A pilot study of childhood-onset Takayasu arteritis using whole exome sequencing suggests oligogenic inheritance involving classical complement, collagen, and autoinflammatory pathways.

Takayasu arteritis (TA) is a chronic granulomatous inflammatory disease affecting the aorta and its branches. Paediatric TA (pTA) may present from 6 months after birth till the adolescent age group. Genetics and pathogenesis of pTA are not fully understood. Earlier studies reported monogenic mutation in NOD2, XIAP, and STAT1 genes in patients with pTA. TA, a relatively rare disease, is more common in geographical pockets, including India. We hypothesized that South Asian patients with pTA, namely, those of Indian subcontinent origin, may have clinically relevant and unique pathogenic variants involving one or more genes, especially those linked to genetically driven vasculitic illnesses, including autoinflammatory pathologies. Children with pTA fulfilling EULAR/PRINTO/PReS classification criteria and presenting with clinical symptoms to the Paediatric Rheumatology clinic of Christian Medical College, Vellore, were included. Blood samples were collected after getting informed consent from parents or guardians and assent forms from children. DNA was extracted from whole blood using the Qiagen DNA extraction kit. Initially, the common variant in Indian population, namely, ADA2 c.139G > A; p.Gly47Arg, was screened, followed by whole exome sequencing. Fourteen children were recruited for the study. Median age of patients was 11 years (4 months-14 years) with a male-to-female ratio of 4:10. Distribution of angiographic subsets by Numano's classification of included children were as follows: type 5 (n = 7), type 4 (n = 5), and type 3 (n = 2). We identified novel variants in ten different genes. This include variants in genes of classical complement pathway, namely, C2, C3, C6, C7, and C9, and other genes, namely, CYBA, SH3BP2, GUCY2C, CTC1, COL5A1, and NLPR3. Two of 14 patients have heterozygous pathogenic variants; this implies that combination of heterozygous variants in C3 and COL5A1 might lead to disease development, suggesting digenic inheritance. One patient has a homozygous variant in CYBA. None of the patients were identified to have ADA2 variants. Whole exome sequencing reveals combination of rare variants in genes C3, COL5A1, and CYBA associated with disease development in children with Takayasu Arteritis. Key Points • We identified novel variants in genes of classical complement pathway, namely, C2, C3, C6, C7, and C9, and other genes, namely, CYBA, SH3BP2, GUCY2C, CTC1, COL5A1, and NLPR3. • Two of 14 patients have heterozygous pathogenic variants in C3 and COL5A1; this may have implications in disease development, suggesting digenic inheritance. • One patient has homozygous variant in CYBA. • None of the patients were identified to have ADA2 variants.

Anti-integrin αvß6 antibody in Takayasu arteritis patients with or without ulcerative colitis.

Background: It has been well documented that Takayasu arteritis (TAK) and ulcerative colitis (UC) coexist in the same patients. HLA-B*52 characterizes the co-occurrence, which is one of the common genetic features between these two diseases, indicating shared underlying pathologic mechanisms. Anti-integrin αvß6 antibody (Ab) is present in sera of UC patients in a highly specific manner. We investigated if there were any associations between anti-integrin αvß6 Ab and TAK, considering the risk HLA alleles. Methods: A total of 227 Japanese TAK patients were recruited in the current study and their serum samples were subjected to measurement of anti-integrin αvß6 Ab by ELISA. The clinical information, including the co-occurrence of UC, was collected. The HLA allele carrier status was determined by Luminex or genotype imputation. Results: The information about the presence of UC was available for 165 patients, among which eight (4.84%) patients had UC. Anti-integrin αvß6 antibody was identified in 7 out of 8 TAK subjects with UC (87.5%) while only 5 out of 157 (3.18%) TAK subjects without UC had the antibody (OR 121, p=7.46×10-8). A total of 99 out of 218 (45.4%) patients were HLA-B*52 carriers. There was no significant association between the presence of anti-integrin αvß6 Ab and HLA-B*52 carrier status in those without UC (OR 2.01, 95% CI 0.33-12.4, p = 0.189). Conclusions: The prevalence of anti-integrin αvß6 Ab was high in TAK patients with UC, but not in the absence of concomitant UC. The effect of HLA-B*52 on anti-integrin αvß6 Ab production would be minimal.

