Abstract
Sarcoidosis is a systemic granulomatous disease of unknown etiology. It may develop in response to an exposure or inflammatory trigger in the background of a genetically primed abnormal immune response. Thus, genetic studies are potentially important to our understanding of the pathogenesis of sarcoidosis. We developed a case-control study which explored the genetic variations between firefighters in the Fire Department of the City of New York (FDNY) with World Trade Center (WTC)-related sarcoidosis and those with WTC exposure, but without sarcoidosis. The loci of fifty-one candidate genes related to granuloma formation, inflammation, immune response, and/or sarcoidosis were sequenced at high density in enhancer/promoter, exonic, and 5’ untranslated regions. Seventeen allele variants of human leukocyte antigen (HLA) and non-HLA genes were found to be associated with sarcoidosis, and all were within chromosomes 1 and 6. Our results also suggest an association between extrathoracic involvement and allele variants of HLA and non-HLA genes found not only on chromosomes 1 and 6, but also on chromosomes 16 and 17. We found similarities between genetic variants with WTC-related sarcoidosis and those reported previously in sporadic sarcoidosis cases within the general population. In addition, we identified several allele variants never previously reported in association with sarcoidosis. If confirmed in larger studies with known environmental exposures, these novel findings may provide insight into the gene-environment interactions key to the development of sarcoidosis.
Highlights
Sarcoidosis is a multisystem granulomatous disease that presents with pulmonary involvement in 90% of cases and extrapulmonary manifestations, mostly skin, in 10% of patients [1]
Our results suggest an association between extrathoracic involvement and genetic variants within several human leukocyte antigen (HLA) and non-HLA genes: HLA-B, PTGS2/COX2, PACERR, notch homolog 4 (NOTCH4), nucleotide-binding oligomerization domain-containing protein 2 (NOD2), and ITGAE
Our results suggest an association between extrathoracic involvement genetic variants under the co-dominant model and are relative to and the alternative allele unless specified with †unless which is in relation to are calculated under the co-dominant model are relative to the alternative allele specified between the risk allele and non-risk allele
Summary
Sarcoidosis is a multisystem granulomatous disease that presents with pulmonary involvement in 90% of cases and extrapulmonary manifestations, mostly skin, in 10% of patients [1]. The annual age-adjusted incidence in the United States (U.S.) between 1946–2013, in a mostly Caucasian cohort, was 10 per 100,000 (9.4 in males and 10.5 in females) [2]. Center (WTC) attacks on September 11, 2001 (9/11), giving an age-adjusted incidence rate of 25 per. 100,000 in mostly Caucasian male WTC-exposed FDNY firefighters between 2002–2015 [4]. A recent population-based study suggests a genetic risk factor for sarcoidosis in a large Swedish cohort, where a 3.7-fold increase in risk of sarcoidosis was observed in those with first-degree relatives with the disease. A case-control etiologic study of sarcoidosis (ACCESS) found a five-fold increase in siblings of those with sarcoidosis [6]
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