Quantile-specific heritability of serum growth factor concentrations

Abstract

Background

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low relative to its distribution.

Methods

Quantile-regression analysis was applied to family sets from the Framingham Heart Study to determine whether the heritability (h²) of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), angiopoietin-2, and angiopoietin-2 (sTie-2) and VEGFR1 (sFlt-1) receptor concentrations were quantile-specific.

Results

Quantile-specific h² (±SE) increased with increasing percentiles of the age- and sex-adjusted VEGF (P_trend<10⁻¹⁶), HGF (P_trend=0.0004), angiopoietin-2 (P_trend=0.0002), sTie-2 (P_trend=1.2 × 10⁻⁵), and sFlt-1 distributions (P_trend=0.04).

Conclusion

Heritabilities of VEGF, HGF, angiopoitein-2, sTie-2 and sFlt-1 concentrations are quantile dependent. This may explain reported interactions of genetic loci (rs10738760, rs9472159, rs833061, rs3025039, rs2280789, rs1570360, rs2010963) with metabolic syndrome, diet, recurrent miscarriage, hepatocellular carcinoma, erysipelas, diabetic retinopathy, and bevacizumab treatment in their effect on VEGF concentrations.

Graphical Abstract

Keywords:

• Gene–environment interaction
• precision medicine
• vascular endothelial growth factor
• hepatocyte growth factor
• angiopoietin-2
• heritability
• angiopoietin-2 (Tie-2) receptor
• VEGFR1 (Flt-1) receptor

Author contributions

The author is responsible for all aspects of the report. The Framingham Study data were obtained from the National Institutes of Health FRAMCOHORT, GEN3, FRAMOFFSPRING Research Materials obtained from the National Heart, Lung, and Blood (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center.

Disclosure statement

No potential conflict of interest was reported by the authors

Ethics approval

Our analyses of these data were approved by Lawrence Berkeley National Laboratory Human Subjects Committee (HSC) 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.

Consent to participate

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.

Availability of data and material

The data are not being published in accordance with the data use agreement between the NIH National Heart Lung, and Blood Institute and Lawrence Berkeley National Laboratory. However, the data that support the findings of this study are available from NIH National Heart Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Centre directly through the website https://biolincc.nhlbi.nih.gov/my/submitted/request. Restrictions apply to the availability of these data, which were used under license for this study. Those wishing a copy of the data set should contact the Blood Institute Biologic Specimen and Data Repository Information Coordinating Center at the above website, where they can find information on human use approval and data use agreement requiring signature by an official with signing authority for their institute.

Additional information

Funding

This research was supported by NIH grant R21ES020700 from the National Institute of Environmental Health Sciences, and an unrestricted gift from HOKA ONE ONE.