Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: Evidence for susceptibility loci on 1q
Introduction
Experimental and clinical evidence indicates that inflammation is central to the initiation and progression of atherosclerosis [1], [2]. Human studies demonstrate that inflammatory biomarkers [3] – such as C-reactive protein (CRP) [4], [5], interleukin-6 (IL-6) [6], monocyte-chemoattractant protein (MCP-1) [7] and soluble intercellular adhesion molecule-1 (sICAM-1) [8] – predict the development of cardiovascular disease (CVD) events. Hence, understanding the determinants of systemic markers of inflammation is increasingly important.
Inflammatory markers are associated with a wide array of CVD risk factors including smoking, blood pressure, obesity, lipid abnormalities and diabetes [4], [9]. Yet, much interindividual variability in systemic inflammatory biomarkers remains unexplained. For instance, in the Family Heart Study, only 20–30% of variability in CRP was explained by environmental factors [10]. Investigators have turned to genetic factors to account for some of the unexplained variability in inflammatory biomarkers.
Several observations drive the interest in genetic variation in inflammatory mediators. Animal models using techniques to knock out or over express inflammatory genes have modulated the risk of atherosclerosis [11], [12]. Human studies have demonstrated that CVD is a heritable condition [13] and have linked inflammatory polymorphisms to CVD [14], [15], [16]. Nevertheless, genetic contribution to blood levels of inflammatory biomarkers is poorly understood.
We hypothesized that biomarkers of vascular inflammation have both genetic and environmental determinants. We submit that identifying genes influencing inflammatory biomarkers might improve our understanding of genetic determinants of CVD. Thus, our objective was to describe heritability and genome-wide linkage for inflammatory biomarkers in a well-characterized community based cohort. We selected biomarkers based on prior animal and human data linking them to CVD [3], [4], [5], [6], [7], [8] and to represent a variety of pathways and stages in the inflammatory cascade. Hence, we included a cytokine [IL-6], chemokine [MCP-1], adhesion molecule [sICAM-1] and acute phase reactant [CRP].
Section snippets
Methods
The data analyzed were from the Framingham Heart Study (described elsewhere [17]). The original cohort was enrolled in 1948. The Framingham Offspring cohort (n = 5124) enrolled children of the original cohort and their spouses; participants have been examined about every 4 years since 1971. Extensive data were gathered at each examination, including medical history, physical examination and laboratory assessment of CVD risk factors. A panel of three investigators using established criteria
Results
Table 1 displays covariate data and inflammatory biomarkers levels, for 508 men and 546 women included in heritability and linkage analyses. Listed covariates explained 27%, 17%, 6% and 13% of the variance for log-transformed CRP, IL-6, MCP-1 and sICAM-1, respectively. Table 2 presents correlations between covariate-adjusted log-transformed inflammatory biomarkers, which were significantly correlated, and estimates of genetic and environmental correlations between biomarkers, which represent
Discussion
We present heritability and linkage results for four inflammatory biomarkers in a large community-based sample. To our knowledge, this is the first report of linkage analyses for inflammatory biomarkers based on a 10 cM genome-wide scan. In the Framingham Study, we found that inflammatory biomarker levels were heritable phenotypes, with estimates ranging from 27% to 45% for unadjusted levels of CRP, IL-6, MCP-1 and sICAM-1 and with slightly lower estimates after covariate adjustments (14–44%).
Acknowledgments
From the NHLBI's Framingham Heart Study, supported by NIH/NHLBI N01-HC-25195 and N01-HV-28178; NIH grants HL64753 & HL76784-01(EJB), DK55656 (JFK), HL70139 (RSV) and HL60886 (JAV and JFK). Dr. Keaney is an American Heart Association Established Investigator. Dr. Vasan a National Institute of Health Research Career Award Recipient (HL04334). We thank Qiong Yang and Larry Atwood for computing assistance and Moira Pryde for reference collection.
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