Quantile-dependent expressivity of serum C-reactive protein concentrations in family sets

Abstract

Background: "Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., C-reactive protein, CRP) is high or low relative to its distribution. We have previously shown that the heritabilities (h ²) of coffee and alcohol consumption, postprandial lipemia, lipoproteins, leptin, adiponectin, adiposity, and pulmonary function are quantile-specific. Whether CRP heritability is quantile-specific is currently unknown.

Methods: Serum CRP concentrations from 2,036 sibships and 6,144 offspring-parent pairs were analyzed from the Framingham Heart Study. Quantile-specific heritability from full-sib (β_FS, h ² ={(1 + 8r_spouseβ_FS)^0.5 - 1}/(2r_spouse)) and offspring-parent regression slopes (β_OP, h ² = 2β_OP/(1 + r_spouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples.

Results: Quantile-specific h ² (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted CRP distribution when estimated from β_OP (P _trend = 0.0004): 0.02 ± 0.01 at the 10th, 0.04 ± 0.01 at the 25th, 0.10 ± 0.02 at the 50th, 0.20 ± 0.05 at the 75th, and 0.33 ± 0.10 at the 90th percentile, and when estimated from β_FS (P _trend = 0.0008): 0.03±0.01 at the 10th, 0.06 ± 0.02 at the 25th, 0.14 ± 0.03 at the 50th, 0.24 ± 0.05 at the 75th, and 0.53 ± 0.21 at the 90th percentile.

Conclusion: Heritability of serum CRP concentration is quantile-specific, which may explain or contribute to the inflated CRP differences between CRP (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), FGB (rs1800787), IL-6 (rs1800795, rs1800796), IL6R (rs8192284), TNF-α (rs1800629) and APOE genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or Staphylococcus aureus bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.

Keywords: Acute response protein; Adiposity; Ankylosing spondylitis; C-reactive protein; Cardiomyopathy; Genetics; Myocardial infarction; Rheumatoid arthritis; Smoking; Surgery.

Figure 1. Quantile-specific offspring-parent (β_OP) and full-sib regression slopes (β_FS) for untransformed CRP concentrations.

(A) Offspring-parent regression slopes (β_OP) for selected quantiles of the offspring’s untransformed CRP concentrations from 6,144 offspring-parent pairs, with corresponding estimates of heritability (h² = 2β_OP/(1 + r_spouse)) (Falconer & Mackay, 1996), where the correlation between spouses was r_spouse = −0.0013. The slopes became progressively greater (i.e., steeper) with increasing quantiles of the CRP distribution. (B) The selected quantile-specific regression slopes were included with those of other quantiles to create the quantile-specific heritability function in the lower panel. Significance of the linear, quadratic and cubic trends and the 95% confidence intervals (shaded region) determined by 1000 bootstrap samples. (C) Quantile-specific full-sib regression slopes (β_FS) from 5,703 full-sibs in 2,036 sibships, with corresponding estimates of heritability as calculated by h² = {(8r_spouseβ_FS + 1)^0.5 − 1}/(2r_spouse) (Falconer & Mackay, 1996).

Figure 2. Quantile-specific offspring-parent (β_OP) and full-sib regression slopes (β_FS) for the offspring’s logarithmically transformed CRP concentrations.

(A) Quantile-specific offspring-parent regression slope (β_OP) for the offspring’s logarithmically transformed CRP concentrations with corresponding estimates of heritability (Falconer & Mackay, 1996), where the correlation between spouses was r_spouse = 0.0482. (B) full-sib regression slopes (β_FS) for logarithmically transformed CRP concentrations.

Figure 3. Simple regression analysis showing larger genotype differences associated with higher estimated average CRP response.

Simple regression analysis of showing larger genotype differences associated with higher estimated average CRP response for the data presented in: (A) Farup, Rootwelt & Hestad (2020) report on the APOE CRP differences (non-carriers minus carriers of ε4-allele) in morbidly obese patients losing weight; (B) Perry et al. (2009) report on the rs3091244 CRP difference (T-allele carrier minus noncarrier) post CABG surgery (P_linear = 0.08); (C) Perry et al. (2009) report on the rs1800947 CRP difference (GG homozygotes minus C-allele carrier) post CABG surgery (P_linear = 0.11); (D) Brull et al. (2003) report on the rs1130864 CRP difference (TT homozygotes minus C-allele carriers) pre- and post CABG surgery (P_linear = 0.02); (E) D’Aiuto et al. (2005) report on the rs1130864 CRP difference (TT homozygotes minus C-allele carriers) following periodontal intensive therapy (P_linear = 0.002); (F) Motoyama et al. (2009) report on the rs1800947 CRP difference (GG homozygotes minus C-allele carriers) following esophagectomy surgery (P_linear = 0.07).

Figure 4. Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs).

Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs showing larger genetic effect size when average CRP concentrations were high) for the data presented in: (A) Pramudji et al. (2019) of the CRP difference between obese and non-obese subjects by the -174 G>C IL-6 polymorphism; (B) Teng et al. (2009) report on the CRP difference between obese and non-obese subjects by the rs2794521 genotypes (P_interaction = 0.034); (C) Teng et al. (2009) report on the CRP difference between obese and non-obese subjects by rs1800947 genotypes (P_interaction = 0.02); (D) Teng et al. (2009) report on the CRP difference between obese and non-obese subjects by the rs1205 genotypes (P_interaction = 0.02); (E) Luetragoon et al. (2018) report on the CRP difference between smokers and nonsmokers by CRP 1800947 genotypes; (F) Shin et al. (2007) report on the CRP difference (mg/dL) between smokers and nonsmokers by IL6 rs1800796 genotypes. *Except where noted.

Figure 5. Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs).

Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs showing larger genetic effect size when average CRP concentrations were high) for the data presented in: (A) Gander et al. (2004) report on the CRP difference between smokers and nonsmokers by CRP rs1800629; (B) Brull et al. (2003) reported on the effect of 48-h military endurance exercise on CRP concentrations by rs1130864 genotypes; (C) Keramat et al. (2017) report on the effect of monounsaturated fat intake on CRP concentrations by APOA2 rs5082 genotypes; (D) Carvalho-Wells et al. (2012) report on the effect of a high fat diet by APOE isoform; (E) Gomez-Delgado et al. (2015) report on the effect of a lowfat diet by CLOCK rs4580704 genotypes; (F) Zee & Ridker (2002) report on the CRP difference between men experiencing vs. not experiencing their first arterial thrombosis during 8.6 year follow-up by CRP rs1800947 genotypes.

Figure 6. Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs).

Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs showing larger genetic effect size when average CRP concentrations were high) for the data presented in: (A) Kovacs et al. (2005) reported on the effect of myocardial infarction by CRP rs3091244 genotypes cross-sectionally; (B) Qi, Rifai & Hu (2007) report on the effect of T2DM by interleukin-6 receptor (IL6R) rs8192284 genotypes (P_interaction = 0.03); (C) Libra et al. (2006) report on the CRP difference between T2DM with (PAD+) and without (PAD−) peripheral arterial disease by IL-6 G(-174)C rs1800795 genotypes; (D) Wypasek et al. (2012) 2012 reported on the effects of coronary artery bypass grafting (CABG) surgery on CRP by fibrinogen beta-chain (FGB) -148C>T genotypes (rs1800787); (E) Wypasek et al. (2010) reported on the effects of CABG surgery on CRP by -174G>C IL-6 (rs1800795) genotypes; (F) Mathew et al. (2007) report on the effects of CABG with cardiopulmonary bypass by CRP +1059G>C (rs1800947) genotypes. *Except where noted.

Figure 7. Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs).

Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs showing larger genetic effect size when average CRP concentrations were high) for the data presented in: (A) Suk Danik et al. (2006) report on the effect of acute coronary syndrome by CRP rs3091244 genotypes; (B) Suk Danik et al. (2006) report on the effect of acute coronary syndrome by CRP rs1800947 genotypes; and (C) Suk Danik et al. (2006) report on the effect of acute coronary syndrome by CRP rs1205 genotypes; (D) Kovacs et al. (2005) report on the effect of myocardial infarction (MI) by CRP rs3091244 genotypes longitudinally; (E) Mölkänen et al. (2010) reported on the effect of Staphylococcus aureus bacteremia by rs3091244 genotypes; (F) Ammitzbøll et al. (2014) report on the effect of early chronic rheumatoid arthritis by CRP rs1205.

Figure 8. Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs).

Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs showing larger genetic effect size when average CRP concentrations were high) for the data presented in: (A) Wielińska et al. (2020) report on the effect of anti-TNF treatment by RANK rs8086340 genotypes; (B) Wielińska et al. (2020) report on the effect of anti-TNF treatment by RANKL rs7325635 genotypes; (C) Vatay et al. (2003) report on the CRP difference between active phase inflammatory bowel disease and healthy controls by tumor necrosis factor alpha (TNF-α) G-308A (rs1800629) promoter polymorphism; (D) Xu, Jiang & Zhang (2020) report on the effect of etanercept treatment in Ankylosing spondylitis patients by CRP rs3091244 genotypes; (E) Liaquat et al. (2014) report on the effect of idiopathic dilated cardiomyopathy by TNF-α (rs1800629) -308G>A genotypes; (F) Liaquat et al. (2014) report on the effect of idiopathic dilated cardiomyopathy by IL-6 rs1800795 (–174 G>C) genotypes.

Figure 9. Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graph).

Precision medicine perspective of genotype-specific CRP differences (histogram inserts) vs. quantile-dependent expressivity perspective (line graphs showing larger genetic effect size when average CRP concentrations were high) for the data presented in Kim et al. (2015) report on the effect of Kawasaki disease by CRP promoter rs12068753 genotypes.