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

doi:10.1161/CIRCGENETICS.108.804245

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 journal › Article › peer-review

48 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 language	English (US)
Pages (from-to)	229-237
Number of pages	9
Journal	Circulation: Cardiovascular Genetics
Volume	2
Issue number	3
DOIs	https://doi.org/10.1161/CIRCGENETICS.108.804245
State	Published - May 2009
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Genetics
Cardiology and Cardiovascular Medicine
Genetics(clinical)

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10.1161/CIRCGENETICS.108.804245

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Schnabel, R. B., Lunetta, K. L., Larson, M. G., Dupuis, J., Lipinska, I., Rong, J., Chen, M. H., Zhao, Z., Yamamoto, J. F., Meigs, J. B., Nicaud, V., Perret, C., Zeller, T., Blankenberg, S., Tiret, L., Keaney, J. F., Vasan, R. S., & Benjamin, E. J. (2009). The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations. Circulation: Cardiovascular Genetics, 2(3), 229-237. https://doi.org/10.1161/CIRCGENETICS.108.804245

Schnabel, RB, Lunetta, KL, Larson, MG, Dupuis, J, Lipinska, I, Rong, J, Chen, MH, Zhao, Z, Yamamoto, JF, Meigs, JB, Nicaud, V, Perret, C, Zeller, T, Blankenberg, S, Tiret, L, Keaney, JF, Vasan, RS & Benjamin, EJ 2009, 'The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations', Circulation: Cardiovascular Genetics, vol. 2, no. 3, pp. 229-237. https://doi.org/10.1161/CIRCGENETICS.108.804245

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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{\texttimes}10-8) and MPO in relation to myeloperoxidase (rs28730837, P=1.9{\texttimes}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{\texttimes}10 -7) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36{\texttimes}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.",

keywords = "Biomarker, Cohort study, Epidemiology, Genetics, Heritability, Inflammation, Single-nucleotide polymorphism, Systemic inflammation",

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

year = "2009",

month = may,

doi = "10.1161/CIRCGENETICS.108.804245",

language = "English (US)",

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pages = "229--237",

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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

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

Abstract

Keywords

ASJC Scopus subject areas

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