The National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases (ORD) convened a workshop on July 25, 2008 to review the studies conducted in the last 10 years in sarcoidosis genetics and define short and long term scientific goals.
Sarcoidosis is a systemic granulomatous disease which can affect multiple organs, with the most common being the lungs, eyes, and skin. The pathological hallmark of the disease is the characteristic noncaseating multinucleated granuloma. In the severe form of the disease, granuloma expansion and/or persistence can lead to fibrosis and loss of organ function. Estimates of the numbers of Americans afflicted with this disease range from 13,000 to 134,000. In the United States (U.S.); between 2,600 and 27,000 new cases are diagnosed each year.
A genetic predisposition to sarcoidosis is indicated by observations of familial clustering, increased concordance in monozygotic twins over other siblings, and variations in susceptibility and disease presentation among different ethnic groups. Genetic studies in sarcoidosis have gone through three phases ? candidate gene studies, affected sib pair (ASP) linkage analysis and most recently, genome wide association studies (GWAS). These phases have been largely driven by sampling convenience, available genotyping technology and statistical methodology. While investigators have failed to identify a specific genetic signature for sarcoidosis, numerous studies have identified genetic associations with specific ethnic groups and disease subtypes. Based on these initial studies, the genetic contribution to sarcoidosis is likely to involve many genes each with modest affect, which in order to be identified will likely require the analysis of large samples consisting of diverse phenotypes and ethnic make up.
A major focus of discussion at the workshop was the lack of uniform clinical phenotypes in sarcoidosis (i.e., phenotypes that everybody can agree upon) among referral centers and individual investigators. Earlier population-based studies, which had been focused more on accurate histopathological diagnoses then comprehensive phenotype, family characteristics, ethnicity, end environmental factors, were discussed. The constitution of a very large registry of sarcoidosis patients that would include detailed phenotypic information was proposed. This would markedly facilitate genetic studies.
Interesting results have been contributed to the field of sarcoidosis genetics by various European groups which have analyzed clusters of patients with different ethnicity compared to the one analyzed in the US; recently, the first genome wide association study (GWAS) conducted in a German population, has identified a strong genetic association between the disease and Annexin A11, a gene with complex and essential functions in several biological pathways, including cell apoptosis and proliferation.
A final recommendation was to promote studies to identify relevant gene networks and pathways important in sarcoidosis, which may prove more informative than studies that focus on single candidate genes.