Abstract

BACKGROUND: "Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., C-reactive protein, CRP) is high or low relative to its distribution. We have previously shown that the heritabilities (<i>h</i> ²) of coffee and alcohol consumption, postprandial lipemia, lipoproteins, leptin, adiponectin, adiposity, and pulmonary function are quantile-specific. Whether CRP heritability is quantile-specific is currently unknown. METHODS: Serum CRP concentrations from 2,036 sibships and 6,144 offspring-parent pairs were analyzed from the Framingham Heart Study. Quantile-specific heritability from full-sib (β_FS, <i>h</i> ² ={(1 + 8r_spouseβ_FS)^0.5 - 1}/(2r_spouse)) and offspring-parent regression slopes (β_OP, <i>h</i> ² = 2β_OP/(1 + r_spouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples. RESULTS: Quantile-specific <i>h</i> ² (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted CRP distribution when estimated from β_OP (<i>P</i> _trend = 0.0004): 0.02 ± 0.01 at the 10th, 0.04 ± 0.01 at the 25th, 0.10 ± 0.02 at the 50th, 0.20 ± 0.05 at the 75th, and 0.33 ± 0.10 at the 90th percentile, and when estimated from β_FS (<i>P</i> _trend = 0.0008): 0.03±0.01 at the 10th, 0.06 ± 0.02 at the 25th, 0.14 ± 0.03 at the 50th, 0.24 ± 0.05 at the 75th, and 0.53 ± 0.21 at the 90th percentile. CONCLUSION: Heritability of serum CRP concentration is quantile-specific, which may explain or contribute to the inflated CRP differences between <i>CRP</i> (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), <i>FGB</i> (rs1800787), <i>IL-6</i> (rs1800795, rs1800796), <i>IL6R</i> (rs8192284), <i>TNF-</i>α (rs1800629) and <i>APOE</i> genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or <i>Staphylococcus aureus</i> bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.