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- Title
Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.
- Authors
Sakaue, Saori; Yamaguchi, Etsuro; Inoue, Yoshikazu; Takahashi, Meiko; Hirata, Jun; Suzuki, Ken; Ito, Satoru; Arai, Toru; Hirose, Masaki; Tanino, Yoshinori; Nikaido, Takefumi; Ichiwata, Toshio; Ohkouchi, Shinya; Hirano, Taizou; Takada, Toshinori; Miyawaki, Satoru; Dofuku, Shogo; Maeda, Yuichi; Nii, Takuro; Kishikawa, Toshihiro
- Abstract
Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10−12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10−12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10−7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production. Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.
- Subjects
PULMONARY alveolar proteinosis; ANTIBODY formation; LUNG diseases; ALLELES; IMMUNOGLOBULINS; ODDS ratio; IMMUNOGENETICS; SURFACE active agents
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21011-y