The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations

Renate B. Schnabel, Kathryn L. Lunetta, Martin G. Larson, Josée Dupuis, Izabella Lipinska, Jian Rong, Ming Huei Chen, Zhenming Zhao, Jennifer F. Yamamoto, James B. Meigs, Viviane Nicaud, Claire Perret, Tanja Zeller, Stefan Blankenberg, Laurence Tiret, John F. Keaney, Ramachandran S. Vasan, Emelia J. Benjamin

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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-α, 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=1.32×10-8) and MPO in relation to myeloperoxidase (rs28730837, P=1.9×10-5). Lowest P values for trans-acting single-nucleotide polymorphisms were observed for APCS with monocyte chemoattractant protein-1 concentrations (rs1374486, P=1.01×10 -7) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36×10-5). 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.

Original languageEnglish (US)
Pages (from-to)229-237
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume2
Issue number3
DOIs
StatePublished - May 2009
Externally publishedYes

Keywords

  • Biomarker
  • Cohort study
  • Epidemiology
  • Genetics
  • Heritability
  • Inflammation
  • Single-nucleotide polymorphism
  • Systemic inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

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