Quantile-Specific Heritability of Inflammatory and Oxidative Stress Biomarkers Linked to Cardiovascular Disease

PURPOSE: Heritability (h(2), the proportion of the phenotypic variance attributable to additive genetic effects) is traditionally assumed to be constant throughout the distribution of the phenotype. However, the heritabilities of circulating C-reactive protein, interleukin-6, plasminogen activator inhibitor type-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) concentrations depend upon whether the phenotype is high or low relative to their distributions (quantile-dependent expressivity), which may account for apparent gene–environment interactions. Whether the heritabilities of other inflammatory biomarkers linked to cardiovascular disease are quantile-dependent remain to be determined. PATIENTS AND METHODS: Quantile-specific offspring-parent (β(OP)) and full-sib regression slopes (β(FS)) were estimated by applying quantile regression to the age- and sex-adjusted phenotypes of families surveyed as part of the Framingham Heart Study. Quantile-specific heritabilities were calculated as: h(2)=2β(OP)/(1+r(spouse)) and h(2)={(1+8r(spouse)β(FS))(0.5)–1}/(2r(spouse)). RESULTS: Heritability (h(2) ± SE) of lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass concentrations increased from 0.11 ± 0.03 at the 10(th) percentile, 0.08 ± 0.03 at the 25(th), 0.12 ± 0.03 at the 50(th), 0.20 ± 0.04 at the 75(th), and 0.26 ± 0.06 at the 90(th) percentile, or 0.0023 ± 0.0006 per each one-percent increase in the phenotype distribution (P(linear trend)= 0.0004). Similarly, h(2) increased 0.0029 ± 0.0011 (P(linear trend)= 0.01) for sP-selectin, 0.0032 ± 0.0009 (P(linear trend)= 0.0001) for soluble intercellular adhesion molecule 1 (sICAM-1), and 0.0026 ± 0.0006 for tumor necrosis factor receptor 2 (TNFR2) (P(linear trend)= 5.0 × 10(−6)) per each one-percent increase in their distributions when estimated from β(OP). Osteoprotegerin and soluble ST2 heritability also increased significantly with increasing percentiles of their distributions when estimated from β(FS). Lp-PLA(2) activity, CD40 ligand, TNFα, interleukin-18, and myeloperoxidase heritability showed no significant quantile-dependence. CONCLUSION: The heritabilities of circulating Lp-PLA(2)-mass, sP-selectin, sICAM-1, TNFR2, osteoprotegerin and soluble ST2 concentrations are quantile-dependent, which may contribute to purported genetic modulations of: 1) sP-selectin’s relationships to venous thrombosis, pulmonary hypertension, type 2 diabetes and atorvastatin treatment; 2) sICAM-I’s relationships to brain abscess and atorvastatin treatment; and 3) Lp-PLA(2)’s relationships to myocardial infarction and preeclampsia.