A Novel Sarcoidosis Risk Locus for Europeans on Chromosome 11q13.1

作者：Fischer Annegret; Schmid Benjamin; Ellinghaus David; Nothnagel Michael; Gaede Karoline I; Schuermann Manfred; Lipinski Simone; Rosenstiel Philip; Zissel Gernot; Hoehne Kerstin; Petrek Martin; Kolek Vitezslav; Pabst Stefan; Grohe Christian; Grunewald Johan; Ronninger Marcus; Eklund Anders; Padyukov Leonid; Gieger Christian; Wichmann H Erich; Nebel Almut; Franke Andre; Mueller Quernheim Joachim; Hofmann Sylvia; Schreiber Stefan^*

来源：American Journal of Respiratory and Critical Care Medicine, 2012, 186(9): 877-885.

DOI：10.1164/rccm.201204-0708OC

• sarcoidosis
• genome-wide association study
• imputation
• Gipie
• PRDX5

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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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 x 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. %26lt;br%26gt;Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis.

• 出版日期2012-11-1
• 单位河北医科大学