Host genetics of susceptibilityMutations in genes underlying atypical familial mycobacteriosis are not found in tuberculosis patients from Siberian populations
Introduction
Tuberculosis (TB) remains one of the most common and dangerous infection diseases worldwide, accounting for more than 1.5 million deaths annually [1]. Host genetic factors are known to be important modifiers of the TB risk as approved by epidemiologic, twins, and molecular genetic studies [2], [3]. In contemporary genetics, there are two main directions in the study of inherited determinants of TB risk: the analysis of common (polygenic) predisposition in endemic areas and the analysis of families with rare monogenic (Mendelian) forms of susceptibility to mycobacterial infection designated as “atypical familial mycobacteriosis” (AFM) or “Mendelian susceptibility to mycobacterial disease” in the OMIM database (MIM #209950) [4], [5].
AFM is defined as a severe clinical disease, disseminated or localized, recurrent, caused by weakly virulent bacteria species, such as Mycobacterium bovis BCG, M. marinum, M. smegmatis, M. avium, Salmonella enterica and others in otherwise healthy individuals. The disease is a rare inherited syndrome, clinically described for the first time in 1951 as a disseminated disease caused by BCG vaccination [6]. It is now established that AFM is caused by mutations in 9 genes: IL12B (p40 subunit of IL-12), IL12RB1 (β1 subunit of the receptor to IL-12), IFNGR1, IFNGR2 (first and second domains of the receptor to IFN-γ), STAT1 (IFN-γ-associated signal transductor and activator of transcription), ISG15 (interferon-induced protein 15), IRF8 (interferon regulatory factor 8), IKBKG (NEMO; main modulator of NF-κ-B), and CYBB (cytochrome b(558), beta subunit) [7], [8]. These mutations have common pathogenetic effect based of the impairment of the IFN-γ signalling, which is the main activator of the macrophages anti-mycobacteria defence [4].
This syndrome was described in more than 500 patients from 44 countries. The age of the patients with AFM is less than 14 years; most of them originate from non-endemic areas of countries and groups with high frequency of inbreeding [9], [10]. Mutations in the IL12RB1 and IFNGR1 genes account for about 80% of all recorded cases of AFM syndrome. Most of the mutations are autosomal, except for X-linked defects in IKBKG and CYBB, and exhibit complete or incomplete penetrance.
Incomplete penetrance of some mutations allowed hypothesising that these genetic abnormalities can be distributed in populations with high frequency (>1%). This, in turn, makes it possible that the rare polymorphisms with major effect to the development of TB and low penetrance can account for susceptibility to the disease in common population and not only in separate families. The results of theoretical estimates of Mendelian susceptibility among children affected by disseminated TB showed that the frequency of AFM can vary between 3% and 45% [11]. This means that almost a half cases of children TB can be caused by Mendelian susceptibility. Also, these mutations can play a significant role in susceptibility to TB among adults. At least one study revealed IL12RB1 loss-of-function homozygous mutations in two out of 50 children with severe TB, thus confirming that some of AFM causing mutations may be responsible for predisposition to TB [12]. To the best of our knowledge, no systematic screening for mutations in AFM genes was carried out in Russia. Therefore, we set out to perform such the screening of the AFM causing mutations in the IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1, IKBKG gene in Tuvinians and Russians, ethnically divergent populations from Siberian region of Russia with high prevalence of TB.
Section snippets
Material and methods
The study protocol was approved by the Ethics Committee of the Research Institute for Medical Genetics of the Siberian Branch of Russian Academy of Medical Sciences. Signed informed consent was obtained from each participant or his/her parents (in case of children).
The study was carried out in three stages (Figure 1). First, we screened for known AFM-causing mutations in patients with most severe forms of primary TB. Then, we carried out a bidirectional Sanger's sequencing to seek novel
Results and discussion
The study was designed to test a hypothesis of an impact of rare mutations and polymorphisms causing AFM syndrome into common (polygenic) predisposition to TB in endemic populations.
On the first stage of the study, in sub-samples of 76 Russians and 38 Tuvinians with most severe forms of TB, we performed a screening for most common AFM causing mutations in the IL12RB1, IFNGR1, IFNGR2, and STAT1 genes. Twelve mutations described at least in two independent cases were chosen for this purpose:
Conclusion
The results of our study do not support a hypothesis about the impact of rare mutations in IFNG/IL12 pathway genes on common susceptibility to TB in endemic populations.
Acknowledgements
The study was supported in part by the grants of Ministry of Education and Science of the Russian Federation N8042 and N8156.
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