Dataset Information

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 (h 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, h ² ={(1 + 8r_spouseβ_FS)^0.5 - 1}/(2r_spouse)) and offspring-parent regression slopes (β_OP, h ² = 2β_OP/(1 + r_spouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples.

Results

Quantile-specific h ² (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted CRP distribution when estimated from β_OP (P _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 (P _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 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.

SUBMITTER: Williams PT

PROVIDER: S-EPMC7894107 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:PURPOSE:"Quantile-dependent expressivity" describes an effect of the genotype that depends upon the level of the phenotype (e.g., whether a subject's triglycerides are high or low relative to its population distribution). Prior analyses suggest that the effect of a genetic risk score (GRS) on fasting plasma triglyceride levels increases with the percentile of the triglyceride distribution. Postprandial lipemia is well suited for testing quantile-dependent expressivity because it exposes each individual's genotype to substantial increases in their plasma triglyceride concentrations. Ninety-seven published papers were identified that plotted mean triglyceride response vs. time and genotype, which were converted into quantitative data. Separately, for each published graph, standard least-squares regression analysis was used to compare the genotype differences at time t (dependent variable) to average triglyceride concentrations at time t (independent variable) to assess whether the genetic effect size increased in association with higher triglyceride concentrations and whether the phenomenon could explain purported genetic interactions with sex, diet, disease, BMI, and drugs. RESULTS:Consistent with the phenomenon, genetic effect sizes increased (P≤0.05) with increasing triglyceride concentrations for polymorphisms associated with ABCA1, ANGPTL4, APOA1, APOA2, APOA4, APOA5, APOB, APOC3, APOE, CETP, FABP2, FATP6, GALNT2, GCKR, HL, IL1b, LEPR, LOX-1, LPL, MC4R, MTTP, NPY, SORT1, SULF2, TNFA, TCF7L2, and TM6SF2. The effect size for these polymorphisms showed a progressively increasing dose-response, with intermediate effect sizes at intermediate triglyceride concentrations. Quantile-dependent expressivity provided an alternative interpretation to their interactions with sex, drugs, disease, diet, and age, which have been traditionally ascribed to gene-environment interactions and genetic predictors of drug efficacy (i.e., personalized medicine). CONCLUSION:Quantile-dependent expressivity applies to the majority of genetic variants affecting postprandial triglycerides, which may arise because the impaired functionalities of these variants increase at higher triglyceride concentrations. Purported gene-drug interactions may be the manifestations of quantile-dependent expressivity, rather than genetic predictors of drug efficacy.

Project description:Interleukin 6 (IL-6) is a moderately heritable pleiotropic cytokine whose elevated concentrations in coronary artery disease, peripheral arterial disease, pulmonary arterial hypertension, Eales' disease, Sjògren's syndrome, osteoarthritis, adenocarcinoma, neuroblastoma, polymyalgia rheumatica, pulmonary tuberculosis, and enterovirus 71 infection, and following coronary artery bypass graft show larger genetic effects than in unaffected low IL-6 controls. We hypothesize that genetic effects may depend upon whether average IL-6 concentrations are high or low, i.e., quantile-dependent expressivity. Quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted serum IL-6 concentrations in families surveyed in the Framingham Heart Study. Quantile-specific heritabilities were calculated as h2 = 2βOP / (1 + rspouse) and h2 = {(1 + 8rspouseβFS)0.5 -1} / (2rspouse)). Heritability (h2 ± SE) of IL-6 concentrations increased from 0.01 ± 0.01 at the 10th percentile (NS), 0.02 ± 0.01 at the 25th (P = 0.009), 0.03 ± 0.01 at the 50th (P = 0.007), 0.04 ± 0.02 at the 75th (P = 0.004), and 0.13 ± 0.05 at the 90th percentile (P = 0.03), or 0.0005 ± 0.0002 for each 1% increase in the offspring's phenotype distribution (Plinear trend = 0.02) when estimated from βOP and from 0.02 ± 0.02 at the 10th (NS), 0.02 ± 0.02 at the 25th (NS), 0.06 ± 0.02 at the 50th (P = 0.01), 0.12 ± 0.04 at the 75th (P = 0.001), and 0.30 ± 0.03 at the 90th percentile (P < 10-16), or 0.0015 ± 0.0007 for each 1% increase in the sibling phenotype distribution (Plinear trend = 0.02) when estimated from βFS. Thus the heritability of serum IL-6 concentrations is quantile dependent, which may contribute in part to the larger genetic effect size reported for diseases and environmental conditions that elevate IL-6 concentrations vis-à-vis unaffected controls.

Project description:Background:"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. adiponectin) is high or low relative to its distribution. We have previously shown that the heritability (h2 ) of adiposity, lipoproteins, postprandial lipemia, pulmonary function, and coffee and alcohol consumption are quantile-specific. Whether adiponectin heritability is quantile specific remains to be determined. Methods:Plasma adiponectin concentrations from 4,182 offspring-parent pairs and 1,662 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (? OP,h2 = 2? OP/(1 + rspouse)) and full-sib regression slopes (? FS, h2 = {(1 + 8rspouse ? FS)0.05-1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples. Results:Quantile-specific h2 (± SE) increased with increasing percentiles of the offspring's age- and sex-adjusted adiponectin distribution when estimated from ? OP (P trend = 2.2 × 10-6): 0.30 ± 0.03 at the 10th, 0.33 ± 0.04 at the 25th, 0.43 ± 0.04 at the 50th, 0.55 ± 0.05 at the 75th, and 0.57 ± 0.08 at the 90th percentile, and when estimated from ? FS (P trend = 7.6 × 10-7): 0.42 ± 0.03 at the 10th, 0.44 ± 0.04 at the 25th, 0.56 ± 0.05 at the 50th, 0.73 ± 0.08 at the 75th, and 0.79 ± 0.11 at the 90th percentile. Consistent with quantile-dependent expressivity, adiponectin's: (1) heritability was greater in women in accordance with their higher adiponection concentrations; (2) relationships to ADIPOQ polymorphisms were modified by adiposity in accordance with its adiponectin-lowering effect; (3) response to rosiglitazone was predicted by the 45T> G ADIPOQ polymorphism; (4) difference by ADIPOQ haplotypes increased linearly with increasing postprandial adiponectin concentrations. Conclusion:Adiponectin heritability is quantile dependent, which may explain sex-specific heritability, gene-environment and gene-drug interactions, and postprandial response by haplotypes.