Promoter Variation in the DC-SIGN–Encoding Gene CD209 Is Associated with Tuberculosis

Abstract

BackgroundTuberculosis, which is caused by Mycobacterium tuberculosis, remains one of the leading causes of mortality worldwide. The C-type lectin DC-SIGN is known to be the major M. tuberculosis receptor on human dendritic cells. We reasoned that if DC-SIGN interacts with M. tuberculosis, as well as with other pathogens, variation in this gene might have a broad range of influence in the pathogenesis of a number of infectious diseases, including tuberculosis.Methods and FindingsWe tested whether polymorphisms in CD209, the gene encoding DC-SIGN, are associated with susceptibility to tuberculosis through sequencing and genotyping analyses in a South African cohort. After exclusion of significant population stratification in our cohort, we observed an association between two CD209 promoter variants (−871G and −336A) and decreased risk of developing tuberculosis. By looking at the geographical distribution of these variants, we observed that their allelic combination is mainly confined to Eurasian populations.ConclusionsOur observations suggest that the two −871G and −336A variants confer protection against tuberculosis. In addition, the geographic distribution of these two alleles, together with their phylogenetic status, suggest that they may have increased in frequency in non-African populations as a result of host genetic adaptation to a longer history of exposure to tuberculosis. Further characterization of the biological consequences of DC-SIGN variation in tuberculosis will be crucial to better appreciate the role of this lectin in interactions between the host immune system and the tubercle bacillus as well as other pathogens.

DC-SIGN (CD209), pentraxin 3 and vitamin D receptor gene variants associate with pulmonary tuberculosis risk in West Africans

“…25 Since the À871 SNP is absent in sub-Saharan Africans, our negative finding can only exclude a causal effect of À336, but we cannot confute a role for the À871/À336 haplotype in non-Africans. The apparent conflict of our data with that of Barreiro et al 5 can be explained by genetic heterogeneity (with different populations having differences in gene variants affecting risk) and is in agreement with the finding that their effect was mainly confined to people of Eurasian descent. One intronic SNPs found to be monomorphic in the Guinea-Bissau population sample.…”

“…The first candidate was the C-type lectin DC-SIGN. A recent study by Barreiro et al 5 indicated an association between two DC-SIGN promoter SNPs (À871G and À336A) and a decrease in the risk of pulmonary TB. These authors investigated a South African population and concluded that the À871G/ À336A combination was largely confined to European and Asian populations.…”

“…4 A recent study by Barreiro et al 5 has shown that, in a South African population sample of European and Asian descent, sequence variation in the DC-SIGN promoter provided protection from TB.…”

Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

“…Inflammation is finely regulated through a complex network of transcription factors and post-translational mechanisms. [40][41][42] It is therefore conceivable that pathogen susceptibility or resistance might also in part reflect differences in gene expression. A future challenge for genetic association studies of human diseases will be to identify polymorphisms in non-coding sequences.…”

Tuberculosis infection: Insight from immunogenomics

“…In addition, the discussion of variants in TLR pathway genes described above may impact DC function. More recently, genetic studies of human DC-SIGN in South Africa have identified two promoter variants, -871G and -336A, that are associated with TB susceptibility [37]. The -336 SNP has also been found to be associated with Dengue fever and alters transcriptional activity at a Sp1-binding site, where the SNP resides [38].…”