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Objective: Familial aggregation of systemic autoimmune diseases is frequently reported, but little is known about how fathers and mothers differentially contribute to the development of autoimmune diseases in their offspring. This study aimed to investigate the impact of maternal and paternal autoimmunity on the risk of offspring rheumatic diseases., Methods: We constructed a nationwide population-based cohort using data from the Maternal and Child Health Database and the Taiwan National Health Insurance Research Data (NHIRD) from 2004 to 2019. The outcome was presence of an autoimmune disease in the offspring. Inverse probability of treatment-weighted Cox models were used to estimate adjusted hazard ratios (aHRs) and 95% CIs for autoimmune diseases., Results: Babies born to a father or mother with an autoimmune disease had, respectively, 1.22 times and 1.38 times the risk of developing an autoimmune disease compared with their counterparts with no parental autoimmune diseases. Maternal autoimmunity substantially contributed to the risk of SLE (aHR = 5.46, 95% CI: 5.28-5.66), and paternal autoimmunity contributed to the risk of JIA (aHR = 1.76, 95% CI: 1.71-1.81) and of type 1 diabetes mellitus (aHR = 1.59, 95% CI: 1.39-1.81) in their offspring. The contributions of mothers to the risk of development of SLE (aHR = 8.55, 95% CI: 8.10-9.02) and inflammatory myopathy (aHR = 2.08, 95% CI: 1.72-2.51) in their offspring were exacerbated in boys. Babies of two parents with an autoimmune disease showed a 1.39-fold risk of developing an autoimmune disease. The maternal contribution effect was stronger for preterm births than for full-term births., Conclusion: This study demonstrated broadly how autoimmune diseases pass from parents to infants of both genders and separately quantified the maternal and paternal contributions to disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Discovery of the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome demonstrates that somatic mutations in haematological precursor cells can cause adult-onset, complex inflammatory disease. Unlike germline mutations, somatic mutations occur throughout the lifespan, are restricted to specific tissue types, and may play a causal role in non-heritable rheumatological diseases, especially conditions that start in later life. Improvements in sequencing technology have enabled researchers and clinicians to detect somatic mutations in various tissue types, especially blood. Understanding the relationships between cell-specific acquired mutations and inflammation is likely to yield key insights into causal factors that underlie many rheumatological diseases. The objective of this review is to detail how somatic mutations are likely to be relevant to clinicians who care for patients with rheumatological diseases, with particular focus on the pathogenetic mechanisms of the VEXAS syndrome., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.)

Ankylosing spondylitis (AS) is a highly heritable chronic inflammatory arthritis characterized by osteoproliferation, fusion of affected joints and systemic manifestations. Many disease associations for AS have been reported through genome-wide association studies; however, identifying modulated genes and functional mechanism remains challenging. This review summarizes current genetic associations involving AS and describes strategic approaches for functional follow-up of disease-associated variants. Fine mapping using methods leveraging Bayesian approaches are outlined. Evidence highlighting the importance of context specificity for regulatory variants is reviewed, noting current evidence in AS for the relevant cell and tissue type to conduct such analyses. Technological advances for understanding the regulatory landscape within which functional variants may act are discussed using exemplars. Approaches include defining regulatory elements based on chromatin accessibility, effects of variants on genes at a distance through evidence of physical interactions (chromatin conformation capture), expression quantitative trait loci mapping and single-cell methodologies. Opportunities for mechanistic studies to investigate the function of specific variants, regulatory elements and genes enabled by genome editing using clustered regularly interspaced short palindromic repeats/Cas9 are also described. Further progress in our understanding of the genetics of AS through functional genomic and epigenomic approaches offers new opportunities to understand mechanism and develop innovative treatments.

