Background: Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are commonly used to screen for coagulation factor deficiencies. Shorter aPTT is also a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT and PT are not well understood. So far only one genome-wide association study (GWAS) has been reported for aPTT in 1,477 participants and none for PT. Methods: We conducted a GWAS for the aPTT in 9,240 European Americans (EAs) from the Atherosclerosis Risk in Communities (ARIC) study and for PT in 1,221 EAs from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS). Replication was assessed by in silico analysis in MICROS (aPTT, n=1,215) and the Lothian Birth Cohorts (LBC) (LBC1936 (aPTT and PT, n=925-989), LBC1921 (aPTT, n=445)), and by de novo genotyping in the Caerphilly study (aPTT, n=882). Subjects on anticoagulants were excluded. Genotyping was conducted with the Affymetrix single nucleotide polymorphism (SNP) array 6.0 or Illumina HumanHap300/370 and imputed to 2.5 million HapMap SNPs. SNPs with imputation quality score < 0.3 or minor allele frequencies 1% were excluded from data analysis. The imputed SNP dosages were analyzed in linear regression adjusted for age, sex, and field center, where applicable. Results: Five loci were associated with aPTT at genome-wide significance of p<5x10-8 that have not been previously reported: F5 (1q23, top SNP rs9332701, missense, β (effect size associated with one copy increase in minor allele)=0.54, p=3.7x10-8), F11 (4q35, rs1593, intronic, β =0.54 and 0.36, p=1.25x10-17 and 2.0x10-8 before and after adjusting for known variants in F11), NSD1 (5q35.2-q35.3, rs11950938, intronic, β =1.00 and 1.21, p=1.11x10-15 and 1.5x10-22 before and after adjusting for known variants in F12 of the same region), C6orf10 (6p21.3, rs2050190, intronic, β =-0.25, p=1.3x10-8), and ABO (9q34.1-q34.2, rs8176704, intronic, tag for A2 group, β =0.19 and 0.89, p=0.02 and 4.3x10-24 before and after adjusting for O blood group). Three of the five loci replicated in at least one replication sample and the other two were directionally consistent in 3 replication samples. Furthermore, meta-analysis pooling the discovery and replication GWAS samples yielded two additional independent loci at chromosomes 1q23 (F5, best SNP rs6028, coding-synonymous, β =0.23, p=5.97x10-9) and 15q25.3 (AGBL1, rs2469184, intronic, β =0.16, p= 4.24x10-8), with consistent associations across studies. The signals at the F5 region were not due to FV Leiden (rs6025, p=0.46 in ARIC). We also confirmed previously reported loci in KNG1, HRG, F11, F12, and ABO (O group). For PT, novel associations from two gene regions reached genome-wide significance in MICROS: F7 (top SNP rs3093253, within an exon but not translated, β =-5.44, p=8.2x10-19) and PROCR (rs6060244, near PROCR, β =4.11, p=3.5x10-9). Both loci replicated in LBC1936. Conclusions: In this large GWAS, six of the nine novel loci associated with the aPTT and PT are coagulation-related and the other three (NSD1, C6orf10, and AGBL1) are new candidate genes not directly involved in coagulation. The C6orf10 gene interacts with TNF-a at the transcription level and was previously associated with inflammatory diseases. These findings may be relevant to the prevention and treatment of coagulation disorders including VTE.
GENOME-WIDE ASSOCIATION STUDY IDENTIFIES MULTIPLE GENETIC LOCI FOR ACTIVATED PARTIAL THROMBOPLASTIN TIME AND PROTHROMBIN TIME
SCHWIENBACHER, Christine;
2010
Abstract
Background: Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are commonly used to screen for coagulation factor deficiencies. Shorter aPTT is also a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT and PT are not well understood. So far only one genome-wide association study (GWAS) has been reported for aPTT in 1,477 participants and none for PT. Methods: We conducted a GWAS for the aPTT in 9,240 European Americans (EAs) from the Atherosclerosis Risk in Communities (ARIC) study and for PT in 1,221 EAs from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS). Replication was assessed by in silico analysis in MICROS (aPTT, n=1,215) and the Lothian Birth Cohorts (LBC) (LBC1936 (aPTT and PT, n=925-989), LBC1921 (aPTT, n=445)), and by de novo genotyping in the Caerphilly study (aPTT, n=882). Subjects on anticoagulants were excluded. Genotyping was conducted with the Affymetrix single nucleotide polymorphism (SNP) array 6.0 or Illumina HumanHap300/370 and imputed to 2.5 million HapMap SNPs. SNPs with imputation quality score < 0.3 or minor allele frequencies 1% were excluded from data analysis. The imputed SNP dosages were analyzed in linear regression adjusted for age, sex, and field center, where applicable. Results: Five loci were associated with aPTT at genome-wide significance of p<5x10-8 that have not been previously reported: F5 (1q23, top SNP rs9332701, missense, β (effect size associated with one copy increase in minor allele)=0.54, p=3.7x10-8), F11 (4q35, rs1593, intronic, β =0.54 and 0.36, p=1.25x10-17 and 2.0x10-8 before and after adjusting for known variants in F11), NSD1 (5q35.2-q35.3, rs11950938, intronic, β =1.00 and 1.21, p=1.11x10-15 and 1.5x10-22 before and after adjusting for known variants in F12 of the same region), C6orf10 (6p21.3, rs2050190, intronic, β =-0.25, p=1.3x10-8), and ABO (9q34.1-q34.2, rs8176704, intronic, tag for A2 group, β =0.19 and 0.89, p=0.02 and 4.3x10-24 before and after adjusting for O blood group). Three of the five loci replicated in at least one replication sample and the other two were directionally consistent in 3 replication samples. Furthermore, meta-analysis pooling the discovery and replication GWAS samples yielded two additional independent loci at chromosomes 1q23 (F5, best SNP rs6028, coding-synonymous, β =0.23, p=5.97x10-9) and 15q25.3 (AGBL1, rs2469184, intronic, β =0.16, p= 4.24x10-8), with consistent associations across studies. The signals at the F5 region were not due to FV Leiden (rs6025, p=0.46 in ARIC). We also confirmed previously reported loci in KNG1, HRG, F11, F12, and ABO (O group). For PT, novel associations from two gene regions reached genome-wide significance in MICROS: F7 (top SNP rs3093253, within an exon but not translated, β =-5.44, p=8.2x10-19) and PROCR (rs6060244, near PROCR, β =4.11, p=3.5x10-9). Both loci replicated in LBC1936. Conclusions: In this large GWAS, six of the nine novel loci associated with the aPTT and PT are coagulation-related and the other three (NSD1, C6orf10, and AGBL1) are new candidate genes not directly involved in coagulation. The C6orf10 gene interacts with TNF-a at the transcription level and was previously associated with inflammatory diseases. These findings may be relevant to the prevention and treatment of coagulation disorders including VTE.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
