A genome-wide association study of pulmonary tuberculosis in Morocco

• Published in: Human genetics Vol. 135; no. 3; pp. 299 - 307
• Main Authors: Grant, A. V., Sabri, A., Abid, A., Abderrahmani Rhorfi, I., Benkirane, M., Souhi, H., Naji Amrani, H., Alaoui-Tahiri, K., Gharbaoui, Y., Lazrak, F., Sentissi, I., Manessouri, M., Belkheiri, S., Zaid, S., Bouraqadi, A., El Amraoui, N., Hakam, M., Belkadi, A., Orlova, M., Boland, A., Deswarte, C., Amar, L., Bustamante, J., Boisson-Dupuis, S., Casanova, J. L., Schurr, E., El Baghdadi, J., Abel, L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2016; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Adolescent; Adult; Age of Onset; Aged; Alleles; Biomedical and Life Sciences; Biomedicine; Blood transfusions; Case-Control Studies; Child; Child, Preschool; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Function; Genes; Genetic Loci; Genetics; Genome-Wide Association Study; Genomes; Genomics; Genotyping Techniques; Hospitals; Human Genetics; Humans; Infant; Infections; Infectious diseases; Introns; Life Sciences; Male; Metabolic Diseases; Middle Aged; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Molecular Medicine; Morocco; Mycobacterium tuberculosis; Original Investigation; Polymorphism, Single Nucleotide; Pulmonary tuberculosis; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reproducibility of Results; Risk Factors; Single nucleotide polymorphisms; Tuberculosis; Tuberculosis, Pulmonary - genetics; Tuberculosis, Pulmonary - microbiology; Young Adult; Morocco; New York; France; United States > US; Paris France; Modest Effect Size; Follow Quality Control; Affected Offspring; High Linkage Disequilibrium; Autosomal SNPs
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-016-1633-2

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.