Triggering of autoimmunity that leads to rheumatic disease has been suggested to depend upon gene-environment interactions occurring in epithelial barriers and associated immune cells. Genetic studies have identified associations of the FAM167A-BLK locus with rheumatoid arthritis, systemic lupus erythematosus (SLE) and Sjögren's syndrome. While BLK (B lymphocyte kinase) has a well-established role in B cells, family with sequence similarity to 167 member A (FAM167A) and its gene family remain uncharacterized. To begin to understand the role of FAM167A in rheumatic disease pathogenesis, we explored this gene family and cloned and investigated the gene products. Expression of quantitative trait locus analysis was performed in immune cells. FAM167A and FAM167B were cloned from human peripheral blood mononuclear cells (PBMC). Gene conservation and protein properties were analysed by online tools, mRNA expression measured in mouse organs by quantitative polymerase chain reaction (qPCR) and protein expression investigated in human tissues by immunohistochemistry. We found that autoimmune risk genotypes within the FAM167A-BLK locus lead to increased expression of FAM167A. The FAM167 gene family includes two members, FAM167A and FAM167B, which are not homologous to any other annotated gene but are evolutionarily conserved. The encoded proteins, which we denote 'disordered autoimmunity' (DIORA)-1 and DIORA-2, respectively, are characterized by a high content of intrinsic disorder. Notably, DIORA-1 has its highest expression in the lung, detectable in both bronchial epithelium and alveolar macrophages with an endosomal localization pattern. In summary, the FAM167A gene is associated with several rheumatic diseases and encodes a novel disordered protein, DIORA-1, which is expressed highly in the lung, consistent with a potential role in disease pathogenesis., (© 2018 British Society for Immunology.)

Objective: To uncover the genetic background of relapsing polychondritis (RPC), a rare autoimmune disease with unknown mechanisms characterized by systemic inflammation of the cartilage, to deepen our understanding of the pathophysiology of RPC and show its distinct genetic characteristics from other rheumatic diseases., Methods: A total of 102 patients with RPC and 1000 healthy subjects were recruited for a two-staged genetic association study and genotyped for six HLA classical loci. Haplotype association tests were also performed. The associations of amino acid (AA) residues and positions with susceptibility to RPC were analysed. Frequencies of representative susceptibility HLA alleles to other rheumatic diseases in RPC were also analysed., Results: HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, which are in linkage disequilibrium with each other, were associated with RPC (P = 1.9 × 10(-6), 1.4 × 10(-5) and 0.00024, respectively). AA residue at position 57 in HLA-DQB1, the most significant position in type I diabetes mellitus, showed the strongest association among AA residues. HLA-DR4, a known susceptibility allele in Germans, showed a trend of susceptibility association without significance (P = 0.067). No associations were observed between the three alleles and clinical phenotypes. Representative susceptibility HLA alleles to RA, SLE, Behçet disease and Takayasu arteritis did not show enrichment in RPC in spite of sufficient statistical power., Conclusions: HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, in linkage disequilibrium with each other, are associated with susceptibility to RPC Importance of HLA-class II loci in RPC susceptibility is suggested. RPC is considered a genetically distinct disease from other rheumatic diseases., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Epigenetics is a key mechanism regulating the expression of genes. There are three main and interrelated mechanisms: DNA methylation, post-translational modification of histone proteins and non-coding RNA. Gene activation is generally associated with lower levels of DNA methylation in promoters and with distinct histone marks such as acetylation of amino acids in histones. Unlike the genetic code, the epigenome is altered by endogenous (e.g. hormonal) and environmental (e.g. diet, exercise) factors and changes with age. Recent evidence implicates epigenetic mechanisms in the pathogenesis of common rheumatic disease, including RA, OA, SLE and scleroderma. Epigenetic drift has been implicated in age-related changes in the immune system that result in the development of a pro-inflammatory status termed inflammageing, potentially increasing the risk of age-related conditions such as polymyalgia rheumatica. Therapeutic targeting of the epigenome has shown promise in animal models of rheumatic diseases. Rapid advances in computational biology and DNA sequencing technology will lead to a more comprehensive understanding of the roles of epigenetics in the pathogenesis of common rheumatic diseases.

Objectives: Polymorphisms in genes related to the IFN pathway were investigated for susceptibility to rheumatic diseases and correlation with gene expression in thymus., Methods: Forty-five polymorphisms were genotyped in Norwegian patients with RA (n = 518), JIA (n = 440), SLE (n = 154) and healthy controls (n = 756). Forty-two thymic samples were used for gene expression analysis. Six hundred and fifty SLE patients and 737 healthy controls from Spain were available for replication., Results: We found a novel association between interferon regulatory factor 5 (IRF5), rs2004640 and JIA, in particular with the polyarthritis RF-negative patients [odds ratio (OR) = 1.60; 95% confidence interval (CI) 1.17, 2.20; P = 0.003]. Also, we confirmed the associations between rs2004640 and SLE (OR = 1.95; 95% CI 1.50, 2.53; P = 3.75 × 10(-7)), which was further strengthened in a meta-analysis (OR = 1.44; 95% CI 1.36, 1.52; P = 2.11 × 10(-37)). Suggestive evidence of association between rs2004640 and RA was found in the Norwegian discovery cohort (OR = 1.19; 95% CI 1.02, 1.40; P = 0.029) and strengthened in a meta-analysis (OR = 1.11; 95% CI 1.05, 1.18; P = 0.00028). Expression levels of exon 1B IRF5 transcripts were dependent on the presence of the rs2004640 T risk allele in thymic tissue, while exon 1A transcript levels correlated with IRF5 promoter CGGGG-indel variants., Conclusion: The IFN pathway gene, IRF5, is a common susceptibility factor for several rheumatic and autoimmune diseases, and risk variants are correlated with expression of alternative IRF5 transcripts in thymus implying a regulatory role.

