Polymorphism of genes associated with infectious lung diseases in Northern Asian populations and in patients with community-acquired pneumonia.

S V Mikhailova,M I Voevoda,L V Shcherbakova,N I Logvinenko,I I Logvinenko

doi:10.18699/vj21.51-o

Abstract

The innate immune system is the first to respond to invading pathogens. It is responsible for invader recognition, immune-cell recruitment, adaptive-immunity activation, and regulation of inflammation intensity. Previously, two single-nucleotide polymorphisms of innate-immunity genes – rs5743708 (Arg753Gln) of the TLR2 gene and rs8177374 (Ser180Leu) of the TIRAP gene – have been shown to be associated with both pneumonia and tuberculosis in humans, but the data are contradictory among different ethnic groups. It has also been reported that rs10902158 at the PKP3-SIGGIR-TMEM16J genetic locus belongs to a haplotype race-specifically associated with tuberculosis. Meanwhile, a gradient of its frequency is observed in Asia. The aim of this work was to assess the effect of selection for the genotypes of the above-mentioned SNPs on the gene pools of populations living in harsh climatic conditions that contribute to the development of infectious lung diseases. We estimated the prevalence of these variants in white and Asian (Chukchis and Yakuts) population samples from Northern Asia and among patients with community-acquired pneumonia (CAP). Carriage of the rs5743708 A allele was found to predispose to severe CAP (odds ratio 2.77, p = 0.021), whereas the GG/CT genotype of rs5743708/rs8177374 proved to be protective against it (odds ratio 0.478, p = 0.022) in white patients. No association of rs10902158 with CAP (total or severe) was found among whites. Stratification of CAP by causative pathogen may help eliminate the current discrepancies between different studies. No significant difference in rs5743708 or rs8177374 was found between adolescent and long-lived white samples. Carriage of the alleles studied is probably not associated with predisposition to longevity among whites in Siberia. Both white and Asian populations studied were different from Western European and East Asian populations in the variants’ prevalence. The frequency of the rs8177374 T (Ser180Leu) variant was significantly higher in the Chukchi sample (p = 0, χ2 = 63.22) relative to the East Asian populations. This result may confirm the hypothesis about the selection of this allele in the course of human migration into areas with unfavorable climatic conditions.

Highlights

Innate immunity constitutes the first barrier against microor ganisms and viruses by destroying infected cells and activating adaptive immunity
Community-acquired pneumonia (CAP) and pulmonary tu berculosis (PTB) are infectious diseases characterized by high mortality, and according to WHO, are ranked consistently among the top 10 leading causes of death in the world
Besides the polymorphisms in genes TLR2 and TIRAP, in this paper, we focused on the PKP3-SIGGIR-TMEM16J gene region

Summary

Introduction

Innate immunity constitutes the first barrier against microor ganisms and viruses by destroying infected cells and activating adaptive immunity. Pneumonia is an inflammatory lower-respiratory-tract disease caused by viruses, bacteria, fungi, and parasites. Streptococcus pneumoniae infection has been considered the main cause of CAP; how ever, it was shown recently that CAP develops mainly as a result of viral infections (influenza A and B viruses, para influenza viruses, adenovirus, respiratory syncytial virus, or coronaviruses) (Choi et al, 2012; Hong et al, 2014; Self et al, 2017). After invasion of the airway epithelium by pathogens, these cells start to produce reactive oxygen species, cytokines, and other mediators to recruit immune cells. Proinflammatory M1 macrophages produce cytokines TNFα, IL-6, IL-1β, IL-12, and IL-23 to enhance inflammation for elimination of the invaders. Anti-inflammatory M2 macro phages produce cytokines IL-4, IL-13, and TGF-β to induce completion of the inflammatory reaction and remodeling of damaged tissue (Moldoveanu et al, 2009; Arango Duque, Descoteaux, 2014; Kumar, 2019)

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