TY - JOUR
T1 - The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations
AU - Schnabel, Renate B.
AU - Lunetta, Kathryn L.
AU - Larson, Martin G.
AU - Dupuis, Josée
AU - Lipinska, Izabella
AU - Rong, Jian
AU - Chen, Ming Huei
AU - Zhao, Zhenming
AU - Yamamoto, Jennifer F.
AU - Meigs, James B.
AU - Nicaud, Viviane
AU - Perret, Claire
AU - Zeller, Tanja
AU - Blankenberg, Stefan
AU - Tiret, Laurence
AU - Keaney, John F.
AU - Vasan, Ramachandran S.
AU - Benjamin, Emelia J.
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
KW - Biomarker
KW - Cohort study
KW - Epidemiology
KW - Genetics
KW - Heritability
KW - Inflammation
KW - Single-nucleotide polymorphism
KW - Systemic inflammation
UR - http://www.scopus.com/inward/record.url?scp=77949331942&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77949331942&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.108.804245
DO - 10.1161/CIRCGENETICS.108.804245
M3 - Article
C2 - 20031590
AN - SCOPUS:77949331942
SN - 1942-325X
VL - 2
SP - 229
EP - 237
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 3
ER -