Document Detail


A genetic instrument for Mendelian randomization of fibrinogen.
MedLine Citation:
PMID:  22388766     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mendelian randomization studies on fibrinogen commonly use a single genetic variant as an instrument, but this may explain only a small proportion of the total phenotypic variance. We examined the contribution of multiple common single nucleotide polymorphisms (SNPs) and haplotypes in the entire fibrinogen gene cluster to plasma fibrinogen levels in two prospective cohorts, for use as instruments in future Mendelian randomization studies. Genotypes for 20 SNPs were determined in 2,778 middle-age (49-64 years) men from the Second-Northwick-Park-Heart Study (NPHS-II). These were replicated in 3,705 men from the Whitehall-II study (WH-II). Plasma fibrinogen levels were determined six times in NPHS-II and three times in WH-II. The minor alleles of four SNPs from the FGB gene, two from the FGA gene, and one from the FGG gene were associated with higher plasma fibrinogen levels. SNP rs1800790 (-455G>A) commonly used in Mendelian randomization studies was associated with R2=1.22% of the covariate adjusted residual variance in fibrinogen level. A variable selection procedure identified one additional SNP: rs2070011 (FGA) altogether explaining R2=1.45% of the residual variance in fibrinogen level. Using these SNPs no evidence for causality between the fibrinogen levels and coronary heart diseases was found in instrumental variables analysis. In the replication cohort, WH-II, the effects of the two SNPs on fibrinogen levels were consistent with the NPHS-II results. There is statistical evidence for several functional sites in the fibrinogen gene cluster that determine an individual's plasma fibrinogen levels. Thus, a combination of several SNPs will provide a stronger instrument for fibrinogen Mendelian randomization studies.
Authors:
Gie Ken-Dror; Steve E Humphries; Meena Kumari; Mika Kivimaki; Fotios Drenos
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Publication Detail:
Type:  Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2012-03-03
Journal Detail:
Title:  European journal of epidemiology     Volume:  27     ISSN:  1573-7284     ISO Abbreviation:  Eur. J. Epidemiol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-06-08     Completed Date:  2012-11-07     Revised Date:  2014-10-19    
Medline Journal Info:
Nlm Unique ID:  8508062     Medline TA:  Eur J Epidemiol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  267-79     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alleles
Coronary Disease / epidemiology,  genetics*
Female
Fibrinogen / genetics*
Follow-Up Studies
Gene Frequency / genetics
Genetic Predisposition to Disease / genetics
Great Britain
Humans
Male
Mendelian Randomization Analysis / methods*
Middle Aged
Multigene Family / genetics
Polymorphism, Single Nucleotide / genetics
Prospective Studies
Survival Analysis
Grant Support
ID/Acronym/Agency:
33014//PHS HHS; AG13196/AG/NIA NIH HHS; G0902037//Medical Research Council; G19/35//Medical Research Council; G8802774//Medical Research Council; HL036310/HL/NHLBI NIH HHS; HL36310/HL/NHLBI NIH HHS; HS06516/HS/AHRQ HHS; PG/07/133/24260//British Heart Foundation; PG2005/014//British Heart Foundation; R01 AG013196/AG/NIA NIH HHS; R01 HL036310/HL/NHLBI NIH HHS; RG/07/008/23674//British Heart Foundation; RG/08/008//British Heart Foundation; RG/08/008/25291//British Heart Foundation; //Department of Health; //Medical Research Council
Chemical
Reg. No./Substance:
9001-32-5/Fibrinogen
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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