B and ITGB3 SNPs was investigated.…”

Quantitative Variation in Plasma Angiotensin‐I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus

“…The likely principal mechanism is a differential susceptibility to thrombosis: people of blood group O have 25% lower plasma levels of von Willebrand factor and Factor VIII, both members of the blood coagulation cascade, and SNPs defining group O are associated with less coagulable blood on standard laboratory coagulation tests. (Tang et al, 2012) Congruent with this observation, ABO genotypes are the strongest risk factor genome-wide for venous thromboembolism (Qi et al, 2010). Nevertheless, other potential mechanisms whereby the pleiotropic ABO locus could contribute to MI risk have been identified through GWAS approaches.…”