Quantile-specific heritability of plasma fibrinogen concentrations

Abstract

BackgroundFibrinogen is a moderately heritable blood protein showing different genetic effects by sex, race, smoking status, pollution exposure, and disease status. These interactions may be explained in part by “quantile-dependent expressivity”, where the effect size of a genetic variant depends upon whether the phenotype (e.g. plasma fibrinogen concentration) is high or low relative to its distribution.PurposeDetermine whether fibrinogen heritability (h2) is quantile-specific, and whether quantile-specifich2could account for fibrinogen gene-environment interactions.MethodsPlasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (βOP,h2= 2βOP/(1+rspouse)) and full-sib regression slopes (βFS,h2= {(1+8rspouseβFS)0.05–1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples.ResultsQuantile-specifich2(±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted fibrinogen distribution when estimated from βOP(Ptrend= 5.5x10-6): 0.30±0.05 at the 10th, 0.37±0.04 at the 25th, 0.48±0.05 at the 50th, 0.61±0.06 at the 75th, and 0.65±0.08 at the 90thpercentile, and when estimated from βFS(Ptrend= 0.008): 0.28±0.04 at the 10th, 0.31±0.04 at the 25th, 0.36±0.03 at the 50th, 0.41±0.05 at the 75th, and 0.50±0.06 at the 90thpercentile. The larger genetic effect at higher average fibrinogen concentrations may contribute to fibrinogen’s greater heritability in women than men and in Blacks than Whites, and greater increase from smoking and air pollution for theFGB-455G>A A-allele. It may also explain greater fibrinogen differences between: 1)FGB-455G>A genotypes during acute phase reactions than usual conditions, 2)GTSM1and IL-6-572C>G genotypes in smokers than nonsmokers, 3)FGB-148C>T genotypes in untreated than treated diabetics, andLPL PvuIIgenotypes in macroalbuminuric than normoalbuminuric patients.ConclusionFibrinogen heritability is quantile specific, which may explain or contribute to its gene-environment interactions. The analyses do not disprove the traditional gene-environment interpretations of these examples, rather quantile-dependent expressivity provides an alternative explanation that warrants consideration.