@article {1153, title = {Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.}, journal = {Circ Cardiovasc Genet}, volume = {2}, year = {2009}, month = {2009 Apr}, pages = {125-33}, abstract = {

BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).

CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.108.825224}, author = {Dehghan, Abbas and Yang, Qiong and Peters, Annette and Basu, Saonli and Bis, Joshua C and Rudnicka, Alicja R and Kavousi, Maryam and Chen, Ming-Huei and Baumert, Jens and Lowe, Gordon D O and McKnight, Barbara and Tang, Weihong and de Maat, Moniek and Larson, Martin G and Eyhermendy, Susana and McArdle, Wendy L and Lumley, Thomas and Pankow, James S and Hofman, Albert and Massaro, Joseph M and Rivadeneira, Fernando and Kolz, Melanie and Taylor, Kent D and van Duijn, Cornelia M and Kathiresan, Sekar and Illig, Thomas and Aulchenko, Yurii S and Volcik, Kelly A and Johnson, Andrew D and Uitterlinden, Andr{\'e} G and Tofler, Geoffrey H and Gieger, Christian and Psaty, Bruce M and Couper, David J and Boerwinkle, Eric and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C and Strachan, David P and Smith, Nicholas L and Folsom, Aaron R} } @article {1284, title = {Genetic predictors of fibrin D-dimer levels in healthy adults.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 May 03}, pages = {1864-72}, abstract = {

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log{\textendash}transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4{\texttimes}10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4{\texttimes}10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9{\texttimes}10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log{\textendash}transformed D-dimer and together accounted for 1.8\% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

}, keywords = {Adult, Aged, Blood Coagulation, European Continental Ancestry Group, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Testing, Genome-Wide Association Study, Humans, Male, Middle Aged, Reference Values, Thromboplastin}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.009480}, author = {Smith, Nicholas L and Huffman, Jennifer E and Strachan, David P and Huang, Jie and Dehghan, Abbas and Trompet, Stella and Lopez, Lorna M and Shin, So-Youn and Baumert, Jens and Vitart, Veronique and Bis, Joshua C and Wild, Sarah H and Rumley, Ann and Yang, Qiong and Uitterlinden, Andr{\'e} G and Stott, David J and Davies, Gail and Carter, Angela M and Thorand, Barbara and Polasek, Ozren and McKnight, Barbara and Campbell, Harry and Rudnicka, Alicja R and Chen, Ming-Huei and Buckley, Brendan M and Harris, Sarah E and Peters, Annette and Pulanic, Drazen and Lumley, Thomas and de Craen, Anton J M and Liewald, David C and Gieger, Christian and Campbell, Susan and Ford, Ian and Gow, Alan J and Luciano, Michelle and Porteous, David J and Guo, Xiuqing and Sattar, Naveed and Tenesa, Albert and Cushman, Mary and Slagboom, P Eline and Visscher, Peter M and Spector, Tim D and Illig, Thomas and Rudan, Igor and Bovill, Edwin G and Wright, Alan F and McArdle, Wendy L and Tofler, Geoffrey and Hofman, Albert and Westendorp, Rudi G J and Starr, John M and Grant, Peter J and Karakas, Mahir and Hastie, Nicholas D and Psaty, Bruce M and Wilson, James F and Lowe, Gordon D O and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C M and Jukema, J Wouter and Deary, Ian J and Soranzo, Nicole and Koenig, Wolfgang and Hayward, Caroline} }