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.

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

Figure 1

A) Offspring-parent regression slopes (β_OP) for selected quantiles of the offspring’s serum vascular endothelial growth factor (VEGF) concentrations, with corresponding estimates of heritability (h²=2β_OP/(1+r_spouse)). The slopes became progressively greater (i.e., steeper) with increasing quantiles of the VEGF distribution. B) “Quantile-specific heritability function” formed by combining the selected quantile-specific regression slopes from above with those of other quantiles. Significance of the linear, quadratic and cubic trends and the 95% confidence intervals (shaded region) were determined by 1000 bootstrap samples. C) Full-sib regression slopes (β_FS) for serum VEGF concentrations, with corresponding estimates of heritability (h²=((1+8r_spouseβ_FS)^0.5-1)/2r_spouse). Heritability calculated from β_OP from panel B included to demonstrate its consistency with β_FS.

Figure 2.

Full-sib regression slopes (β_FS) by quantiles of the serum hepatocyte growth factor (HGF), angiopoietin-2, soluble angiopoietin receptor (sTie-2), and soluble VEGFR1 receptor (sFlt-1) distributions.

Figure 3.

Precision medicine perspective of genotype-specific effects on serum VEGF concentrations (histogram inserts) vs. quantile-dependent expressivity perspective of larger genetic effect size when average VEGF concentrations were high (line graphs) for: A) Suenaga et al.’s 2019 report on bevacizumab-induced reductions in serum VEGF concentrations by CCL5 (C-C motif chemokine ligand 5) rs2280789 genotypes; B) Suenaga et al.’s 2018 report on regorafenib-induced increases in VEGF concentrations by CCL5 rs2280789 genotypes; C) Ghazizadeh et al.’s 2017 report of the VEGF difference between patients with and without metabolic syndrome by rs6921438 genotypes; D) Ghazizadeh et al.’s 2018 report of the VEGF difference between patients with and without metabolic syndrome by rs10738760 genotypes; E) Oana et al.’s 2014 report on the VEGF differences between obese and normal-weight children by IL-6 (interleukin 6) rs1800796 genotypes; F) Schüler et al. 2018 report on the increase in VEGF concentrations when switching from a 6-wk low fat to 6-wk high fat isocaloric diet by rs9472159 genotypes.

Figure 4.

Precision medicine perspective of genotype-specific effects on serum growth factor concentrations (histogram inserts) vs. quantile-dependent expressivity perspective of larger genetic effect size when average VEGF or HGF concentrations were high (line graphs) for: A) Baitello et al.’s 2016 report of the VEGF difference between hepatocellular carcinoma and cirrhosis or healthy controls by VEGF rs3025039 genotypes; B) Baitello et al.’s 2016 report of the VEGF difference between hepatocellular carcinoma and cirrhosis or healthy controls by VEGF rs1570360 genotypes; C) Almawi et al’s 2013 report on the VEGF difference between women with recurrent spontaneous miscarriage vs. multiparous women by VEGF −460T/C (rs833061) genotypes; D) Emene et al.’s 2017 report on the reduction in HGF concentrations from the initial acute phase of an erysipelas infection to its recovery phase by superoxide dismutase 2 (SOD2) rs11575993 genotypes; E) Choudhuri et al.’s 2015 report on the VEGF difference between T2DM patients with and without proliferative diabetic retinopathy by rs2010963 genotypes; F) Choudhuri et al.’s 2015 report on the VEGF difference between patients with proliferative diabetic retinopathy and healthy controls by rs3025039 genotypes.