Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations

Abstract

"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., triglycerides) is high or low relative to its distribution in the population. Quantile-specific offspring-parent regression slopes (β_OP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h²), estimated by 2β_OP/(1 + r_spouse), decreased 0.0047 ± 0.0007 (P = 2.9 × 10^-14) for each one-percent decrement in fasting triglyceride concentrations, i.e., h² ± SE were: 0.428 ± 0.059, 0.230 ± 0.030, 0.111 ± 0.015, 0.050 ± 0.016, and 0.033 ± 0.010 at the 90th, 75th, 50th, 25th, and 10th percentiles of the triglyceride distribution, respectively. Consistent with quantile-dependent expressivity, 11 drug studies report smaller genotype differences at lower (post-treatment) than higher (pre-treatment) triglyceride concentrations. This meant genotype-specific triglyceride changes could not move in parallel when triglycerides were decreased pharmacologically, so that subtracting pre-treatment from post-treatment triglyceride levels necessarily created a greater triglyceride decrease for the genotype with a higher pre-treatment value (purported precision-medicine genetic markers). In addition, sixty-five purported gene-environment interactions were found to be potentially attributable to triglyceride's quantile-dependent expressivity, including gene-adiposity (APOA5, APOB, APOE, GCKR, IRS-1, LPL, MTHFR, PCSK9, PNPLA3, PPARγ2), gene-exercise (APOA1, APOA2, LPL), gene-diet (APOA5, APOE, INSIG2, LPL, MYB, NXPH1, PER2, TNFA), gene-alcohol (ALDH2, APOA5, APOC3, CETP, LPL), gene-smoking (APOC3, CYBA, LPL, USF1), gene-pregnancy (LPL), and gene-insulin resistance interactions (APOE, LPL).

Figure 1

(upper panel) presents the offspring-parent regression slopes (β_OP) for selected quantiles of the offsprings’ total triglyceride 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 triglyceride distribution. These quantile-specific regression slopes were included with those of other quantiles to create the quantile-specific heritability function in the lower panel. The statistical significance of the linear, quadratic and cubic trends and the 95% confidence intervals (shaded region) were determined by 1000 bootstrap samples. 1 mg/dL = 0.01129 mmol/L.

Figure 2

Full-sib regression slopes (β_FS) vs. quantiles of the sib’s triglyceride and VLDL-cholesterol distribution.

Figure 3

Offspring-parent regression slopes (β_OP) vs. quantiles of the offsprings’ log-transformed triglyceride concentrations.

Figure 4

Precision medicine perspective of different mean triglyceride reductions by genotypes following 160 mg/d fenofibrate or fenofibrate/statin combination therapy (histogram inserts of mean changes by genotype) vs. quantile-dependent expressivity interpretation (larger pre-treatment genetic effect size when average triglycerides concentrations were high vs. lower, requiring nonparallel triglycerides reductions by genotype), for: (A) Lai et al.’s 2007 report of 87 APOA5 56 G carriers vs. 703 non-carriers (genotype difference in mean triglyceride reduction P = 0.006); (B) Cardona’s et al.’s 2009 report of 14 APOA5 -1131C carriers vs. 22 non-carriers; (C) Perez-Martinez et al.’s 2009 report of protected group (N = 236) consisting of the common allele homozygotes for GCKR rs780094C > T (CC), APOA5 −1131 T > C (TT), and APOA5 56 C > G (CC); an intermediate group (N = 490) consisting of homozygotes for GCKR rs780094C > T (CC) and carriers of the rare allele for either APOA5 −1131 T > C (CT or CC) or APOA5 56 C > G (CG or GG) or carriers of the rare allele for GCKR rs780094C > T (CT or TT) and homozygotes for both APOA5 −1131 T > C (TT) and APOA5 56 C > G (CC); and a risk group (N = 118) consisting of carriers of the rare allele for GCKR rs780094C > T (CT or TT) and carriers of the rare allele for either APOA5 −1131 T > C (CT or CC) or APOA5 56 C > G (CG or GG) with triglycerides > 1.69 mmol/L at baseline; (D) Brautbar et al.’s 2011 report on 47 GG, 256 GA and 371 AA genotypes of rs3741298 in the APOA5-ZNF259 gene region who were also statin treated; (E) Brautbar et al.’s 2011 report on 27 CC, 202 CG and 445 GG genotypes of rs964184 in the APOA5-ZNF259 gene region who were also statin treated; and (F) Irvin et al.’s 2010 report on 81 APOE ε2-carrier, 454 ε3ε3, and 203 ε4-carriers.

