Quantile-specific heritability of monocyte chemoattractant protein-1, and relevance to rs1024611-disease interactions

Monocyte chemoattractant protein-1 (MCP-1) concentrations are 34% to 47% heritable. Larger -2518 G/A (rs1024611) genotypes differences are reported for: 1) MCP-1 production in stimulated vs. basal cells; and 2) MCP-1 concentrations in diseased (sepsis, brain abscess, hepatitis B virus, Alzheimer's disease, Behcet's disease, and systemic lupus erythematosus) vs. healthy patients. Those results suggest that the -2518 G/A effect size may depend on whether the phenotype is high or low relative to its distribution (quantile-dependent expressivity).

To test whether quantile-dependent expressivity applies more broadly to genetic influences on MCP-1 concentrations, 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 serum MCP-1 concentrations of Framingham Heart Study families. Quantile-specific heritabilities were calculated as h² = 2β_OP/(1 + r_spouse) and h²={(1 + 8r_spouseβ_FS)^0.5-1}/(2r_spouse)).

Heritability (h² ± SE) of MCP-1 concentrations increased from 0.15 ± 0.05 at the 10th percentile of the MCP-1 distribution, 0.23 ± 0.04 at the 25th, 0.32 ± 0.05 at the 50th, 0.43 ± 0.07 at the 75th, and 0.44 ± 0.07 at the 90th percentile, or an 0.0041 ± 0.0009 increase for each one-percent increment in the MCP-1 distribution (P_{linear trend} = 2.4 × 10^-5) when estimated from β_OP, and (P_{linear trend} = 7.7 × 10^-9) when estimated from β_FS. Compared to the 10th percentile, β_OP-estimated h² was 3-fold greater at the 90th percentile (P_difference = 0.0003), and 6.9-fold greater when estimated from β_FS (P_difference = 3.3 × 10^-6). Re-analysis of in vivo comparison of MCP-1 concentrations in controls vs. patients with MCP-1-elevating conditions, and in vitro studies of MCP-1 production in basal vs. stimulated cells, show rs1024611 genotypes differences that were consistent with quantile-dependent expressivity.

The heritability of circulating MCP-1 concentrations is quantile-dependent.