Williams Paul T
Molecular Biophysics & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
J Inflamm Res. 2022 Jan 5;15:85-103. doi: 10.2147/JIR.S347402. eCollection 2022.
Heritability ( , the proportion of the phenotypic variance attributable to additive genetic effects) is traditionally assumed to be constant throughout the distribution of the phenotype. However, the heritabilities of circulating C-reactive protein, interleukin-6, plasminogen activator inhibitor type-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) concentrations depend upon whether the phenotype is high or low relative to their distributions (quantile-dependent expressivity), which may account for apparent gene-environment interactions. Whether the heritabilities of other inflammatory biomarkers linked to cardiovascular disease are quantile-dependent remain to be determined.
Quantile-specific offspring-parent (β) and full-sib regression slopes (β) were estimated by applying quantile regression to the age- and sex-adjusted phenotypes of families surveyed as part of the Framingham Heart Study. Quantile-specific heritabilities were calculated as: =2β/(1+r) and ={(1+8rβ)-1}/(2r).
Heritability ( ± SE) of lipoprotein-associated phospholipase A2 (Lp-PLA) mass concentrations increased from 0.11 ± 0.03 at the 10 percentile, 0.08 ± 0.03 at the 25, 0.12 ± 0.03 at the 50, 0.20 ± 0.04 at the 75, and 0.26 ± 0.06 at the 90 percentile, or 0.0023 ± 0.0006 per each one-percent increase in the phenotype distribution (P= 0.0004). Similarly, increased 0.0029 ± 0.0011 (P= 0.01) for sP-selectin, 0.0032 ± 0.0009 (P= 0.0001) for soluble intercellular adhesion molecule 1 (sICAM-1), and 0.0026 ± 0.0006 for tumor necrosis factor receptor 2 (TNFR2) (P= 5.0 × 10) per each one-percent increase in their distributions when estimated from β. Osteoprotegerin and soluble ST2 heritability also increased significantly with increasing percentiles of their distributions when estimated from β. Lp-PLA activity, CD40 ligand, TNFα, interleukin-18, and myeloperoxidase heritability showed no significant quantile-dependence.
The heritabilities of circulating Lp-PLA-mass, sP-selectin, sICAM-1, TNFR2, osteoprotegerin and soluble ST2 concentrations are quantile-dependent, which may contribute to purported genetic modulations of: 1) sP-selectin's relationships to venous thrombosis, pulmonary hypertension, type 2 diabetes and atorvastatin treatment; 2) sICAM-I's relationships to brain abscess and atorvastatin treatment; and 3) Lp-PLA's relationships to myocardial infarction and preeclampsia.
传统上认为遗传力（即表型方差中可归因于加性遗传效应的比例）在整个表型分布中是恒定的。然而，循环C反应蛋白、白细胞介素-6、纤溶酶原激活物抑制剂1型（PAI-1）和单核细胞趋化蛋白1（MCP-1）浓度的遗传力取决于表型相对于其分布是高还是低（分位数依赖性表达），这可能解释了明显的基因-环境相互作用。与心血管疾病相关的其他炎症生物标志物的遗传力是否存在分位数依赖性仍有待确定。
通过对作为弗雷明汉心脏研究一部分所调查家庭的年龄和性别调整后的表型应用分位数回归，估计分位数特异性子代-亲代（β）和全同胞回归斜率（β）。分位数特异性遗传力计算如下： =2β/(1+r) 以及 ={(1+8rβ)-1}/(2r)。
脂蛋白相关磷脂酶A2（Lp-PLA）质量浓度的遗传力（±标准误）从第10百分位数处的0.11±0.03、第25百分位数处的0.08±0.03、第50百分位数处的0.12±0.03、第75百分位数处的0.20±0.04以及第90百分位数处的0.26±0.06逐渐增加，即表型分布每增加1%，遗传力增加0.0023±0.0006（P = 0.0004）。同样，从β估计时，可溶性P选择素（sP-selectin）每增加1%，遗传力增加0.0029±0.0011（P = 0.01），可溶性细胞间黏附分子1（sICAM-1）增加0.0032±0.0009（P = 0.0001），肿瘤坏死因子受体2（TNFR2）增加0.0026±0.0006（P = 5.0×10）。从β估计时，骨保护素和可溶性ST2的遗传力也随着其分布百分位数的增加而显著增加。Lp-PLA活性、CD40配体、肿瘤坏死因子α（TNFα）、白细胞介素-18和髓过氧化物酶的遗传力未显示出明显的分位数依赖性。
循环Lp-PLA质量、sP选择素、sICAM-1、TNFR2、骨保护素和可溶性ST2浓度的遗传力具有分位数依赖性，这可能有助于解释以下方面所谓的基因调节作用：1）sP选择素与静脉血栓形成、肺动脉高压、2型糖尿病和阿托伐他汀治疗的关系；2）sICAM-1与脑脓肿和阿托伐他汀治疗的关系；3）Lp-PLA与心肌梗死和先兆子痫的关系。
