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Chlamydia pneumoniae infection, chronic inflammation and risk of lung cancer

Principal Investigator
Name
Anil Chaturvedi
Degrees
-
Institution
NCI, DCEG, IIB
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2005-0014
Initial CDAS Request Approval
Apr 21, 2006
Title
Chlamydia pneumoniae infection, chronic inflammation and risk of lung cancer
Summary
Lung cancer is the most common cancer and the leading cause of cancer mortality in the United States. While smoking is the most substantial risk factor for lung cancer, other co-factors are believed to play a role in increasing risk. Recent epidemiologic studies have consistently associated chronic infection with the bacterium Chlamydia pneumoniae (Cpn) with increased lung cancer risk. Cpn infections are hypothesized to increase lung cancer risk by causing chronic inflammation. However, studies addressing the functional role of chronic Cpn infections in lung cancer risk are lacking. The current proposal aims to confirm and further characterize the etiologic role of chronic Cpn infections in lung cancer. To achieve this, we propose to utilize a "pathway approach" by characterizing the presence of chronic Cpn infections, measuring levels of inflammatory markers (high sensitivity- C-reactive protein [hs-CRP] and neopterin), and characterizing single nucleotide polymorphisms (SNPs) in the immunity and inflammation pathway. We propose to conduct a matched case-control study nested within the Prostate, Lung, Colorectal, and Ovarian cancers trial (PLCO) screening arm. Controls (n=631) will be matched to lung cancer cases (n=543) based on age, sex, year of serum sampling, and stratum of smoking (i.e. never, current, and former smokers), and for current and former smokers the duration and intensity of smoking and time since quitting. Pre-diagnostic serum will be used to measure Cpn antibodies, hs-CRP, and neopterin. To investigate the role of genetics on lung cancer risk, we will characterize SNPs in a large array of immunity and inflammation genes using the Illumina OPA technology. We will investigate 1536 SNPs in a panel of 220 genes that directly participate or interact with components of immunity and its overlapping effect on inflammation. Given the significant public health impact of lung cancer worldwide, a systematic pathway approach to characterizing factors acting in concert or independent of cigarette smoking may aid in identifying populations at high risk of lung cancer and in devising novel prevention strategies.
Aims

Primary aims : Examine the association between chronic Chlamydia pneumoniae infection and the risk of lung cancer. We will measure IgA antibodies to Chlamydia elementary bodies and IgG antibodies to Chlamydial heat shock protein-60 as markers of chronic Cpn infection. Analyses will test the hypothesis whether chronic Cpn infection increases the risk of lung cancer after accounting for confounding through matching or multivariate analyses. Examine the association between markers of chronic inflammation and immune activation (C-reactive protein (CRP) and neopterin) and the risk of lung cancer. High sensitivity C-reactive protein will be measured in the serum as a marker of low-grade inflammation. Neopterin will be measured in the serum as a marker of immune system activation. We will test whether elevated levels of CRP and elevated levels of neopterin are associated with lung cancer risk. Examine the association between selected cytokine gene polymorphisms and the risk of lung cancer. SNPs will be characterized in Th1 (IL-2, TNF-a, and IFN-g) and Th2 (IL-4, IL-6, IL-10, and IL-13) cytokine genes and in intracellular modulators of inflammation genes (i?B and iNOS). Analyses will test the hypothesis whether polymorphisms in the aforementioned genes modulate the risk of lung cancer. Characterize the interaction between Chlamydia pneumoniae infection and a) smoking, b) chronic inflammation and c) cytokine gene polymorphisms, on the risk of lung cancer. We will assess whether chronic Cpn infection interacts with cigarette smoking, presence of low-grade inflammation, and host genetics to modulate the risk of lung cancer. Secondary aims: Characterize the interaction between smoking and a) chronic inflammation and b) cytokine gene polymorphisms, on the risk of lung cancer. Examine the proportion of Chlamydia pneumoniae related risk of lung cancer that is mediated through chronic inflammation (assessment of direct and indirect effects of Chlamydia pneumoniae infection on risk of lung cancer). Examine the association between Chlamydia pneumoniae infection and the different sub-types of lung cancer. Explore the associations of SNPs in an extended panel of immunity and inflammatory genes with risk of lung cancer and Cpn infection.

Collaborators

Barry Fields (Centers for Disease Control and Prevention)
Neil Caporaso (NCI, DCEG)
Stephen Chanock (Core Genotyping Facility)
Nilanjan Chatterjee (Biostatistics Branch)
Anil Chaturvedi (NCI, DCEG)
Eric Engels (NCI, DCEG)
James Goedert (NCI, DCEG)
Maria-Lucia Tondella (Centers for Disease Control and Prevention)

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