Epidemiological Trends of Rheumatoid Arthritis and PADI4, PTPN22, and HLA-DRB9 Genes Distribution in the Kazakhstan Population

Abstract

BACKGROUND: The prevalence of rheumatoid arthritis (RA) is 1% in the global population. The lack of epidemiological studies in developing countries makes it difficult to obtain a complete global epidemiological picture of RA. RA develops due to the interaction of multiple genetic and environmental factors, though the contribution of these factors to the various disease occurrence seen in different populations is unclear. AIM: The aim of our study was to analyze the dynamics of the general prevalence and incidence of RA among the population of Kazakhstan in 2017–2019 as well as to investigate the three most common single-nucleotide polymorphisms (SNP) of RA in the Kazakhstan population. METHODS: The analysis of statistical data on Form 12 “On the health of the people and the health care system” was carried out. Prevalence and incidence rates were calculated according to generally accepted rules. Demographic data for the Republic of Kazakhstan were obtained from the official website stat.gov.kz. Our study included 70 RA patients and 113 control subjects. Blood samples were collected and genotyped for peptidylarginine deiminase 4 (PADI4), protein tyrosine phosphatase 22, and human leukocyte antigen (HLA)-DRB9 SNPs by reverse transcription polymerase chain reaction. RESULTS: The prevalence of RA in Kazakhstan in 2017–2019 was 0.36–0.38%, with an incidence rate of 0.085–0.087%, which can be comparable to data of other countries in Central Asia. The allele and genotypes frequency analyses were carried out between patients and controls. The HLA-DRB9 showed significant association of the G allele odds ratio (OR) 1.96 (95% confidence interval [CI]: 1.252–3.081), p= 0.0025 and G/G genotype OR = 3.67 (95% CI: 1.58–8.54), p = 0.00162 with RA in our sample. Strong association between anti-citrullinated protein antibody (ACPA) profile and PADI4 (OR 12.19 [95% CI: 2.19–67.94], p = 0.00115) was found. CONCLUSION: There was an increase in RA prevalence with age among females and a higher crude prevalence and incidence of RA in the southern regions of Kazakhstan. HLA-DRB9 prevailed in Kazakhstani patients with RA, PADI4 showed association with ACPA-positive RA. Further studies on larger samples are required to confirm our obtained results.

Association Study of Anticitrullinated Peptide Antibody Status with Clinical Manifestations and SNPs in Patients Affected with Rheumatoid Arthritis: A Pilot Study

“…Recently, we published a study on HLA-DRB9, PADI4, and PTPN22 gene distribution in Kazakhstani RA patients, which revealed, among other data, an association of PADI4 with the ACPA-positive form of RA [ 29 ]. Similar to what was found in this study, PTPN22 did not show any association with RA, RF-positive, or ACPA-positive status [ 29 ].…”

“…The CTLA4 (cytotoxic T-lymphocyte associated protein 4) sends the inhibitory signal to T cells and provides its regulation [ 15 ], STAT4 (signal transducer and activator of transcription 4) provides phosphorylation in response to proinflammatory cytokines and activates the transcription process under the interleukin-12 control [ 16 ], TAGAP (T cell activation Rho GTPase activating protein) regulates T-cell activation effecting its cytoskeleton [ 17 ], COG6 (component of oligomeric Golgi complex 6) provides a Golgi apparatus functioning [ 18 ], TRAF1 (tumor necrosis factor receptor-associated factor-1) encoding the certain protein of TNF superfamily mediates the antiapoptotic signals coming from TNF receptors [ 19 ], ETS1 (proto-oncogene 1, transcription factor) encodes a protein responsible of a large number of gene expression leading to stem cells and tumor process development [ 20 ], FCRL3 (Fc receptor like-3) encodes a protein that is an Fc receptor-like glycoprotein capable of influencing the activation of immunoreceptor-tyrosine [ 21 ], LBH (limb bud and heart development) regulates WNT signaling pathway [ 22 ], and the roles of LINC01104 (long intergenic nonprotein coding RNA 1104) and other genes are being investigated. Further studies aimed at validating early identified SNPs in different populations demonstrated significant variabilities in genetic predisposition to RA in various ethnicities [ 8 , 23 – 29 ].…”

Screening for Deleterious non-synonymous SNPs in Human CCL21 Gene using in-silico analysis

“…The roles of SNPs have been detected in the non-MHC genes, such as PTPN22 and MHC genes like HLA-DRB-1 which are potent and can drive inflammatory response in RA. Many studies revealed >150 SNPs in RA located at more than 70 gene loci (Jalil, et al, 2013-Issilbayeva, et al, 2021.…”