Abstract
Immunogenetic host factors are associated with susceptibility or protection to tuberculosis (TB). Strong associations of HLA class II genes with TB are reported. We analyzed the HLA-DRB1*04 alleles to identify subtypes associated with pulmonary TB and their interaction with risk factors such as alcohol, smoking, and gender in 316 pulmonary TB patients and 306 healthy individuals from the Brazilian Amazon. The HLA-DRB1*04 was prevalent in patients with pulmonary TB (p<0.0001; OR = 2.94; 95% CI = 2.12 to 4.08). Direct nucleotide sequencing of DRB1 exon 2 identified nine subtypes of HLA-DRB1*04. The subtype HLA-DRB1*04:11:01 (p = 0.0019; OR = 2.23; 95% CI = 1.34 to 3.70) was associated with susceptibility to pulmonary TB while DRB1*04:07:01 (p<0.0001; OR = 0.02; 95% CI = 0.001 to 0.33) to protection. Notably, the interaction between alcohol and HLA-DRB1*04:11:01 increased the risk for developing pulmonary TB (p = 0.0001; OR = 51.3; 95% CI = 6.81 to 386). Multibacillary pulmonary TB, the clinical presentation of disease transmission, was strongly associated with interaction to alcohol (p = 0.0026; OR = 11.1; 95% CI = 3.99 to 30.9), HLA-DRB1*04:11:01 (p = 0.0442; OR = 2.01; 95% CI = 1.03 to 3.93) and DRB1*04:92 (p = 0.0112; OR = 8.62; 95% CI = 1.63 to 45.5). These results show that HLA-DRB1*04 are associated with pulmonary TB. Interestingly, three subtypes, DRB1*04:07:01, DRB1*04:11:01 and DRB1*04:92 of the HLA-DRB1*04 could be potential immunogenetic markers that may help to explain mechanisms involved in disease development.
Highlights
Tuberculosis (TB), a serious public health problem worldwide, is caused by Mycobacterium tuberculosis complex (MTBC) with M. tuberculosis being the most common [1, 2]
Our study aimed to identifying subtypes of Human Leukocyte Antigen (HLA)-DRB1Ã04 in patients with pulmonary TB to correlate with risk factors for the development of disease and to explain the HLA role on the high incidence rate of TB cases in the Amazonas state
The generic HLA-DRB1Ã04 allele was most common in pulmonary TB patients, showing strong association with susceptibility to disease
Summary
Tuberculosis (TB), a serious public health problem worldwide, is caused by Mycobacterium tuberculosis complex (MTBC) with M. tuberculosis being the most common [1, 2]. In 2014, the Amazonas state had an incidence rate of 68.4 cases of TB/100.000 habitants that is well above the national average and ranks first in relation to other states [4] Several risk factors such as HIV-infected individuals [5, 6], diabetes mellitus [7, 8], smoking [9], alcohol [10, 11], under-nutrition [12, 13] and host immunogenetic factors [14,15,16,17,18] are associated with susceptibility to TB. The generic HLA-DRB1Ã04 was frequent in pulmonary TB patients (unpublished data), but this gene has many subtypes and is very important to determine which alleles are associated with the disease For this reason, our study aimed to identifying subtypes of HLA-DRB1Ã04 in patients with pulmonary TB to correlate with risk factors for the development of disease and to explain the HLA role on the high incidence rate of TB cases in the Amazonas state
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