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Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.
- Source :
-
Nature communications [Nat Commun] 2021 Feb 15; Vol. 12 (1), pp. 1032. Date of Electronic Publication: 2021 Feb 15. - Publication Year :
- 2021
-
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 <superscript>-12</superscript> ). 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 <superscript>-12</superscript> ), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10 <superscript>-7</superscript> ). 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.
- Subjects :
- Adult
Aged
Alleles
Asian People
Autoantibodies biosynthesis
Autoimmune Diseases ethnology
Autoimmune Diseases immunology
Autoimmune Diseases pathology
Case-Control Studies
Chromosomes, Human, Pair 6
Female
Gene Expression
Gene Frequency
Genome-Wide Association Study
Granulocyte-Macrophage Colony-Stimulating Factor antagonists & inhibitors
Granulocyte-Macrophage Colony-Stimulating Factor immunology
HLA-DRB1 Chains immunology
Humans
Japan
Male
Middle Aged
Odds Ratio
Protein Isoforms genetics
Pulmonary Alveolar Proteinosis ethnology
Pulmonary Alveolar Proteinosis immunology
Pulmonary Alveolar Proteinosis pathology
Pulmonary Surfactants immunology
Pulmonary Surfactants metabolism
Risk
Autoantibodies genetics
Autoimmune Diseases genetics
Genetic Predisposition to Disease
Granulocyte-Macrophage Colony-Stimulating Factor genetics
HLA-DRB1 Chains genetics
Pulmonary Alveolar Proteinosis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33589587
- Full Text :
- https://doi.org/10.1038/s41467-021-21011-y