Human Molecular Genetics Advance Access published online on January 3, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddm378
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ALOX5 variants associated with susceptibility to human pulmonary tuberculosis
1 Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany 2 Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany 3 National Reference Center for Mycobacteria, Research Center Borstel, Borstel, Germany 4 Department of Community Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana 5 Health Research Unit, Ghana Health Service, Accra, Ghana 6 Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi, Ghana 7 Department of Pharmaceutical Analytics, Institute of Pharmacy, Eberhard Karls University, Tuebingen, Germany
* Correspondence to Prof. Christian G. Meyer Bernhard Nocht Institute for Tropical Medicine Bernhard Nocht Str. 74 20359 Hamburg Germany phone +49 40 42818-501 fax +49 40 42818-512 Email: c.g.meyer{at}bni-hamburg.de
Received September 26, 2007; Revised November 29, 2007; Accepted December 21, 2007
The 5-lipoxygenase (ALOX5) derived lipid mediators leukotrienes and lipoxins have regulatory functions in inflammation by modulating activities of immune cells and cytokine production. Recently it was shown in ALOX5–/- mice that host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase.
ALOX5 polymorphisms were genotyped in 1916 sputum-positive patients with pulmonary tuberculosis from Ghana and in 2269 exposed, apparently healthy controls. Polymorphisms of a variable number of tandem repeats (VNTR) of the ALOX5 promoter and of the exonic non-synonymous variant g.760G>A were analysed by fragment length determination and fluorescence resonance energy transfer, respectively, and DNA sequencing. Mycobacterial lineages of >1400 isolates were differentiated biochemically and genetically.
Carriers of one variant (n repeats
5) and one wild-type VNTR allele (n=5) or of the exonic allele g.760A had a higher risk of tuberculosis [Pcorrected=0.026, OR 1.19 (95% CI 1.04 - 1.37) and Pcorrected=0.026, OR 1.21 (95% CI, 1.04-1.41) respectively]. The association of the exonic variant was stronger in infections caused by the mycobacterial lineage M. africanum West-African 2 [Pcorrected=0.024, OR 1.70; (95% CI 1.2 - 2.6)]. Determination of haplotypes revealed the strongest associaton with tuberculosis for the "non-5/760A" haplotype compared to the "non-5/760G" haplotype (P=0.003, OR 1.50).
Our observation of an association of ALOX5 variants with susceptibility to tuberculosis contributes evidence of the importance of 5-lipoxygenase products to the regulation of immune responses to M. tuberculosis.
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