Dataset Information

Genetic predictors of fibrin D-dimer levels in healthy adults.

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–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=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-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–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.

SUBMITTER: Smith NL

PROVIDER: S-EPMC3095913 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

Genetic predictors of fibrin D-dimer levels in healthy adults.

Smith Nicholas L NL Huffman Jennifer E JE Strachan David P DP Huang Jie J Dehghan Abbas A Trompet Stella S Lopez Lorna M LM Shin So-Youn SY Baumert Jens J Vitart Veronique V Bis Joshua C JC Wild Sarah H SH Rumley Ann A Yang Qiong Q Uitterlinden Andre G AG Stott David J DJ Davies Gail G Carter Angela M AM Thorand Barbara B Polašek Ozren O McKnight Barbara B Campbell Harry H Rudnicka Alicja R AR Chen Ming-Huei MH Buckley Brendan M BM Harris Sarah E SE Peters Annette A Pulanic Drazen D Lumley Thomas T de Craen Anton J M AJ Liewald David C DC Gieger Christian C Campbell Susan S Ford Ian I Gow Alan J AJ Luciano Michelle M Porteous David J DJ Guo Xiuqing X Sattar Naveed N Tenesa Albert A Cushman Mary M Slagboom P Eline PE Visscher Peter M PM Spector Tim D TD Illig Thomas T Rudan Igor I Bovill Edwin G EG Wright Alan F AF McArdle Wendy L WL Tofler Geoffrey G Hofman Albert A Westendorp Rudi G J RG Starr John M JM Grant Peter J PJ Karakas Mahir M Hastie Nicholas D ND Psaty Bruce M BM Wilson James F JF Lowe Gordon D O GD O'Donnell Christopher J CJ Witteman Jacqueline C M JC Jukema J Wouter JW Deary Ian J IJ Soranzo Nicole N Koenig Wolfgang W Hayward Caroline C

Circulation 20110418 17

<h4>Background</h4>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.<h4>Methods and results</h4>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-dime ...[more]

PMID: 21502573

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Project description:Bullous pemphigoid (BP), the most frequent blistering dermatosis in the elderly, is associated with increased mortality. The severity of BP can be assessed by detecting the anti-BP180 immunoglobulin G (IgG) concentration, but the lab test is not available in many community clinics. BP patients are usually in a hypercoagulable state with increased levels of D-dimer and fibrin degradation products (FDPs). We aimed to evaluate the use of D-dimer and FDPs in assessing BP severity. We compared the levels of plasma D-dimer, plasma FDPs, eosinophil counts, eosinophil cationic protein, and serum anti-BP180 IgG concentration between 48 typical BP patients and 33 Herpes zoster (HZ) patients (control group). Correlational analyses were conducted to determine the relationships between the lab values and common BP severity markers. The plasma D-dimer and FDP levels were higher in BP patients than in HZ controls (D-dimer: 3297 ± 2517 µg/L vs. 569.70 ± 412.40 µg/L; FDP: 9.74 ± 5.88 mg/L vs. 2.02 ± 1.69 mg/L, respectively, P < 0.0001). Significant positive correlations were found between D-dimer/FDP levels and BP severity markers (i.e. anti-BP180 IgG concentration [D-dimer: r = 0.3928, P = 0.0058; FDP: r = 0.4379, P = 0.0019] and eosinophil counts [D-dimer: r = 0.3625, P = 0.0013; FDP: r = 0.2880, P = 0.0472]) in BP patients. We also found an association between FDP and urticaria/erythema lesions (r = 0.3016, P = 0.0372), but no other BPDAI components. In 19 BP patients with complete remission after systemic glucocorticoid treatment, D-dimer and FDP levels decreased post-therapy (D-dimer: 5559 ± 7492 µg/L vs. 1738 ± 1478 µg/L; P < 0.0001; FDP: 11.20 ± 5.88 mg/L vs. 5.13 ± 3.44 mg/L; P = 0.0003), whereas they did not in BP patients with treatment resistant. Plasma D-dimer and FDP are convenient markers to evaluate BP severity assistant on BPDAI and eosinophil counts. FDP is also helpful for inflammatory lesions in BP patients.

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Dataset Information

Genetic predictors of fibrin D-dimer levels in healthy adults.

Background

Methods and results

Conclusions

Publications

Genetic predictors of fibrin D-dimer levels in healthy adults.

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