Serum osteoprotegerin and its gene polymorphisms in patients with Takayasu's arteritis: a bicentric cross-sectional study.

INTRODUCTION: Takayasu's arteritis (TAK) patients are at an elevated risk of metabolic syndrome and cardiovascular diseases (CVD). Currently, there are no well-validated biomarkers to assess this risk in this population. Previous research in different cohorts has linked serum levels of osteoprotegerin (OPG) and its polymorphisms to accelerated atherosclerosis and a marker of poor prognosis in CVD. Thus, we assessed this protein as a potential biomarker of CVD in TAK patients. OBJECTIVES: To evaluate the serum levels of OPG and its SNPs (single nucleotide polymorphisms) in TAK patients and healthy controls, and to associate these parameters with clinical data. METHODS: This bicentric cross-sectional study included TAK patients who were compared with healthy individuals (control group). The serum levels of OPG and the frequency of OPG SNPs [1181G > C (rs2073618), 245 A > C (rs3134069), 163T > C (rs3102735), and 209 C > T (rs3134070)] were compared between the both groups and associated with clinical data. RESULTS: In total, 101 TAK patients and 93 controls were included in the study. The serum levels of OPG (3.8 ± 1.9 vs. 4.3 ± 1.8pmol/L, respectively; P = 0.059), and its four polymorphisms were comparable between both groups. In an additional analysis of only TAK patients, serum OPG levels and its four genes were not associated with any CVD parameters, except for higher OPG levels among patients without dyslipidemia. CONCLUSION: No significant differences were observed in serum OPG levels or in the genotype frequencies of OPG SNPs between the patient and control groups. Similarly, no correlation was found between laboratory parameters and clinical data on CVD risk in TAK patients.

Dysregulation of long non-coding RNAs in Takayasu arteritis: A proof-of-concept study.

Takayasu arteritis (TAK) is a rare systemic vasculitis primarily affecting the aorta and its major branches. Early diagnosis is critical to prevent severe vascular complications, yet current biomarkers are insufficient. This proof-of-concept study explores the potential of long non-coding RNAs (lncRNAs) in TAK, an area largely unexplored. In this cross-sectional study, 53 TAK patients, 53 healthy controls, and 10 rheumatoid arthritis (RA) patients were enrolled. Clinical evaluations, disease activity assessments, and lncRNA expression levels were analyzed. TAK patients exhibited significant dysregulation in several lncRNAs, including THRIL (19.4, 11.1-48.8 vs. 62.5, 48.6-91.4 arbitrary units [a.u.]; p < 0.0001), HIF1A-AS1 (4.5, 1.8-16.6 vs. 26.5, 19.8-33.7 a.u.; p < 0.0001), MALAT-1 (26.9, 13.8-52.5 vs. 92.1, 58.5-92.1 a.u.; p < 0.0001), and HOTAIR (8.0, 2.5-24.5 vs. 36.0, 30.0-43.8 a.u.; p < 0.0001), compared to healthy controls. Notably, HOTAIR (area under the ROC curve [AUC] = 0.825), HIF1A-AS1 (AUC = 0.820), and THRIL (AUC = 0.781) demonstrated high diagnostic potential with superior specificity (approximately 95%). While lncRNAs showed diagnostic promise, no significant correlations with TAK activity were observed. Comparative analysis with RA patients revealed distinct lncRNA expression patterns. This study unveils significant dysregulation of lncRNAs THRIL, HIF1A-AS1, and HOTAIR in TAK patients, underscoring their potential as biomarkers and opening avenues for further research into the mechanistic roles of these lncRNAs in TAK pathogenesis.

High-throughput sequencing reveals the change of TCR α chain CDR3 with Takayasu arteritis.

