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Thomas A. Neff Lecture. Advances in the Genetics of Sarcoidosis

¹ Division of Pulmonary, Critical Care, and Sleep Medicine, Mount Sinai Medical Center, New York, New York

Correspondence and requests for reprints should be addressed to Michael C. Iannuzzi, M.D., Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1232, New York, NY 10029. E-mail: michael.iannuzzi{at}mountsinai.org

ABSTRACT

Familial aggregation and racial differences in incidence support the notion that sarcoidosis occurs in genetically susceptible hosts. Siblings of those affected with sarcoidosis have a modestly increased disease risk, with an odds ratio of about 5. HLA genes have been the most extensively studied susceptibility genes in sarcoidosis. Many other attractive candidate genes have been evaluated using the case–control study design, but few have been confirmed. Confounding by population stratification likely explains much of the failure to replicate initial findings. A genomewide scan performed in German families with follow-up fine mapping studies has yielded a highly attractive candidate gene, BTNL2 in the MHC II region on chromosome 6. BTNL2, a member of the B7 family of costimulatory molecules, likely functions to down-regulate T-cell activation. A BTNL2 single-nucleotide polymorphism associated with sarcoidosis is predicted to result in a truncated nonfunctioning protein. Association of BTNL2 with sarcoidosis has been confirmed in both white and African Americans. A genomewide scan with follow-up fine mapping studies in African American families has identified chromosome 5 as potentially harboring candidate genes. Additional linkage analysis in the African American families stratified according to genetic ancestry demonstrated that linkage signals varied according to degree of admixture. Certain chromosomal regions were also found linked to specific phenotypes. Follow-up fine mapping studies of the linked regions are underway.

Key Words: sarcoidosis • genetics • BTNL2

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