Association Study of Genes Controlling IL-12-dependent IFN-gamma Immunity: STAT4 Alleles Increase Risk of Pulmonary Tuberculosis in Morocco

作者：Sabri Ayoub; Grant Audrey V; Cosker Kristel; El Azbaoui Safa; Abid Ahmed; Rhorfi Ismail Abderrahmani; Souhi Hicham; Janah Hicham; Alaoui Tahiri Kebir; Gharbaoui Yasser; Benkirane Majid; Orlova Marianna; Boland Anne; Deswarte Caroline; Migaud Melanie; Bustamante Jacinta; Schurr Erwin; Boisson Dupuis Stephanie; Casanova Jean Laurent; Abel Laurent^*; El Baghdadi Jamila

来源：Journal of Infectious Diseases, 2014, 210(4): 611-618.

DOI：10.1093/infdis/jiu140

• genetic association
• family-based study
• candidate pathway
• IL-12
• IFN-gamma
• STAT4
• pulmonary tuberculosis
• eQTL
• Behcet disease
• common variant

Background. Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon gamma (IFN-gamma) circuit in antimycobacterial immunity.
Methods. We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-gamma circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population.
Results. Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P=.0013-.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset <25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06-2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression.
Conclusions. Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression.

• 出版日期2014-8-15
• 单位McGill; 中国地震局