Genetic and Environmental Factors and Systemic Inflammation

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Genetic and Environmental Factors and Systemic Inflammation

Schnabel RB, Lunetta KL, Larson MG, et al. The Relation of Genetic and Environmental Factors to Systemic Inflammatory Biomarker Concentrations. Circ Cardiovasc Genet 2009;2:229-237.

doi: 10.1161/CIRCGENETICS.108.804245


Original Articles
The Relation of Genetic and Environmental Factors to Systemic Inflammatory Biomarker Concentrations
Renate B. Schnabel, MD, MSc; Kathryn L. Lunetta, PhD; Martin G. Larson, ScD; Josée Dupuis, PhD; Izabella Lipinska, PhD; Jian Rong, MS; Ming-Huei Chen, PhD; Zhenming Zhao, MS; Jennifer F. Yamamoto, BS; James B. Meigs, MD, MPH; Viviane Nicaud, MA; Claire Perret, MSc; Tanja Zeller, PhD; Stefan Blankenberg, MD; Laurence Tiret, PhD; John F. Keaney, Jr, MD; Ramachandran S. Vasan, MD and Emelia J. Benjamin, MD, ScM
From the NHLBIs Framingham Heart Study (R.B.S., J.R., M.-H.C., R.S.V., E.J.B.), Framingham, Mass; Departments of Medicine (R.S.V., E.J.B.) and Preventive Medicine (E.J.B.), and Whitaker Cardiovascular Institute (I.L., R.S.V., E.J.B.), Boston University School of Medicine, Boston, Mass; Boston University’s Mathematics and Statistics Department (M.G.L.); Departments of Epidemiology (K.L.L., J.D., M.-H.C., Z.Z., J.F.Y., E.J.B.) and Biostatistics (K.L.L., J.D., M.-H.C., Z.Z., J.F.Y., E.J.B.), Boston University School of Public Health; Department of Medicine (J.B.M.), Massachusetts General Hospital, Harvard Medical School; University of Massachusetts Medical School (J.F.K.), Boston, Mass; INSERM; Université Pierre et Marie Curie-Paris6 (V.N., C.P., L.T., R.S.V., E.J.B.), Paris, France; Department of Medicine II (T.Z., S.B.), Johannes Gutenberg-University, Mainz, Germany; and Division of Cardiovascular Medicine, University of Massachusetts Medical School (J.F.K.), Worcester, MA.
Correspondence to Emelia J. Benjamin, MD, ScM, Department of Medicine and Epidemiology, Boston University School of Medicine and Public Health, Framingham Heart Study, 73 Mount Wayte Ave. Suite 2, Framingham, MA 01702-5827. E-mail

Received July 2, 2008; accepted February 13, 2009.

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, 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 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=1.32x10–8) and MPO in relation to myeloperoxidase (rs28730837, P=1.9x10–5). Lowest P values for trans-acting single-nucleotide polymorphisms 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

Article handled by Guest Editor Eric B. Rimm, ScD.
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Copyright © 2009 American Heart Association, Inc.