Figure 5

Precision medicine perspective of mean changes in triglyceride concentrations by genotypes (histogram inserts) vs. quantile-dependent expressivity perspective of larger genetic effect size when average triglycerides concentrations were high vs. low requiring nonparallel changes in triglycerides by genotype, for: (A) Brisson et al.’s 2015 report on 160 mg/d fenofibrate therapy in 44 carriers of LPL P207L mutation vs. 247 non-mutants; (B) Pedro-Botet et al.’s report on 10 mg/day of atorvastatin’s effect in 10 male APOE ε2-carriers, 111 male ε3ε3, and 74 male ε4-carriers; (C) Carmena et al.’s 2012 report on 80 mg/d lovastatin’s effect on 7 APOE ε2+, 58 ε3ε3, and 29 ε4+ familial hypercholesterolemia (FH) patients; (D) Anagnostopoulou et al. 2007 report of 10–40 mg/d simvastatin in 160 carriers of the I-allele and 20 VV homozygotes of the CEPT I405V polymorphism; (E) Balakrishnan et al.’s 2002 report of 93 patients who received pancreas transplants by APOE isoforms; (F) Cabello et al.’s 2018 report on the effect of bexarotene treatment on carriers of the APOA5 -1131T > C or APOC3 388 T > C mutations vs. non-mutations.

Figure 6

Precision medicine perspective of different mean changes in triglyceride concentrations by genotypes (histogram inserts) vs. quantile-dependent expressivity perspective of larger genetic effect size when average triglycerides concentrations were high vs. low requiring nonparallel changes in triglycerides by genotype, for: (A) Jenaa et al.’s 1997 report on the triglyceride response to 10-week weight loss diet in 58 H2H2 homozygotes and 57 H1-carriers of the of the LPL Hind III polymorphism (P = 0.03), (B) Yamasaki et al.’s 2015 report on the effect of a 3 month weight loss intervention in 87 TT, 163 TC, and 43 CC genotypes of the APOA5 -1131T > CT polymorphism, (C) Pollin et al.’s 2011 reported on the effect of a one-year lifestyle intervention in 919 subjects by the GCKR rs1260326 P446L polymorphism; (D) Ruaño et al.’s report on the effect of 6-month exercise training in 53 homozygotes and 22 A-allele carriers of the APOA1 −75 G/A polymorphism; (E) Lin et al.’s report on the effect of going from a 54% carbohydrate/31% fat diet to a 70% carbohydrate/15% fat diet on 36 TT and 20 C-carriers of the APOA5 -1131T > C polymorphism; (F) Humphries et al.’s 1996 report on the triglyceride response to a high saturated fat (26% SFA, 10% MUFA, 2% PUFA) and high polyunsaturated fat diets (9% SFA, 6% MUFA, 23% PUFA) in 45 H + and 10 H- genotypes of the LPL Hindlll gene loci.

Figure 7

Precision medicine perspective of different mean changes in triglyceride concentrations by genotypes (histogram inserts) vs. quantile-dependent expressivity perspective of larger genetic effect size when average triglycerides concentrations were high vs. low requiring nonparallel changes in triglycerides by genotype, for: (A) Carvalho-Wells et al.’s 2012 report on the triglyceride response to switching from a low-fat (24% fat, 59% carbohydrate) to high-fat diet (38% fat, 45% carbohydrate with 3.45 g DHA/d) in 44 APOE ε3ε3 homozygotes vs. 44 ε3ε4 heterozygotes (P_interaction = 0.03); (B) Kang et al.’s 2014 report of switching from their usual to a refined rice diet in 43 TT homozygotes and 50 C carriers of the APOA5 -1131 T > C polymorphism. (C) Vallée Marcotte et al.’s 2016 report on starting omega-3 (n-3) fatty acid supplementation in 142 AA homozygotes and 66 AC heterozygotes of the neurexophilin-1 (NXPH1) rs7806226 polymorphism; (D) Vallée Marcotte et al.’s 2016 report on starting omega-3 (n-3) fatty acid supplementation in 155 TT homozygotes and 53 CT heterozygotes of the V-MYB avian myeloblastosis viral oncogene homolog (MYB) rs11154794.