Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin

Abstract

Background: “Quantile-dependent expressivity” is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution. Methods: Quantile-specific offspring-parent regression slopes (β_OP) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study. Results: Quantile-specific heritability ( h²), estimated by 2β_OP/(1 + r_spouse), increased 0.0045 ± 0.0007 ( p = 8.8 × 10⁻¹⁴) for each 1% increment in the fasting glucose distribution, that is, h² ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin ( p = 1.2 × 10⁻⁶), homeostatic model assessment of insulin resistance (HOMA-IR, p = 5.3 × 10⁻⁵), insulin/glucose ratio ( p = 3.9 × 10⁻⁵), proinsulin ( p = 1.4 × 10⁻⁶), proinsulin/insulin ratio ( p = 2.7 × 10⁻⁵), and glucose concentrations during a glucose tolerance test ( p = 0.001), and their logarithmically transformed values. Discussion/Conclusion: These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between ACE, ADRB3, PPAR-γ2, and TNF-α polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity ( APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2), gene-exercise ( INS), gene-diet ( ACSL1, ELOVL6, IRS-1, PLIN, S100A9), and gene-socioeconomic interactions.