Quantile-specific heritability of plasma fibrinogen concentrations

BACKGROUND: Fibrinogen 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. PURPOSE: Determine whether fibrinogen heritability (h(2)) is quantile-specific, and whether quantile-specific h(2) could account for fibrinogen gene-environment interactions. METHODS: Plasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (β(OP), h(2) = 2β(OP)/(1+r(spouse))) and full-sib regression slopes (β(FS), h(2) = {(1+8r(spouse)β(FS))(0.05)–1}/(2r(spouse))) were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. RESULTS: Quantile-specific h(2) (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted fibrinogen distribution when estimated from β(OP) (P(trend) = 5.5x10(-6)): 0.30±0.05 at the 10(th), 0.37±0.04 at the 25(th), 0.48±0.05 at the 50(th), 0.61±0.06 at the 75(th), and 0.65±0.08 at the 90(th) percentile, and when estimated from β(FS) (P(trend) = 0.008): 0.28±0.04 at the 10(th), 0.31±0.04 at the 25(th), 0.36±0.03 at the 50(th), 0.41±0.05 at the 75(th), and 0.50±0.06 at the 90(th) percentile. 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 the FGB -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) GTSM1 and IL-6 -572C>G genotypes in smokers than nonsmokers, 3) FGB -148C>T genotypes in untreated than treated diabetics, and LPL PvuII genotypes in macroalbuminuric than normoalbuminuric patients. CONCLUSION: Fibrinogen 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.