TY - JOUR
T1 - Whole genome sequencing identifies variants associated with sarcoidosis in a family with a high prevalence of sarcoidosis
AU - Fritz, Daan
AU - Ferwerda, Bart
AU - Brouwer, Matthijs C.
AU - van de Beek, Diederik
N1 - Funding Information: Matthijs Brouwer is supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw; NWO-Vidi grant 2019 [917.17.308]). Diederik van de Beek is supported by grants from the Netherlands Organization for Health Research and Development (ZonMw; NWO-Vici grant 2019 [918.19.627]), the European Research Council (ERC Starting Grant 281156), and an innovation grant by the board of directors of the Academic Medical Center, Amsterdam, The Netherlands. No potential conflict of interest relevant for this article exists. Publisher Copyright: © 2021, The Author(s).
PY - 2021/9
Y1 - 2021/9
N2 - Objective: We studied genetic risk factors associated with sarcoidosis within a family with a high prevalence of this disease. Methods: We studied 41 members of a family with a high rate of sarcoidosis, including an index patient with treatment-resistant neurosarcoidosis. Whole genome sequencing was performed for six affected family members and variations associated with loss of function were filtered out as candidate genes. Findings were validated by using amplicon sequencing within all 41 family members with DNA available and candidate genes were screened on absence and presence within the sarcoidosis affected and non-affected. Results: Family members (n = 61) from 5 generations were available for participation including 13 subjects diagnosed with sarcoidosis (20%). Analyses identified 36 candidate variants within 34 candidate genes. Variations within three of these genes (JAK2, BACH2, and NCF1) previously have been associated with autoimmune diseases. Conclusions: We identified 34 genes with a possible role in the etiology of sarcoidosis, including JAK2. Our results may suggest evaluation of JAK inhibitors in treatment-resistant sarcoidosis.Key Points• JAK2 has a potential role in the etiology of sarcoidosis and is a potential therapeutic target.• We identified 33 additional candidate genes of which BACH2 and NCF1 have been previously associated with autoimmune disease.
AB - Objective: We studied genetic risk factors associated with sarcoidosis within a family with a high prevalence of this disease. Methods: We studied 41 members of a family with a high rate of sarcoidosis, including an index patient with treatment-resistant neurosarcoidosis. Whole genome sequencing was performed for six affected family members and variations associated with loss of function were filtered out as candidate genes. Findings were validated by using amplicon sequencing within all 41 family members with DNA available and candidate genes were screened on absence and presence within the sarcoidosis affected and non-affected. Results: Family members (n = 61) from 5 generations were available for participation including 13 subjects diagnosed with sarcoidosis (20%). Analyses identified 36 candidate variants within 34 candidate genes. Variations within three of these genes (JAK2, BACH2, and NCF1) previously have been associated with autoimmune diseases. Conclusions: We identified 34 genes with a possible role in the etiology of sarcoidosis, including JAK2. Our results may suggest evaluation of JAK inhibitors in treatment-resistant sarcoidosis.Key Points• JAK2 has a potential role in the etiology of sarcoidosis and is a potential therapeutic target.• We identified 33 additional candidate genes of which BACH2 and NCF1 have been previously associated with autoimmune disease.
KW - All genetics
KW - All immunology
KW - Association studies in genetics
KW - Case-control studies
UR - http://www.scopus.com/inward/record.url?scp=85105288477&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s10067-021-05684-w
DO - https://doi.org/10.1007/s10067-021-05684-w
M3 - Article
C2 - 33903979
SN - 0770-3198
VL - 40
SP - 3735
EP - 3743
JO - Clinical Rheumatology
JF - Clinical Rheumatology
IS - 9
ER -