title: Pathway Analyses Identify Novel Variants in the WNT Signaling Pathway Associated with Tuberculosis in Chinese Population.
abstract: Tuberculosis remains a global public health problem, and its immunopathogenesis is still poorly understood. In this study, 25 single nucleotide polymorphisms (SNPs) in the WNT pathway were evaluated in relation to tuberculosis risk in a Chinese Han discovery set, and 6 candidate susceptible SNPs were further validated in a Chinese Tibetan cohort. Luciferase reporter assay, RT-qPCR and Western blot were used to assess the functionality of the important WNT polymorphisms. Five polymorphisms were associated with tuberculosis susceptibility after Bonferroni correction: SFRP1 rs4736958, CTNNB1 rs9859392, rs9870255 and rs3864004 showed decreased tuberculosis risk; SFRP1 rs7832767 was related to an increased risk (OR = 1.81, 95% CI = 1.30-2.52, p = 0.010). Patients with TT genotype of rs4736958 and rs7832767 correlated with higher CRP concentrations (p = 0.003, <0.001, respectively). Functional assays revealed that mutant alleles of rs9859392 (G), rs9870255 (C) and rs3864004 (A) were associated with significantly decreased transcriptional activity, lower CTNNB1 mRNA expression and p-β-catenin level, which were consistent with their effects of decreasing TB risk. Our results provide evidences that WNT pathway polymorphisms influence tuberculosis susceptibility and host immune response to Mycobacterium tuberculosis, suggesting that these variations may serve as novel markers for identifying the risk of developing tuberculosis.
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Pulmonary Disease, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Xingbo
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Bei
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Jingya
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Binwu
authors.initials: B
authors.lastname: Ying
mesh_terms: D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014376:Tuberculosis / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D051176:beta Catenin