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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

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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 (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.

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AVAILABILITY OF DATA AND MATERIALS

The data used in these analyses are available from NIH National Heart Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center directly through the website https://biolincc.nhlbi.nih.gov/my/submitted/request/. Simultaneous quantile regression was performed using the sqreg command of Stata (version. 11, StataCorp, College Station, TX).

Abbreviations

β FS :

Full-sib regression slope

β OP :

Offspring-parent regression slope

BMI:

Body mass index

CABG:

Coronary artery bypass graft

CAD:

Coronary artery disease

COPD :

Chronic obstructive pulmonary disease

EV71:

Enterovirus 71

GWAS:

Genomewide association study

h 2 :

Heritability in the narrow sense

IL-6:

Interleukin-6

LPS:

Lipopolysaccharide

MODS :

Multiple organ dysfunction syndrome

PAD :

Peripheral arterial disease

PAH:

Pulmonary arterial hypertension

PMR:

Polymyalgia rheumatica

T2DM:

Type 2 diabetes mellitus

VEGF :

Vascular endothelial growth factor

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Funding

The Framingham Heart Study was conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract Nos. N01-HC-25195 and HHSN268201500001I). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. This research was supported by grant R21ES020700 from the National Institute of Environmental Health Sciences, and an unrestricted gift from HOKA ONE ONE. The funders had no role in the preparation of this manuscript.

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  1. Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division, 1 Cyclotron Road, Berkeley, CA, 94720, USA

    Paul T. Williams

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The author (PTW) was responsible for the project conception, development of overall research plan, analyzing data including performed the statistical analysis, and writing of the paper.

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Lawrence Berkeley National Laboratory Human Subjects Committee (HSC) approved the analyses of these data for protocol “Gene-environment interaction vs. quantile-dependent penetrance of established SNPs (107H021)” LBNL holds Office of Human Research Protections Federal-Wide Assurance number FWA 00006253. Approval number 107H021-13MR20.

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All surveys were conducted under the direction of the Framingham Heart Study human use committee guidelines, with signed informed consent from all participants or parent and/or legal guardian if < 18 years of age.

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Williams, P.T. Quantile-Dependent Expressivity of Serum Interleukin-6 Concentrations as a Possible Explanation of Gene-Disease Interactions, Gene-Environment Interactions, and Pharmacogenetic Effects. Inflammation 45, 1059–1075 (2022). https://doi.org/10.1007/s10753-021-01601-0

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