Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division, Berkeley, CA, United States of America.
PLoS One. 2022 Jan 7;17(1):e0262395. doi: 10.1371/journal.pone.0262395. eCollection 2022.
Fibrinogen is a moderately heritable blood protein showing different genetic effects by sex, race, smoking status, pollution exposure, and disease status. These interactions may be explained in part by "quantile-dependent expressivity", where the effect size of a genetic variant depends upon whether the phenotype (e.g. plasma fibrinogen concentration) is high or low relative to its distribution.
Determine whether fibrinogen heritability (h2) is quantile-specific, and whether quantile-specific h2 could account for fibrinogen gene-environment interactions.
Plasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (βOP, h2 = 2βOP/(1+rspouse)) and full-sib regression slopes (βFS, h2 = {(1+8rspouseβFS)0.05-1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples.
Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted fibrinogen distribution when estimated from βOP (Ptrend = 5.5x10-6): 0.30±0.05 at the 10th, 0.37±0.04 at the 25th, 0.48±0.05 at the 50th, 0.61±0.06 at the 75th, and 0.65±0.08 at the 90th percentile, and when estimated from βFS (Ptrend = 0.008): 0.28±0.04 at the 10th, 0.31±0.04 at the 25th, 0.36±0.03 at the 50th, 0.41±0.05 at the 75th, and 0.50±0.06 at the 90th percentile. The larger genetic effect at higher average fibrinogen concentrations may contribute to fibrinogen's greater heritability in women than men and in Blacks than Whites, and greater increase from smoking and air pollution for the FGB -455G>A A-allele. It may also explain greater fibrinogen differences between: 1) FGB -455G>A genotypes during acute phase reactions than usual conditions, 2) GTSM1 and IL-6 -572C>G genotypes in smokers than nonsmokers, 3) FGB -148C>T genotypes in untreated than treated diabetics, and LPL PvuII genotypes in macroalbuminuric than normoalbuminuric patients.
Fibrinogen heritability is quantile specific, which may explain or contribute to its gene-environment interactions. The analyses do not disprove the traditional gene-environment interpretations of these examples, rather quantile-dependent expressivity provides an alternative explanation that warrants consideration.
纤维蛋白原是一种中等遗传的血液蛋白，其遗传效应因性别、种族、吸烟状况、污染暴露和疾病状态而异。这些相互作用部分可以用“分位数依赖表达性”来解释，即遗传变异的效应大小取决于表型（例如血浆纤维蛋白原浓度）相对于其分布是高还是低。
确定纤维蛋白原遗传度（h2）是否具有分位数特异性，以及分位数特异性 h2 是否可以解释纤维蛋白原的基因-环境相互作用。
分析了来自弗雷明汉心脏研究的 5689 对父母-子女和 1932 对全同胞的血浆纤维蛋白原浓度。通过分位数回归，使用非参数显著性从 1000 个自举样本中分配，稳健地估计了来自父母-子女（βOP，h2=2βOP/（1+rspouse））和全同胞回归斜率（βFS，h2=（1+8rspouseβFS）0.05-1/（2rspouse））的分位数特异性遗传度。
当从βOP 估计时，分位数特异性 h2（±SE）随着子女年龄和性别调整后的纤维蛋白原分布的百分位数增加而增加（Ptrend=5.5x10-6）：第 10 百分位为 0.30±0.05，第 25 百分位为 0.37±0.04，第 50 百分位为 0.48±0.05，第 75 百分位为 0.61±0.06，第 90 百分位为 0.65±0.08；当从βFS 估计时，分位数特异性 h2（Ptrend=0.008）：第 10 百分位为 0.28±0.04，第 25 百分位为 0.31±0.04，第 50 百分位为 0.36±0.03，第 75 百分位为 0.41±0.05，第 90 百分位为 0.50±0.06。在较高的平均纤维蛋白原浓度下更大的遗传效应可能导致纤维蛋白原在女性中的遗传度高于男性，在黑人中的遗传度高于白人，并且在 FGB-455G>A A-等位基因中从吸烟和空气污染的影响更大。它还可能解释以下方面的纤维蛋白原差异更大：1）在急性反应期与通常条件相比，FGB-455G>A 基因型之间的差异，2）在吸烟者与非吸烟者相比，GTSM1 和 IL-6-572C>G 基因型之间的差异，3）在未经治疗的糖尿病患者与接受治疗的糖尿病患者相比，FGB-148C>T 基因型之间的差异，以及在大量白蛋白尿患者与正常白蛋白尿患者相比，LPL PvuII 基因型之间的差异。
纤维蛋白原遗传度具有分位数特异性，这可能解释或有助于其基因-环境相互作用。这些例子的传统基因-环境解释并没有被否定，而是分位数依赖表达性提供了一个值得考虑的替代解释。
