Schnabel Renate B, Lunetta Kathryn L, Larson Martin G, Dupuis Josée, Lipinska Izabella, Rong Jian, Chen Ming-Huei, Zhao Zhenming, Yamamoto Jennifer F, Meigs James B, Nicaud Viviane, Perret Claire, Zeller Tanja, Blankenberg Stefan, Tiret Laurence, Keaney John F, Vasan Ramachandran S, Benjamin Emelia J
NHLBIs Framingham Heart Study, Framingham, MA 01702-5827, USA.
Circ Cardiovasc Genet. 2009 Jun;2(3):229-37. doi: 10.1161/CIRCGENETICS.108.804245. Epub 2009 Mar 31.
Environmental and genetic correlates of inflammatory marker variability are incompletely understood. In the family-based Framingham Heart Study, we investigated heritability and candidate gene associations of systemic inflammatory biomarkers.
In offspring participants (n=3710), we examined 11 inflammatory biomarkers (CD40 ligand, C-reactive protein, intercellular adhesion molecule-1, interleukin-6, urinary isoprostanes, monocyte chemoattractant protein-1, myeloperoxidase, P-selectin, tumor necrosis factor-alpha, tumor necrosis factor receptor II, fibrinogen). Heritability and bivariate genetic and environmental correlations were assessed by Sequential Oligogenic Linkage Analysis routines in 1012 family members. We examined 1943 tagging single-nucleotide polymorphisms in 233 inflammatory pathway genes with >or=5 minor allele carriers using a general genetic linear model. Clinical correlates explained 2.4% (CD40 ligand) to 28.5% (C-reactive protein) of the variability in inflammatory biomarkers. Estimated heritability ranged from 10.9% (isoprostanes) to 44.8% (P-selectin). Most correlations between biomarkers were weak although statistically significant. A total of 45 single-nucleotide polymorphism-biomarker associations met the q-value threshold of 0.25. Novel top single-nucleotide polymorphisms were observed in ICAM1 gene in relation to intercellular adhesion molecule-1 concentrations (rs1799969, P=1.32 x 10(-8)) and MPO in relation to myeloperoxidase (rs28730837, P=1.9 x 10(-5)). Lowest P values for trans-acting single-nucleotide polymorphisms were observed for APCS with monocyte chemoattractant protein-1 concentrations (rs1374486, P=1.01 x 10(-7)) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36 x 10(-5)). Novel potential candidates (APCS, MPO) need to be replicated.
Our community-based data support the relevance of clinical and genetic factors for explaining variation in inflammatory biomarker traits.
炎症标志物变异性的环境和遗传相关性尚未完全明确。在基于家族的弗雷明汉心脏研究中，我们调查了全身炎症生物标志物的遗传力及候选基因关联。
在子代参与者（n = 3710）中，我们检测了11种炎症生物标志物（CD40配体、C反应蛋白、细胞间黏附分子-1、白细胞介素-6、尿异前列腺素、单核细胞趋化蛋白-1、髓过氧化物酶、P选择素、肿瘤坏死因子-α、肿瘤坏死因子受体II、纤维蛋白原）。通过对1012名家庭成员进行顺序寡基因连锁分析程序来评估遗传力以及双变量遗传和环境相关性。我们使用通用遗传线性模型检测了233个炎症通路基因中1943个标签单核苷酸多态性（minor allele携带者≥5）。临床相关性解释了炎症生物标志物变异性的2.4%（CD40配体）至28.5%（C反应蛋白）。估计遗传力范围为10.9%（异前列腺素）至44.8%（P选择素）。生物标志物之间的大多数相关性较弱，尽管具有统计学意义。共有45个单核苷酸多态性-生物标志物关联达到了q值阈值0.25。在ICAM1基因中观察到与细胞间黏附分子-1浓度相关的新型顶级单核苷酸多态性（rs1799969，P = 1.32×10⁻⁸），以及与髓过氧化物酶相关的MPO（rs28730837，P = 1.9×10⁻⁵）。对于与单核细胞趋化蛋白-1浓度相关的APCS，观察到反式作用单核苷酸多态性的最低P值（rs1374486，P = 1.01×10⁻⁷），并在与白细胞介素-6浓度相关的IL6R中得到证实（rs8192284，P = 3.36×10⁻⁵）。新型潜在候选基因（APCS、MPO）需要重复验证。
我们基于社区的数据支持临床和遗传因素对于解释炎症生物标志物特征变异的相关性。
