Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Curtis, James; Luo, Yang; Zenner, Helen; Cuchet-Lourenço, Delphine; Wu, Changxin; Lo, Kitty; Maes, Mailis; Alisaac, Ali; Stebbings, Emma; Liu, Jimmy Z; Kopanitsa, Liliya; Ignatyeva, Olga; Balabanova, Yanina; Nikolayevskyy, Vladyslav; Baessmann, Ingelore; Thye, Thorsten; Meyer, Christian G.; Nürnberg, Peter; Horstmann, Rolf D.; Drobniewski, Francis; Plagnol, Vincent; Barrett, Jeffrey C.; Nejentsev, Sergey

doi:10.1038/ng.3248

Cited by 162 publications

(183 citation statements)

References 32 publications

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“…The chromosome 18 SNP was also not replicated in South African (Chimusa et al 2014) nor in Chinese (Dai et al 2011; Wang et al 2013) populations, suggesting that this signal may be restricted to certain ethnicities. Finally, our Moroccan results were consistent with the recently reported Russian ASAP1 signal (Curtis et al 2015), although they were not significant in our sample of smaller size.…”

Section: Discussionsupporting

confidence: 90%

“…However, in the case–control replication population, we found a significant association of rs4331426 with PTB with the same direction of association as that previously reported. We finally examined the ASAP1 SNPs recently reported to be associated with PTB in the Russian GWA study (Curtis et al 2015). The two main associated SNPs were successfully imputed (scores of 0.93 for rs4733781 and 0.99 rs10956514) in our family-based population.…”

Section: Resultsmentioning

confidence: 99%

“…Replication of the chromosome 18q11.2 signal in two independent Chinese study populations provided conflicting results (Dai et al 2011; Wang et al 2013). The Russian study identified a cluster of intronic ASAP1 variants in a study population of over 15,000 subjects, also with a weak effect size (OR = 0.84 for the most significant SNP rs4733781), with possible functional involvement in dendritic cell mobility (Curtis et al 2015). Another GWA study combining Japanese and Thai samples reported a variant with a modest effect on chromosome 20q12 among PTB subjects with age of onset <45 years (Mahasirimongkol et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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A genome-wide association study of pulmonary tuberculosis in Morocco

et al. 2016

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Although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (PTB) susceptibility, the identification of specific genes and alleles influencing PTB risk has proven to be difficult. Previous genome-wide association (GWA) studies have identified only three novel loci with modest effect sizes in sub-Saharan African and Russian populations. We performed a GWA study of 550,352 autosomal SNPs in a family-based discovery Moroccan sample (on the full population and on the subset with PTB diagnosis at <25 years), which identified 143 SNPs with p < 1 × 10−4. The replication study in an independent case/control sample identified four SNPs displaying a p < 0.01 implicating the same risk allele. In the combined sample including 556 PTB subjects and 650 controls these four SNPs showed suggestive association (2 × 10−6 < p < 4 × 10−5): rs358793 and rs17590261 were intergenic, while rs6786408 and rs916943 were located in introns of FOXP1 and AGMO, respectively. Both genes are involved in the function of macrophages, which are the site of latency and reactivation of Mycobacterium tuberculosis. The most significant finding (p = 2 × 10−6) was obtained for the AGMO SNP in an early (<25 years) age-at-onset subset, confirming the importance of considering age-at-onset to decipher the genetic basis of PTB. Although only suggestive, these findings highlight several avenues for future research in the human genetics of PTB.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A genome-wide association study of pulmonary tuberculosis in Morocco

et al. 2016

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“…It is vital to determine whether those who remain healthy have a genetically endowed high level of resistance to tuberculosis or whether the resistance is affected by environmental or other exogenous factors24. The genome-wide association study (GWAS) identified several susceptibility loci for tuberculosis in sub-Saharan African, Russian and Moroccan populations252627. However, the follow-up studies reported conflicting results28.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of IL-17A, IL-17F, TLR4 and miR-146a in association with the risk of pulmonary tuberculosis

Wang

et al. 2016

Sci Rep

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Genetic factors affect host susceptibility to pathogens. In this population-based case control study, we explored the genetic polymorphisms of IL-17, TLR4 and miR-146a in association with pulmonary tuberculosis in a Chinese Han population. We recruited 1601 pulmonary tuberculosis patients matched with 1526 healthy controls and genotyped twelve functional single nucleotide polymorphisms (SNPs). After the correction for multiple comparisons, two SNPs (rs10759932 and rs2737190) in the TLR4 gene remained significant. Individuals carrying the rs2737190-AG genotype (vs. AA) had a significantly increased risk of either clinical tuberculosis (OR: 1.31, 95% CI: 1.11–1.53) or sputum smear-positive tuberculosis (OR: 1.35, 95% CI: 1.13–1.61). Stratification analysis revealed that the effects of genetic variations on tuberculosis were more evident among non-smokers. People with haplotype TLR4 rs10983755G–rs10759932C had a significantly increased risk of tuberculosis (OR: 3.43, 95% CI: 2.34–5.05). Moreover, we found that SNPs of rs3819024 in IL-17A and rs763780 in IL-17F were weakly related to a prognosis of tuberculosis. Our results suggest that genetic polymorphisms of IL-17 and TLR4 may play a role in host susceptibility to tuberculosis in the Chinese Han population. More work is necessary to identify specific causative variants of tuberculosis underlying the observed associations.

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“…SNPs in the ASAP1 gene on chromosome 8q24 have been associated with PTB in the Russian population 12. However, in Icelanders these SNPs do not associate with PTB (rs10956514[G] P=0.66, OR=0.99, Supplementary Table 10).…”

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confidence: 99%

HLA class II sequence variants influence tuberculosis risk in populations of European ancestry

et al. 2016

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Mycobacterium tuberculosis (M. tuberculosis) infections cause 9.0 million new tuberculosis (TB) cases and 1.5 million deaths annually1. To search for sequence variants that confer risk of TB we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with TB (8,162 cases and 277,643 controls), pulmonary TB (PTB), and M. tuberculosis infection. We found association of three sequence variants in the HLA class II region: rs557011[T] (MAF=40.2%) with M. tuberculosis infection (OR =1.14, P=3.1×10-13) and PTB (OR=1.25, P=5.8×10-12) and rs9271378[G] (MAF=32.5%) with PTB (OR=0.78, P=2.5×10-12), both located between HLA-DQA1 and HLA-DRB1. Finally, a missense variant p.Ala210Thr in HLA-DQA1, (MAF=19.1%, rs9272785) shows association with M. tuberculosis infection (P=9.3×10-9, OR=1.14). The association of these variants with PTB was replicated in large samples of European ancestry from Russia and Croatia (P< 5.9×10-4). These findings demonstrate that the HLA class II region contributes to the complex genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.

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Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Cited by 162 publications

References 32 publications

A genome-wide association study of pulmonary tuberculosis in Morocco

A genome-wide association study of pulmonary tuberculosis in Morocco

Genetic polymorphisms of IL-17A, IL-17F, TLR4 and miR-146a in association with the risk of pulmonary tuberculosis

HLA class II sequence variants influence tuberculosis risk in populations of European ancestry

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