OBJECTIVE: Takayasu arteritis (TAK) is an inflammatory disease of blood vessels, and its pathogenesis is not clear at present. In this study, we explored the immunological characteristics of T cell receptor (TCR) α-chain complementarity-determining region 3 (CDR3) in patients with TAK. METHODS: Five untreated patients with TAK were collected from June 2019 to December 2019. Four healthy blood samples were matched as the control group. The blood mononuclear cells were separated, and RNA was extracted for reverse transcription to obtain complementary DNA. Then high-throughput sequencing was performed. The quality of samples was evaluated by principal component analysis. We compared the diversity and expression of TCR α-chain between TAK group and control group. R software was used for statistical analysis and drawing, and Mann-Whitney U test was used to analyze the differences between the two groups. RESULTS: The results showed that there was a significant difference in the diversity of TCR α-chain CDR3 between the two groups. Three V region genes expression significantly higher in the TAK patients than in the control group. A total of 196 VJ rearrangement genes are significantly different between the two groups, of which 149 rearrangement genes in the TAK group are lower than those in the control group, and 47 rearrangement genes in the TAK group are higher than those in the control group. CONCLUSION: Patients with TAK have a unique TCR α-chain CDR3 library. These characteristic genes may be a marker for early diagnosis and provide a new theoretical basis for treating TAK.

Arterite de Takayasu em uma lactente com história de dois familiares acometidos / Takayasu's arteritis in an infant with a family with three affected siblings

Objetivos: Por um período consecutivo de 27 anos, 5367 pacientes foram acompanhados na Unidade de Reumatologia Pediátrica do Instituto da Criança. Destes, 17 (0,003%) casos tiveram o diagnóstico de arterite de Takayasu. Uma delas (0,0001%) apresentou antecedentes familiares desta vasculite primária e será descrita. Descrição: Os autores reportam uma lactente do sexo feminino, com história familiar de três irmãos acometidos por arterite de Takayasu. Esta paciente, com 8 meses de idade, apresentou acidente vascular encefálico, hipertensão arterial com diferença de pressão arterial nos quatro membros e redução dos pulsos periféricos. As provas de atividade inflamatória foram elevadas: velocidade de hemossedimentação 37 mm/1ª hora e proteína C reativa 19 mg/L. A angiorressonância evidenciou estenoses de aorta infra-renal, artérias carótidas, artérias cerebral anterior direita e renais, preenchendo os novos critérios de arterite de Takayasu. O tratamento foi realizado com corticoterapia, metrotrexate, pulsoterapia com ciclofosfamida e anti-hipertensivos, com melhora discreta da hipertensão. Conclusão: Arterite de Takayasu é uma vasculite rara em um serviço terciário de reumatologia pediátrica e este diagnóstico deve ser considerado em lactente com doença vascular e redução dos pulsos arteriais...

Objectives: For a period of 27 consecutive years, 5079 patients were followed at the Pediatric Rheumatology Unit of the Instituto da Criança. Of these, 17 (0.003%) cases had a diagnosis of Takayasu’s arteritis. One (0.0001%) had family history of primary vasculitis and will be described. Description: The authors report a female infant with familial history of three siblings affected by Takayasu’s arteritis. This patient’s at 8-month-old had stroke, hypertension with blood pressure differences in all four limbs and reduction of peripheral pulses. The evidence of inflammatory activity was high: erythrocyte sedimentation rate 37 mm/1st hour and C-reactive protein 19 mg/L. The magnetic resonance imaging showed stenosis of the infrarenal aorta, carotid arteries, right anterior cerebral arteries and kidney, filling the new criteria of Takayasu’s arteritis. The treatment was carried out with steroids, methotrexate, intravenous cyclophosphamide and anti-hypertensive drugs, with a slight improvement in hypertension. Conclusion: Takayasu’s arteritis is a rare vasculitis in a tertiary pediatric rheumatology and this diagnosis should be considered in children with vascular disease and reduction of arterial pulses...