Objective: To analyse the autoimmune response to DNA damage response factors in systemic autoimmune rheumatic disease (SARD) patients and to determine their association with autoantibodies to Ku antigen., Methods: We have screened the serum of 239 patients suffering from SARD, including systemic lupus erythematosus, systemic sclerosis and rheumatoid arthritis to detect the occurrence of autoantibodies to Ku and four other DNA damage response factors that form macromolecular complexes with Ku using an immunoprecipitation assay., Results: We identified samples positive for autoantibodies to Ku (20.5%), DNA-dependent protein kinase catalytic subunit (DNA-PKcs, 8.4%) and poly(ADP-ribose) polymerase (5.9%), and report for the first time autoantibodies directed against two additional DNA repair proteins, Werner (6.3%) and Mre11 (9.6%). Remarkably, we found a striking correlation between the production of antibodies to Ku and the other four Ku-binding factors. Sixty-five percent of anti-Ku-positive sera were found to contain at least one of the four anti-DNA repair antibodies vs only 10% of the anti-Ku-negative sera., Conclusion: Our results suggest that the autoantibodies directed against Ku are elicited by macromolecular protein complexes containing Ku and the associated DNA damage proteins. The presence of autoantibodies directed against macromolecular complexes known to play roles in the DNA damage response provides evidence that B-cell responses to latent or persistent DNA damage may be present at the onset or during the development of autoimmunity in certain SARDs.

Objective: To assess whether combined evidence shows the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) C1858T polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases., Methods: We surveyed studies on the PTPN22 C1858T polymorphism and autoimmune diseases using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes T/T (recessive effect), T/T + C/T (dominant effect) and T-allele in random effects models., Results: Twenty-nine studies with 43 comparisons including 13 rheumatoid arthritis (RA), six systemic lupus erythematosus (SLE), six type-1 DM (T1D), three Grave's disease (GD), four inflammatory bowel diseases (IBD), three juvenile idiopathic arthritis (JIA), two psoriasis, two multiple sclerosis, two Addison's disease and two Celiac disease were available for the meta-analysis. The overall odds ratios (ORS) for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (OR for T-allele = 1.58, 1.49, 1.85, 1.61, respectively, P < 0.00001). This meta-analysis showed the association between the T-allele and the T/T genotype and JIA (OR = 1.34, P = 0.03; OR = 1.97, P = 0.02) but did not reveal the association between the PTPN22 C1858T polymorphism and IBD, psoriasis, multiple sclerosis, Addison's disease and Celiac disease., Conclusion: This meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA, supporting evidence of association of the PTPN22 gene with subgroup of autoimmune diseases.

Objective: Juvenile localized scleroderma (JLS) includes a number of conditions often grouped together. With the long-term goal of developing uniform classification criteria, we studied the epidemiological, clinical and immunological features of children with JLS followed by paediatric rheumatology and dermatology centres., Methods: A large, multicentre, multinational study was conducted by collecting information on the demographics, family history, triggering environmental factors, clinical and laboratory features, and treatment of patients with JLS., Results: Seven hundred and fifty patients with JLS from 70 centres were enrolled into the study. The disease duration at diagnosis was 18 months. Linear scleroderma (LS) was the most frequent subtype (65%), followed by plaque morphea (PM) (26%), generalized morphea (GM) (7%) and deep morphea (DM) (2%). As many as 15% of patients had a mixed subtype. Ninety-one patients (12%) had a positive family history for rheumatic or autoimmune diseases; 100 (13.3%) reported environmental events as possible trigger. ANA was positive in 42.3% of the patients, with a higher prevalence in the LS-DM subtype than in the PM-GM subtype. Scl70 was detected in the sera of 3% of the patients, anticentromere antibody in 2%, anti-double-stranded DNA in 4%, anti-cardiolipin antibody in 13% and rheumatoid factor in 16%. Methotrexate was the drug most frequently used, especially during the last 5 yr., Conclusion: This study represents the largest collection of patients with JLS ever reported. The insidious onset of the disease, the delay in diagnosis, the recognition of mixed subtype and the better definition of the other subtypes should influence our efforts in educating trainees and practitioners and help in developing a comprehensive classification system for this syndrome.

