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Quantile-Dependent Expressivity of Serum Interleukin-6 Concentrations as a Possible Explanation of Gene-Disease Interactions, Gene-Environment Interactions, and Pharmacogenetic Effects.

ABSTRACT: 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 (β_OP) and full-sib regression slopes (β_FS) 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 = 2β_OP / (1 + r_spouse) and h² = {(1 + 8r_spouseβ_FS)^0.5 -1} / (2r_spouse)). 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 (P_{linear trend} = 0.02) when estimated from β_OP 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 (P_{linear trend} = 0.02) when estimated from β_FS. 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.

SUBMITTER: Williams PT

PROVIDER: S-EPMC9106828 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Quantile-Dependent Expressivity of Serum Interleukin-6 Concentrations as a Possible Explanation of Gene-Disease Interactions, Gene-Environment Interactions, and Pharmacogenetic Effects.

Williams Paul T PT

Inflammation 20220107 3

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 de ...[more]

PMID: 34993731

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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.MethodsPlasma 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 (β OP,h2 = 2β OP/(1 + rspouse)) and full-sib regression slopes (β FS, h2 = {(1 + 8rspouse β FS)0.05-1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples.ResultsQuantile-specific h2 (± SE) increased with increasing percentiles of the offspring's age- and sex-adjusted adiponectin distribution when estimated from β 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 β 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.ConclusionAdiponectin heritability is quantile dependent, which may explain sex-specific heritability, gene-environment and gene-drug interactions, and postprandial response by haplotypes.

Project description:"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (βFS) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed βFS increased significantly with increasing percentiles of the offspring's age- and sex-adjusted leptin distribution (Plinear = 0.0001), which was accelerated at the higher concentrations (Pquadratic = 0.0003). βFS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, Pdifference = 3.6 × 10-6). Consistent with quantile-dependent expressivity, the βFS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP, LEPR, MnSOD, PPARγ, PPARγ2, and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. βFS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (Plinear = 0.04 and Plinear = 8.5 × 10-6, respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male-female differences in heritability and some gene-environment interactions.

Project description: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.MethodsSerum 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, h 2 ={(1 + 8rspouseβFS)0.5 - 1}/(2rspouse)) and offspring-parent regression slopes (βOP, h 2 = 2βOP/(1 + rspouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples.ResultsQuantile-specific h 2 (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted CRP distribution when estimated from βOP (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 βFS (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.ConclusionHeritability 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.

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.

Dataset Information

Quantile-Dependent Expressivity of Serum Interleukin-6 Concentrations as a Possible Explanation of Gene-Disease Interactions, Gene-Environment Interactions, and Pharmacogenetic Effects.

Publications

Quantile-Dependent Expressivity of Serum Interleukin-6 Concentrations as a Possible Explanation of Gene-Disease Interactions, Gene-Environment Interactions, and Pharmacogenetic Effects.

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