Abstract
We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, Pcorr.<0.029, Odds ratio = 2.42, 95% Confidence Interval = 1.34–4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, pcorr.<0.024, Odds ratio 3.45, 95% Confidence Interval = 1.26–9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease.
Highlights
Tuberculosis (TB) is the leading killer among infectious diseases and constitutes a major health problem in developing world, with yearly incidences of around 8.7 million cases globally [1]
We found that the homozygous carriers of three variable number of tandem repeats (VNTR) repeats of FAM46A gene were strongly associated with susceptibility to tuberculosis (Table 1)
These results need to be confirmed in other populations/groups. This is the first report of an association between the FAM46A gene VNTR polymorphisms and any disease [19,20]
Summary
Tuberculosis (TB) is the leading killer among infectious diseases and constitutes a major health problem in developing world, with yearly incidences of around 8.7 million cases globally [1]. Mycobacterium tuberculosis (MTB) is the main cause of this disease. About 30% of the world population is exposed to MTB, only 10% of those exposed become infected. Only half of the infected individuals develop clinical TB within two years of infection, while the other half of infected individuals may develop clinical TB later in life or maintain latent infection for the rest of their lives [2,3]. MTB is a very resilient bacterium due to many factors including a significant ability to adapt to the environment and to inhibit phagosome maturation. Long latency, coupled with reactivation under conditions that weaken the immune system, contributes to the resilience of MTB [4,5]
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