The genes of the major histocompatibility complex (HLA) play a significant role in the genetic predisposition to juvenile idiopathic arthritis (JIA) and determine up to 18 % of disease risk. This work was aimed to reveal associations of the HLA characteristic pattern with two clinically different forms of JIA in the Belarusian population. 24 patients diagnosed with systemic JIA, 24 patients with oligoarticular JIA and 24 healthy controls were included into the study. High-throughput HLA typing for 11 loci was performed using TruSight HLA v2 Sequencing Panel (Illumina) on the MiSeq system. DQB1*04:02:01 (p = 0.026; OR 5.88 [1.20–28.72]), DRB1*08:01:01 (p = 0.07; OR 3.94 [1.01–15.39]) and DR8-haplotype (p = 0.006; OR 3.95 [1.34–11.63]) frequencies were significantly higher in patients with oligoarthritis but not systemic JIA when compared with controls. While DQA1*05:01:01 and DQB1*02:01:01 alleles showed a protective effect against both systemic (p = 0.007, OR 0.08 [0.009–0.65]; p = 0.01, OR 0.09 [0.01–0.83]) and oliarticular JIA (p = 0.026, OR 0.16 [0.03–0.79]; p = 0.046, OR 0.2 [0.04–1.00], the negative association of the DRB1*03:01 allele was revealed only for systemic JIA (p = 0.03, OR 0.11 [0.01–0.88]). Thus, the obtained results suggest that different HLA-patterns are involved into the formation of various JIA subtypes.
Разнообразие причин возникновения суставного синдрома (СС) и сходство его клинической картины при многих заболеваниях значительно осложняют проведение дифференциальной диагностики. Для ювенильного идиопатического артрита (ЮИА) до сих пор не существует высокоспецифичных лабораторных тестов, при этом прогноз течения и эффективность терапии зависят от своевременной постановки диагноза. Цель: изучить ассоциации полиморфных вариантов генов, продукты которых вовлечены в регуляцию и реализацию функций иммунной системы, с риском развития различных подтипов ЮИА и другой патологии суставов у детского населения Республики Беларусь. В трех группах детей (275 пациентов с ЮИА, 230 - с патологией суставов различного генеза, за исключением ЮИА, 291 - без аутоиммунных и хронических воспалительных заболеваний (контроль)) методами real-time PCR и PCR-RFLP был проведен молекулярно-генетический анализ 11 полиморфных локусов 8 генов: STAT4 (rs7574865), CTLA4 (rs231775), PTPN2 (rs2542151, rs7234029), IL-6 (rs1800795), IL-6R (rs2228145, rs4845618), RUNX1 (rs9979383), FOXP3 (rs3761548, rs2232365), TRAF1/C5 (rs3761847). Установлено, что гомозиготы СС в локусе rs1800795 гена IL-6 ассоциированы с ЮИА в целом (OR 1,75 [1,18-2,58], р=0,0058), а гомозиготы GG в локусе rs3761847 гена TRAF1/C5 - с системной формой ЮИА (OR 2,79 [1,29-6,06], p=0,01). Показано, что генотип GG по локусу rs3761847 гена TRAF1/C5 (р=0,04; OR 1,66 [1,03-2,68]), генотип СС (р=0,0002; OR 2,26 [1,47-3,47]) и аллель С (р=0,006; OR 2,01 [1,14-3,52]) по локусу rs1800795 гена IL6 ассоциированы c дебютом ЮИА в возрасте до 5 лет. Олигоартрит, серонегативный полиартрит и системный ЮИА различаются между собой по частотам распространенности аллельных вариантов в локусах rs3761847 гена TRAF1/C5 и rs7574865 гена STAT4. Группа пациентов с ЮИА в целом значительно отличается от группы пациентов с СС по индивидуальным локусам генов IL-6R (rs2228145, rs4845618), FOXP3 (rs2232365), TRAF1/C5 (rs3761847), а также по частотам 33 парных комбинаций генотипов исследуемых полиморфных вариантов. Среди пациентов с ЮИА выявлены зависимые от пола особенности распространения генотипов по полиморфным вариантам генов IL-6R (rs2228145, rs4845618) и RUNX1 (rs9979383). Полученные данные о генетически обусловленных различиях отдельных подтипов ЮИА, а также ЮИА и СС при другой патологии суставов могут служить основой для разработки дополнительных критериев дифференциальной диагностики заболеваний суставов у детей. The variety of causes of the articular syndrome (AS) and the similarity of its clinical manifestation in many diseases significantly complicate the differential diagnosis. Despite the prognosis of the juvenile idiopathic arthritis (JIA) depends on the early diagnosis, there are still no highly specific laboratory tests. Objective: to assess the association of the polymorphic loci of the genes involved into the regulation and implementation of the immune system functions with predisposition to the JIA and other joint pathology in children in the Republic of Belarus. Three groups of children: 275 patients with JIA, 230 patients with joint pathology of various origins, with the exception of JIA and 291 children without autoimmune and chronic inflammatory diseases (control) were genotyped for 11 polymorphic loci of 8 genes: STAT4 (rs7574865), CTLA4 (rs231775), PTPN2 (rs2542151, rs7234029), IL-6 (rs1800795), IL-6R (rs2228145, rs4845618), RUNX1 (rs9979383)) TRAF1/C5 (rs3761847) using real-time PCR and PCR-RFLP. It was found that CC genotype at the rs1800795 locus of the IL-6 gene is associated with the JIA in the general (OR 1.75 [1.18 - 2.58], p = 0.0058), and GG genotype at the rs3761847 locus of the TRAF1/C5 gene - with the systemic JIA (OR 2.79 [1.29 - 6.06], p = 0.01). GG genotype at the rs3761847 locus of the TRAF1/C5 (р = 0.04; OR 1.66 [1.03 - 2.68]) gene and CC genotype (р = 0.0002; OR 2.26 [1.47 - 3.47]) as well as C allele (р = 0.006; OR 2,01 [1.14 - 3.52]) at the rs1800795 locus of the IL-6 gene are associated with early-onset JIA (≤ 5 years). The most common JIA subtypes (oligoarthritis, seronegative polyarthritis, systemic arthritis) differ in the prevalence of allelic variants at the rs3761847 loci of the TRAF1/C5 gene and rs7574865 of the STAT4 gene. JIA patients differ significantly from the AS patients at the following loci: IL-6R (rs2228145, rs4845618), FOXP3 (rs2232365), TRAF1/C5 (rs3761847), as well by the frequencies of 33 paired genotype combinations of the studied polymorphisms. Among JIA patients, sex-dependent features of the genotype distribution in polymorphic variants of the IL-6R (rs2228145, rs4845618) and RUNX1 (rs9979383) genes were revealed. Conclusion. The data obtained indicate genetically determined differences between JIA subtypes as between JIA and AS in case of other joint pathology. This can be used as a basis for the additional criteria development for the differential diagnosis of joint diseases in children.
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