Dataset Information

Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina.

ABSTRACT: We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 3' UTR SNP rs3212227 (unadjusted allelic p?=?0.04; additive genotypic p?=?0.05, OR?=?0.78, 95% CI [0.61-0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p?=?0.05; additive genotypic p?=?0.05, OR?=?0.76, 95% CI [0.58-1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p?=?0.002; additive genotypic p?=?0.05, OR?=?0.78, 95% CI [0.61-1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it.

SUBMITTER: Morris GA

PROVIDER: S-EPMC3037276 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina.

Morris Gerard A J GA Edwards Digna R Velez DR Hill Philip C PC Wejse Christian C Bisseye Cyrille C Olesen Rikke R Edwards Todd L TL Gilbert John R JR Myers Jamie L JL Stryjewski Martin E ME Abbate Eduardo E Estevan Rosa R Hamilton Carol D CD Tacconelli Alessandra A Novelli Giuseppe G Brunetti Ercole E Aaby Peter P Sodemann Morten M Østergaard Lars L Adegbola Richard R Williams Scott M SM Scott William K WK Sirugo Giorgio G

PloS one 20110209 2

We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 contr ...[more]

PMID: 21339808

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Project description:The Guinea-Bissau family of strains is a unique group of the Mycobacterium tuberculosis complex that, although genotypically closely related, phenotypically demonstrates considerable heterogeneity. We have investigated 414 M. tuberculosis complex strains collected in Guinea-Bissau between 1989 and 2008 in order to further characterize the Guinea-Bissau family of strains. To determine the strain lineages present in the study sample, binary outcomes of spoligotyping were compared with spoligotypes existing in the international database SITVIT2. The major circulating M. tuberculosis clades ranked in the following order: AFRI (n?=?195, 47.10%), Latin-American-Mediterranean (LAM) (n?=?75, 18.12%), ill-defined T clade (n?=?53, 12.8%), Haarlem (n?=?37, 8.85%), East-African-Indian (EAI) (n?=?25, 6.04%), Unknown (n?=?12, 2.87%), Beijing (n?=?7, 1.68%), X clade (n?=?4, 0.96%), Manu (n?=?4, 0.97%), CAS (n?=?2, 0.48%). Two strains of the LAM clade isolated in 2007 belonged to the Cameroon family (SIT61). All AFRI isolates except one belonged to the Guinea-Bissau family, i.e. they have an AFRI_1 spoligotype pattern, they have a distinct RFLP pattern with low numbers of IS6110 insertions, and they lack the regions of difference RD7, RD8, RD9 and RD10, RD701 and RD702. This profile classifies the Guinea-Bissau family, irrespective of phenotypic biovar, as part of the M. africanum West African 2 lineage, or the AFRI_1 sublineage according to the spoligtyping nomenclature. Guinea-Bissau family strains display a variation of biochemical traits classically used to differentiate M. tuberculosis from M. bovis. Yet, the differential expression of these biochemical traits was not related to any genes so far investigated (narGHJI and pncA). Guinea-Bissau has the highest prevalence of M. africanum recorded in the African continent, and the Guinea-Bissau family shows a high phylogeographical specificity for Western Africa, with Guinea-Bissau being the epicenter. Trends over time however indicate that this family of strains is waning in most parts of Western Africa, including Guinea-Bissau (p?=?0.048).

Project description:Tuberculosis (TB) is the leading cause of death from a single infectious agent. According to the WHO, 85% of cases in 2018 were pulmonary tuberculosis (PTB), making it the most prevalent form of the disease. Although the bacillus responsible for disease, Mycobacterium tuberculosis (MTB), is estimated to infect 1.7 billion people worldwide, only a small portion of those infected (5-10%) will transition into active TB. Because such a small fraction of infected people develop active disease, we hypothesized that underlying host genetic variation associates with developing active pulmonary disease. Variation in CLEC4E has been of interest in previous association studies showing either no effect or protection from PTB. For our study we assessed 60 SNPs in 11 immune genes, including CLEC4E, using a case-control study from Guinea-Bissau. The 289 cases and 322 controls differed in age, sex, and ethnicity all of which were included in adjusted models. Initial association analysis with unadjusted logistic regression revealed putative association with seven SNPs (p < 0.05). All SNPs were then assessed in an adjusted model. Of the six SNPs that remained significant, three of them were assigned to the CLEC4E gene (rs12302046, rs10841847, and rs11046143). Of these, only rs10841847 passed FDR adjustment for multiple testing. Adjusted regression analyses showed that the minor allele at rs10841847 associated with higher risk of developing PTB (OR = 1.55, CI = 1.22-1.96, p-value = 0.00036). Based on these initial association tests, CLEC4E seemed to be the predictor of interest for PTB risk in this population. Haplotype analysis (2-SNP and 3-SNP windows) showed that minor alleles in segments including rs10841847 were the only ones to pass the threshold of global significance, compared to other haplotypes (p-value < 0.05). Linkage disequilibrium patterns showed that rs12302046 is in high LD with rs10841847 (r2 = 0.67), and all other SNPs lost significance when adjusted for rs10841847 effects. These findings indicate that rs10841847 in CLEC4E is the single best predictor of pulmonary tuberculosis risk in our study population. These results provide evidence for the hypothesis that genetic variation of CLEC4E influences risk to TB in Guinea-Bissau.

Dataset Information

Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina.

Publications

Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina.

Similar Datasets

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