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Genetic, Immunologic, and Environmental Basis of Sarcoidosis
Annals of the American Thoracic Society, 2017
Sarcoidosis is a multisystem disease with tremendous heterogeneity in disease manifestations, severity, and clinical course that varies among different ethnic and racial groups. To better understand this disease and to improve the outcomes of patients, a National Heart, Lung, and Blood Institute workshop was convened to assess the current state of knowledge, gaps, and research needs across the clinical, genetic, environmental, and immunologic arenas. We also explored to what extent the interplay of the genetic, environmental, and immunologic factors could explain the different phenotypes and outcomes of patients with sarcoidosis, including the chronic phenotypes that have the greatest healthcare burden. The potential use of current genetic, epigenetic, and immunologic tools along with study approaches that integrate environmental exposures and precise clinical phenotyping were also explored. Finally, we made expert panel-based consensus recommendations for research approaches and pr...
Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (SAGA) study
Genes and Immunity, 2007
The sarcoidosis genetic analysis (SAGA) study previously identified eight chromosomal regions with suggestive evidence for linkage to sarcoidosis susceptibility in African-American sib pairs. Since the clinical course of sarcoidosis is variable and likely under genetic control, we used the affected relative pair portion of the SAGA sample (n ¼ 344 pairs) to perform multipoint linkage analyses with covariates based on pulmonary and organ involvement phenotypes. Chest radiographic resolution was the pulmonary phenotype with the highest LOD (logarithm of the backward odds, or likelihood ratio) score of 5.11 at D1S3720 on chromosome 1p36 (P ¼ 4 Â 10 À5 ). In general, higher LOD scores were attained for covariates that modeled clustered organ system involvement rather than individual organ systems, with the cardiac/renal group having the highest LOD score of 6.65 at chromosome 18q22 (P ¼ 2 Â 10 À5 ). The highest LOD scores for the other three organ involvement groups of liver/spleen/bone marrow, neuro/lymph and ocular/skin/joint were 3.72 at 10p11 (P ¼ 0.0004), 5.16 at 7p22 (P ¼ 4 Â 10 À5 ) and 2.93 at 10q26 (P ¼ 0.001), respectively. Most of the phenotype linkages did not overlap with the regions previously found linked to susceptibility. Our results suggest that genes influencing clinical presentation of sarcoidosis in African Americans are likely to be different from those that underlie disease susceptibility.
Phenotypes of organ involvement in sarcoidosis
The European respiratory journal, 2018
Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease invo...
Identification of Immune-relevant Factors Conferring Sarcoidosis Genetic Risk
American journal of respiratory and critical care medicine, 2015
To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1726 German sarcoidosis cases and 5482 controls were genotyped for 128,705 SNPs using the Illumina Immunochip for the screening step. The remaining 3955 cases, 7514 controls and 684 parents of affected offspring were used for validation and replication of 44 candidate and 2 established risk SNPs. Four novel susceptibility loci were identified with genome-wide significance in the European case control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1) and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA-region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA DPB...
Sarcoidosis extent relates to molecular variability
Clinical and Experimental Immunology, 2017
Summary The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti-tumour necrosis factor (TNF)-α] and ustekinumab [anti-interleukin (IL)−12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T...
Genes & Immunity, 2017
Sarcoidosis is a complex disease of unknown etiology characterized by the presence of granulomatous inflammation. Though various immune system pathways have been implicated in disease, the relationship between the genetic determinants of sarcoidosis and other inflammatory disorders has not been characterized. Herein, we examined the degree of genetic pleiotropy common to sarcoidosis and other inflammatory disorders to identify shared pathways and disease systems pertinent to sarcoidosis onset. To achieve this, we quantify the association of common variant polygenic risk scores from nine complex inflammatory disorders with sarcoidosis risk. Enrichment analyses of genes implicated in pleiotropic associations were further used to elucidate candidate pathways. In European-Americans, we identify significant pleiotropy between risk of sarcoidosis and risk of asthma (R 2 =2.03%; p=8.89×10 −9), celiac disease (R 2 =2.03%; p=8.21×10 −9), primary biliary cirrhosis (R 2 =2.43%; p=2.01×10 −10), and rheumatoid arthritis Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Epidemiology of familial sarcoidosis in the UK
Thorax, 2000
Background-The last comprehensive epidemiological studies on familial sarcoidosis in the UK were more than 25 years ago, reporting another aVected family member in 1.7% of index cases. A significant proportion of like-sex over unlike-sex pairs, an excess of mother-child over father-child associations, and a preponderance of monozygous over dizygous twins was noted. Another study reported ethnic heterogeneity in familial disease. This study was undertaken to identify the risk ratio (S) for siblings of familial sarcoidosis in the UK, to determine if the previous epidemiological findings have persisted, and to reassess whether ethnic heterogeneity prevails in familial disease. Method-Questionnaires were sent to 406 index patients. Results-Two hundred and sixty eight replies (66%) were received. Twenty four of the original 406 index patients (5.91%) were found to have at least one other relative (first, second or third degree) with biopsy proven sarcoidosis. A S value of 36-73 was calculated indicating significant familial clustering of the disease. Ethnically the families comprised 62.5% Caucasian, 29.2% Afro-Caribbean, and 8.3% Asian. Mean age at diagnosis was 39.8 years for women and 40.9 years for men with a male to female ratio of 1:1.7. This diVered for the Asian families in which all the aVected members were male. Three sets of female twins (two monozygous and one dizygous) were included. There was an equal distribution of like-sex (primarily female) and unlike-sex families as well as mother-child and father-child pairs. Pulmonary involvement was predominant irrespective of ethnicity, as was the need for corticosteroid treatment. Conclusions-These results support the theory that a shared determinant (either genetic or environmental) is operating in familial sarcoidosis and suggest that this determinant is similar for all ethnic groups.