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Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.
RESUMEN
STUDY OBJECTIVE: The Icelandic Sarcoidosis Study (ISS) contains all tissue-verified cases of sarcoidosis in Iceland since 1981. The present study has extended registration and verification to the start of 2004, thus covering over 23 years and a total of 234 cases. The aim of this study was to elucidate the prevalence, clinical manifestation and long-term prognosis of sarcoid arthritis in this unselected nationwide cohort. The presence of joint or muscle symptoms was registered in 20% of these cases. METHODS: We used a questionnaire to register the lung and joint symptoms and all participants were offered a clinical evaluation with standardized interview and physical examination, including a count of the number of painful and/or inflamed joints. RESULTS: Forty-seven (20%) of the 234 individuals in the ISS reported skeletal symptoms. In thirty-nine cases (17%) it was possible to confirm a history of inflammatory joint disorder. The mean age was 45 years: women 46 years (30-66), men 43 years (28-66). In 82% of the cases one or both ankles were involved. In 22 or 56% of the cases (13 female and 9 male) reliable data on the disease course were obtained; 87% of the patients had full recovery in less than 6 months, while 13% of the patients (all female) experienced chronic arthritic disease. CONCLUSIONS: Our nationwide-based data confirmed that around a fifth of all those diagnosed with sarcoidosis will develop joint symptoms associated with their sarcoidosis, most usually in the ankle. The prognosis is favourable, but a subgroup of female patients may develop chronic polyarthritis. It is urgent to study further in detail the risk factors for a chronic arthritic condition in sarcoidosis; thus, it would be possible to offer those at risk of arthritis modifying anti-rheumatic treatment in the early phase of their disease course.
