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


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 >or=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 x 10(-8)) and MPO in relation to myeloperoxidase (rs28730837, P=1.9 x 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 x 10(-7)) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36 x 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.
Schnabel
Renate B
RB
NHLBIs Framingham Heart Study, Framingham, MA 01702-5827, USA.
Lunetta
Kathryn L
KL
Larson
Martin G
MG
Dupuis
Josée
J
Lipinska
Izabella
I
Rong
Jian
J
Chen
Ming-Huei
MH
Zhao
Zhenming
Z
Yamamoto
Jennifer F
JF
Meigs
James B
JB
Nicaud
Viviane
V
Perret
Claire
C
Zeller
Tanja
T
Blankenberg
Stefan
S
Tiret
Laurence
L
Keaney
John F
JF
Vasan
Ramachandran S
RS
Benjamin
Emelia J
EJ
D000483:Alleles; D015415:Biomarkers / Q000032:analysis; D015331:Cohort Studies; D055812:Community-Based Participatory Research; D005787:Gene Frequency; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D018836:Inflammation Mediators / Q000032:analysis*; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D015415:Biomarkers; D018836:Inflammation Mediators