Quantile-Dependent Expressivity of Serum Interleukin-6 Concentrations as a Possible Explanation of Gene-Disease Interactions, Gene-Environment Interactions, and Pharmacogenetic Effects.

Interleukin 6 (IL-6) is a moderately heritable pleiotropic cytokine whose elevated concentrations in coronary artery disease, peripheral arterial disease, pulmonary arterial hypertension, Eales' disease, Sjògren's syndrome, osteoarthritis, adenocarcinoma, neuroblastoma, polymyalgia rheumatica, pulmonary tuberculosis, and enterovirus 71 infection, and following coronary artery bypass graft show larger genetic effects than in unaffected low IL-6 controls. We hypothesize that genetic effects may depend upon whether average IL-6 concentrations are high or low, i.e., quantile-dependent expressivity. Quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted serum IL-6 concentrations in families surveyed in the Framingham Heart Study. Quantile-specific heritabilities were calculated as h2 = 2βOP / (1 + rspouse) and h2 = {(1 + 8rspouseβFS)0.5 -1} / (2rspouse)). Heritability (h2 ± SE) of IL-6 concentrations increased from 0.01 ± 0.01 at the 10th percentile (NS), 0.02 ± 0.01 at the 25th (P = 0.009), 0.03 ± 0.01 at the 50th (P = 0.007), 0.04 ± 0.02 at the 75th (P = 0.004), and 0.13 ± 0.05 at the 90th percentile (P = 0.03), or 0.0005 ± 0.0002 for each 1% increase in the offspring's phenotype distribution (Plinear trend = 0.02) when estimated from βOP and from 0.02 ± 0.02 at the 10th (NS), 0.02 ± 0.02 at the 25th (NS), 0.06 ± 0.02 at the 50th (P = 0.01), 0.12 ± 0.04 at the 75th (P = 0.001), and 0.30 ± 0.03 at the 90th percentile (P < 10-16), or 0.0015 ± 0.0007 for each 1% increase in the sibling phenotype distribution (Plinear trend = 0.02) when estimated from βFS. Thus the heritability of serum IL-6 concentrations is quantile dependent, which may contribute in part to the larger genetic effect size reported for diseases and environmental conditions that elevate IL-6 concentrations vis-à-vis unaffected controls.