TY - JOUR
T1 - A novel sarcoidosis risk locus for europeans on chromosome 11q13.1
AU - Fischer, Annegret
AU - Schmid, Benjamin
AU - Ellinghaus, David
AU - Nothnagel, Michael
AU - Gaede, Karoline I.
AU - Schürmann, Manfred
AU - Lipinski, Simone
AU - Rosenstiel, Philip
AU - Zissel, Gernot
AU - Höhne, Kerstin
AU - Petrek, Martin
AU - Kolek, Vitezslav
AU - Pabst, Stefan
AU - Grohé, Christian
AU - Grunewald, Johan
AU - Ronninger, Marcus
AU - Eklund, Anders
AU - Padyukov, Leonid
AU - Gieger, Christian
AU - Wichmann, H. Erich
AU - Nebel, Almut
AU - Franke, Andre
AU - Müller-Quernheim, Joachim
AU - Hofmann, Sylvia
AU - Schreiber, Stefan
PY - 2012/11/1
Y1 - 2012/11/1
N2 - Rationale: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. Objectives: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genomewide association scan for these phenotypes. Methods: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. Measurements and Main Results:We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 3 10-18. The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus sharedby sarcoidosis, Crohndisease and psoriasis.
AB - Rationale: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. Objectives: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genomewide association scan for these phenotypes. Methods: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. Measurements and Main Results:We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 3 10-18. The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus sharedby sarcoidosis, Crohndisease and psoriasis.
UR - http://www.scopus.com/inward/record.url?scp=84868031310&partnerID=8YFLogxK
U2 - 10.1164/rccm.201204-0708OC
DO - 10.1164/rccm.201204-0708OC
M3 - Journal articles
C2 - 22837380
AN - SCOPUS:84868031310
SN - 1073-449X
VL - 186
SP - 877
EP - 885
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 9
ER -