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PubMed2025

Associations of PTPN22 and PADI4 polymorphisms with rheumatoid arthritis in ASWAN.

BACKGROUND: Rheumatoid Arthritis (RA) is a prevalent autoimmune disease affecting approximately 84,338 individuals in Egypt. Genetic predispositions, such as the PTPN22 and PADI4 genes, are linked to RA risk. PTPN22, a protein tyrosine phosphatase, a regulator of T-cell receptor signalling and PADI4, which is involved in citrullination, have shown varying levels of association with RA across populations. Studies have been inconclusive regarding their roles in RA susceptibility, progression, and activity. PATIENTS AND METHODS: A total of 240 participants were included in this study, RA patients and healthy controls from Aswan, Egypt. Genomic analysis was conducted to evaluate PTPN22 and PADI4 polymorphisms and their associations with RF and ACPA, Also, their correlation with disease activity markers, such as ESR, CRP, PGA and the Disease Activity Score (DAS28). RESULTS: No significant association between PTPN22 and RA with p value ≥ 0.05 with good matching regarding age and sex. However, PTPN22 significantly correlated with RF and ACPA, with p-value of 0.006 and < 0.001, respectively, suggesting its diagnostic value in RA. No significant associations were found between PTPN22 and disease activity markers such as the ESR and CRP. In contrast, PADI4 levels were elevated in the control groups with p value < 0.001 which is against the study hypothesis, which conflicts with findings from other studies. Despite this, PADI4 demonstrated greater specificity (73.3%), in RA diagnosis than did PTPN22 (45.3%), making it a potential diagnostic marker in combination with RF and ACPA. CONCLUSION: Our study revealed no significant associations between PTPN22 or PADI4 polymorphisms and RA susceptibility in the Aswan population. However, both genes were correlated with diagnostic markers such as RF and ACPA. The PADI4 has potential as a diagnostic marker with high specificity.

African↗

PubMed2015

Ptpn22 and Cd2 Variations Are Associated with Altered Protein Expression and Susceptibility to Type 1 Diabetes in Nonobese Diabetic Mice.

By congenic strain mapping using autoimmune NOD.C57BL/6J congenic mice, we demonstrated previously that the type 1 diabetes (T1D) protection associated with the insulin-dependent diabetes (Idd)10 locus on chromosome 3, originally identified by linkage analysis, was in fact due to three closely linked Idd loci: Idd10, Idd18.1, and Idd18.3. In this study, we define two additional Idd loci--Idd18.2 and Idd18.4--within the boundaries of this cluster of disease-associated genes. Idd18.2 is 1.31 Mb and contains 18 genes, including Ptpn22, which encodes a phosphatase that negatively regulates T and B cell signaling. The human ortholog of Ptpn22, PTPN22, is associated with numerous autoimmune diseases, including T1D. We, therefore, assessed Ptpn22 as a candidate for Idd18.2; resequencing of the NOD Ptpn22 allele revealed 183 single nucleotide polymorphisms with the C57BL/6J (B6) allele--6 exonic and 177 intronic. Functional studies showed higher expression of full-length Ptpn22 RNA and protein, and decreased TCR signaling in congenic strains with B6-derived Idd18.2 susceptibility alleles. The 953-kb Idd18.4 locus contains eight genes, including the candidate Cd2. The CD2 pathway is associated with the human autoimmune disease, multiple sclerosis, and mice with NOD-derived susceptibility alleles at Idd18.4 have lower CD2 expression on B cells. Furthermore, we observed that susceptibility alleles at Idd18.2 can mask the protection provided by Idd10/Cd101 or Idd18.1/Vav3 and Idd18.3. In summary, we describe two new T1D loci, Idd18.2 and Idd18.4, candidate genes within each region, and demonstrate the complex nature of genetic interactions underlying the development of T1D in the NOD mouse model.

Alleles↗

PubMed2026

Genomic Structural Equation Modeling Identifies a Shared Inflammatory Genetic Dimension Across Inflammatory Arthritis Phenotypes and Biomarkers.

BACKGROUND: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C-reactive protein (CRP) and interleukin-6 (IL-6), yet the extent of their common genetic basis remains unclear. AIMS: We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers. MATERIALS AND METHODS: We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL-6, fitted a single common factor, and performed multivariate GWAS followed by fine-mapping, transcriptome-wide association, gene-based analysis, pathway enrichment, and cell-type and spatial mapping. RESULTS: A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome-wide significant SNPs across 10 independent lead loci, including one novel signal. Fine-mapping prioritized high-confidence variants near PTPN22, the CRP gene cluster and a urate-associated locus. Gene-level analyses converged on DCLRE1B, PTPN22, IL6R, NLRP3 and HNF1A, with pathway enrichment implicating inflammasome assembly and metabolic-inflammatory overlap. Cell-type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues. DISCUSSION: These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine-receptor and metabolic pathways. CONCLUSION: Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.

TWAS↗

PubMed2026

Genome-wide etiology analysis of autoimmune hypothyroidism supports somatic mutations of at-risk DNA as the underlying cause.

Autoimmune hypothyroidism (AIHT) is the most common autoimmune disease. Through an unidentified mechanism, the immune system attacks the thyroid gland, destroys thyroid follicular cells, and causes hypothyroidism. A new theory poses that all DNA is continuously damaged and, as a result, is exposed to somatic mutations at a constant rate. Based on this theory, several assumptions related to epidemiology and DNA sequence can be made. These have been summarized as a method called genome-wide etiology analysis (GWEA) to facilitate the interpretation of GWAS results of autoimmune diseases. Here, GWEA is applied to AIHT. The results show that existing epidemiological and genomic data of AIHT adhere to the principles of GWEA. Therefore, AIHT appears to be the result of somatic mutations in people at risk for the disease. AIHT develops once sufficient mutations create a new "autoimmune pathway" driven by non-self-signal and supported by neopeptide formation and signal amplification. Given the random nature of somatic mutations throughout life, the new theory explains why some people with AIHT develop additional autoimmune diseases, why family members may develop a range of non-AIHT autoimmune diseases, why the age of onset cannot be predicted, and why AIHT is transferred to the following generations through dominant inheritance with delayed, incomplete penetrance.

Humans↗