Quantile-dependent expressivity of serum C-reactive protein concentrations in family sets

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 (h2) 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 (βFS, h2 ={(1 + 8rspouseβFS)0.5 − 1}/(2rspouse)) and offspring-parent regression slopes (βOP, h2 = 2βOP/(1 + rspouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples. Results Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted CRP distribution when estimated from βOP (Ptrend = 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 βFS (Ptrend = 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 CRP (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), FGB (rs1800787), IL-6 (rs1800795, rs1800796), IL6R (rs8192284), TNF-α (rs1800629) and APOE genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or Staphylococcus aureus bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.

Quantile-Dependent Expressivity of Serum Uric Acid Concentrations

“…The primary hypothesis is whether the urate heritability is quantile-dependent. The statistical methods employed have been described in detail [14][15][16][17][18][19][20][21][22][23][24][25][26]. Briefly, age and sex adjustment was performed using standard least-squares regression within each cohort separately with sex, age, age 2 , sex × age, and sex × age 2 as independent variables.…”

“…“Quantile-dependent expressivity” hypothesizes that the effects of genetic variants on phenotypes may depend on whether the phenotype (e.g., uric acid concentration) is high or low relative to its distribution [ 13 ]. The heritability of adiposity [ 13 , 14 ]; plasma concentrations of triglyceride [ 13 , 15 ], total cholesterol [ 16 ], high-density lipoproteins [ 13 , 17 , 18 ], leptin [ 19 ], adiponectin [ 20 ], plasminogen activator inhibitor type-1 [ 21 ], and C-reactive protein concentrations [ 22 ]; postprandial lipemia [ 23 ]; pulmonary function [ 24 ]; and intakes of alcohol [ 25 ] and coffee [ 26 ] are quantile-dependent, whereas height and the intakes of other macronutrients are not [ 13 , 14 , 25 ]. An important consequence of quantile-dependent expressivity is that the selection of subjects by characteristics that distinguish high vs. low phenotype values is expected to produce different genetic effects [ 18 ].…”

“…Traditionally, these have been interpreted as gene-environment interactions where environmental conditions modify genetic influences or where genotypes modify the susceptibility of the phenotype to the environment [ 18 ]. However, many reported gene-drug, gene-diet, and gene-environment interactions have been shown to be potentially attributable wholly or in part to quantile-dependent expressivity for adiposity (56 examples of interactions [ 14 ]), postprandial lipemia (64 examples [ 23 ]), serum triglycerides (76 examples [ 15 ]), total cholesterol (22 examples [ 16 ]), high-density lipoprotein cholesterol (88 examples [ 17 , 18 ]), adiponectin (15 examples [ 20 ]), leptin (16 examples [ 19 ]), plasminogen activator inhibitor type-1 (21 examples [ 21 ]), and C-reactive protein concentrations (50 examples [ 22 ]).…”

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

“…The statistical analyses have been described elsewhere, [12][13][14][15][16][17][18][19][20][21][22][23][24][25] and summarized briefly here. Individual subject values are the average of the age-and sex-adjusted concentrations over all available exams.…”

“…12,22,23 One potential consequence of quantile-dependent expressivity is that sampling by characteristics that distinguish high-vs low-valued phenotypes may produce genetic differences traditionally ascribed to geneenvironment, gene-drug and gene-diet interactions when a simpler explanation of quantile-dependence might suffice. 15 We have previously demonstrated quantile-dependent expressivity for C-reactive protein, 25 a nonspecific acutephase reactant, 26 and interleukin-6, 27 a primary stimulator for the production of most acute-phase proteins. 28 Specifically, their heritabilities increased significantly with their increasing serum concentrations, such that larger genetic effects at higher vis-à-vis lower concentrations might contribute to published examples of their genedrug, gene-diet, and gene-environment interactions.…”