Objectives: To review the fundamental concepts of pharmacogenetics and analyse how the broad principles of this rapidly emerging field may influence the treatment of rheumatic disease in future., Methods: The names of common rheumatic drugs and the terms 'pharmacogenetics', 'pharmacogenomics' and 'genetic polymorphism' were used as keywords to search the Medline and Current Contents databases. General review articles on pharmacogenetics were also examined., Results: Pharmacogenetics is the study of how genetic differences influence the variability in drug toxicity and efficacy. Although the principles of pharmacogenetics have been known for several decades, recent technological advances have hastened the possibility of direct clinical applications. Most studies so far have been phenotypic analyses, but genotyping is now readily available for many polymorphisms. There are several examples pertinent to rheumatology that illustrate the important principles and foretell the usefulness of pharmacogenetics in individualizing therapy. However, further studies are needed., Conclusions: Because traditional pharmacotherapy in rheumatology has been empirical and because of the slow acting nature of many anti-rheumatic medications, the risk of significant side-effects and the increasing armamentarium of drugs available, pharmacogenetics is particularly relevant to rheumatology. There are many scientific and non-scientific concerns that should be addressed in future studies.

The wide individual variations seen in all metabolic pathways which have been examined largely explain differences in drug dose response and toxicity. In some cases, distinct sub-sets occur where the enzyme activity is markedly different from that in the rest of the population (genetic polymorphism). Studies on isolated enzymes and use of restriction fragment length polymorphisms have in some cases helped to elucidate the relevant molecular biology. However, the lack of certain concordance between genotype and phenotype has shown that many questions remain unanswered. As more information becomes available at the molecular level, it may be easier to gain an understanding of the endogenous biochemistry which underlies the human condition. Either genotyping or phenotyping may then be used to predict potential drug side-effects or clinical outcomes.

Several studies of DNA restriction fragment length polymorphism (RFLP) in ankylosing spondylitis (AS) have been carried out. The association between a recently identified class I HLA 9.2 kb PvuII RFLP and AS remain controversial. In order to evaluate this possible association in an Euro-Caucasian population, the genomic DNA of 42 AS patients and 18 patients with Reiter's syndrome (RS) and 42 healthy controls was analysed. Non-association between 9.2 kb PvuII RFLP and AS or RS was observed. As described previously, a strong association between this fragment and HLA-A3 and/or HLA-A9 antigens was demonstrated. A study of two families showed that this RFLP segregates with HLA-A3 and/or HLA-A9 and independently of the HLA-B27. Our findings support the view that the 9.2 kb PvuII fragment is not universally associated with AS.

Genetic variants at DRB1 (Dw subtypes), DQB, and C4 loci were compared in rheumatoid disease subjects with or without the extra-articular feature of Felty's syndrome or major vasculitis. DR4 positive subjects with rheumatoid arthritis alone showed no preferential associations with DQB or Dw variants or with C4 null alleles. Felty's subjects showed associations with the DQB encoded DQw7 allele and with the C4B null allele but no preferential associations with any Dw subtype of DR4. By contrast DR4 +ve rheumatoid-vasculitic subjects showed associations with the Dw14 as well as with DQw7 and the C4A null allele. These different MHC associations in different clinical disease subsets show that rheumatoid disease is immunogenetically heterogeneous and suggest that MHC genes outside the DRB1 locus may also influence susceptibility or modify expression of the rheumatoid disease process.

Fifty patients who presented with typical palindromic rheumatism of at least 6 months' duration were tissue-typed for HLA A, B, C antigens. DR typing was also performed but was not possible for technical reasons in three patients. Twenty-three patients who had progressed to definite or classical rheumatoid arthritis (RA) after a mean interval of 5 years were compared with 20 patients whose palindromic attacks had persisted over a similar period. Both groups showed a significantly higher frequency of DR4 antigen than a control population. The RA group also showed an increased frequency of DR1. There was no significant difference in the frequency of DR4 or any other DR antigen between the two patient groups. The frequency of B27 antigen was significantly higher in the palindromic group compared with the controls. It is suggested that although DR4 may be associated with a tendency to inflammatory joint problems, environmental or other unrelated genetic factors may be more important in determining the progression of palindromic rheumatism to RA.