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Open Access Short Report

Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study

Noffisat O Oki1, Alison A Motsinger-Reif1*, Paulo RZ Antas2, Shawn Levy3, Steven M Holland4 and Timothy R Sterling25*

Author Affiliations

1 Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA

2 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

3 Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA

4 Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

5 Center for Health Services Research, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

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BMC Research Notes 2011, 4:28  doi:10.1186/1756-0500-4-28

Published: 31 January 2011

Abstract

Background

Approximately 5-10% of persons infected with M. tuberculosis develop tuberculosis, but the factors associated with disease progression are incompletely understood. Both linkage and association studies have identified human genetic variants associated with susceptibility to pulmonary tuberculosis, but few genetic studies have evaluated extrapulmonary disease. Because extrapulmonary and pulmonary tuberculosis likely have different underlying pathophysiology, identification of genetic mutations associated with extrapulmonary disease is important.

Findings

We performed a pilot genome-wide association study among 24 persons with previous extrapulmonary tuberculosis and well-characterized immune defects; 24 pulmonary tuberculosis patients and 57 patients with M. tuberculosis infection served as controls. The Affymetrix GeneChip Human Mapping Xba Array was used for genotyping; after careful quality control, genotypes at 44,175 single nucleotide polymorphisms (SNPs) were available for analysis. Eigenstrat quantified population stratification within our sample; logistic regression, using results of the Eigenstrat analysis as a covariate, identified significant associations between groups. Permutation testing controlled the family-wise error rate for each comparison between groups. Four SNPs were significantly associated with extrapulmonary tuberculosis compared to controls with M. tuberculosis infection; one (rs4893980) in the gene PDE11A, one (rs10488286) in KCND2, and one (rs2026414) in PCDH15; one was in chromosome 7 but not associated with a known gene. Two additional variants were significantly associated with extrapulmonary tuberculosis compared with pulmonary tuberculosis; one (rs340708) in the gene FAM135B and one in chromosome 13 but not associated with a known gene. The function of all four genes affects cell signaling and activity, including in the brain.

Conclusions

In this pilot study, we identified 6 novel variants not previously known to be associated with extrapulmonary tuberculosis, including two SNPs more common in persons with extrapulmonary than pulmonary tuberculosis. This provides some support for the hypothesis that the pathogenesis and genetic predisposition to extrapulmonary tuberculosis differs from pulmonary tuberculosis. Further study of these novel SNPs, and more well-powered genome-wide studies of extrapulmonary tuberculosis, is warranted.