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

PURPOSE

Heritability ( , 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) and full-sib regression slopes (β) 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: =2β/(1+r) and ={(1+8rβ)-1}/(2r).

RESULTS

Heritability ( ± SE) of lipoprotein-associated phospholipase A2 (Lp-PLA) mass concentrations increased from 0.11 ± 0.03 at the 10 percentile, 0.08 ± 0.03 at the 25, 0.12 ± 0.03 at the 50, 0.20 ± 0.04 at the 75, and 0.26 ± 0.06 at the 90 percentile, or 0.0023 ± 0.0006 per each one-percent increase in the phenotype distribution (P= 0.0004). Similarly, increased 0.0029 ± 0.0011 (P= 0.01) for sP-selectin, 0.0032 ± 0.0009 (P= 0.0001) for soluble intercellular adhesion molecule 1 (sICAM-1), and 0.0026 ± 0.0006 for tumor necrosis factor receptor 2 (TNFR2) (P= 5.0 × 10) per each one-percent increase in their distributions when estimated from β. Osteoprotegerin and soluble ST2 heritability also increased significantly with increasing percentiles of their distributions when estimated from β. Lp-PLA activity, CD40 ligand, TNFα, interleukin-18, and myeloperoxidase heritability showed no significant quantile-dependence.

CONCLUSION

The heritabilities of circulating Lp-PLA-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's relationships to myocardial infarction and preeclampsia.