Published Online
on March 31, 2009

A more recent version of this article appeared on June 1, 2009

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Original Article

The Relation of Genetic and Environmental Factors to Systemic Inflammatory Biomarker Concentrations

Renate B. Schnabel¹; Kathryn L. Lunetta²; Martin G. Larson²; Josée Dupuis²; Izabella Lipinska³; Jian Rong¹; Ming-Huei Chen⁴; Zhenming Zhao²; Jennifer F. Yamamoto²; James B. Meigs⁵; Viviane Nicaud⁶; Claire Perret⁶; Tanja Zeller⁷; Stefan Blankenberg⁷; Laurence Tiret⁶; John F. KeaneyJr.⁸; Ramachandran S. Vasan⁹ and Emelia J. Benjamin^9,10

¹ NHLBI's Framingham Study, Framingham, MA;
² Boston University School of Public Health, Boston, MA;
³ Boston University School of Medicine, Boston, MA;
⁴ NHLBI's Framingham Study, Framingham, MA & Boston University School of Public Health, Boston, MA;
⁵ Massachusetts General Hospital & Harvard Medical School, Boston, MA;
⁶ INSERM & Université Pierre et Marie Curie, Paris, France;
⁷ Johannes Gutenberg-University, Mainz, Germany;
⁸ University of Massachusetts Medical School, Worcester, MA;
⁹ NHLBI's Framingham Study, Framingham & Boston University School of Medicine, Boston, MA

¹⁰ E-mail: emelia{at}bu.edu

Background—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.

Methods and Results—In Offspring participants (n=3710), we examined 11 inflammatory biomarkers [CD40 ligand, C-reactive protein, intercellular adhesion molecule-1 (ICAM1), 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 (SOLAR) in 1012 family members. We examined 1943 tagging SNPs in 233 inflammatory pathway genes with 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 SNP-biomarker associations met the q-value threshold of 0.25. Novel top SNPs were observed in ICAM1 gene in relation to ICAM1 concentrations (rs1799969, p=1.32x10^-8) and MPO in relation to myeloperoxidase (rs28730837, p=1.9x10^-5). Lowest p-values for trans-acting SNPs were observed for APCS with monocyte chemoattractant protein-1 concentrations (rs1374486, p=1.01x10^-7) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, p=3.36x10^-5). Novel potential candidates (APCS, MPO) need to be replicated.

Conclusions—Our community-based data support the relevance of clinical and genetic factors for explaining variation in inflammatory biomarker traits.

Key Words: epidemiology • genetics • inflammation • single nucleotide polymorphism • heritability • systemic inflammation • biomarker • cohort study