In survivors of COVID-19, quantitative analysis of expiratory chest CT images demonstrated that small airways disease with the presence of air trapping is a long-lasting sequelae of SARS-CoV-2 infection.
Sarcoidosis is a complex systemic disease. Our study aimed to 1) identify novel alleles associated with sarcoidosis susceptibility; 2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility; 3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1,335 sarcoidosis cases and 1,264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1,487 cases and 1,504 controls). The EA cohort was recruited from National Jewish Health, Cleveland Clinic, University of California San Francisco, and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis. The AA cohort was from a previous study with subjects enrolled from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. 49 SNPs in HLA-DRA, -DRB9, -DRB5, -DQA1, and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA. Among them, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101, and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage. In summary, we identified several novel SNPs and three HLA alleles associated with sarcoidosis susceptibility in the largest EA population evaluated to date using an integrative analysis of genetics and transcriptomics. We also replicated our findings in an AA population.
Background
Most phenotyping paradigms in sarcoidosis are based on expert opinion; however, no paradigm has been widely adopted because of the subjectivity in classification. We hypothesized that cluster analysis could be performed on common clinical variables to define more objective sarcoidosis phenotypes.
Methods
We performed a retrospective cohort study of 554 sarcoidosis cases to identify distinct phenotypes of sarcoidosis based on 29 clinical features. Model-based clustering was performed using the VarSelLCM R package and the Integrated Completed Likelihood (ICL) criteria were used to estimate number of clusters. To identify features associated with cluster membership, features were ranked based on variable importance scores from the VarSelLCM model, and additional univariate tests (Fisher’s exact test and one-way ANOVA) were performed using q-values correcting for multiple testing. The Wasfi severity score was also compared between clusters.
Results
Cluster analysis resulted in 6 sarcoidosis phenotypes. Salient characteristics for each cluster are as follows: Phenotype (1) supranormal lung function and majority Scadding stage 2/3; phenotype (2) supranormal lung function and majority Scadding stage 0/1; phenotype (3) normal lung function and split Scadding stages between 0/1 and 2/3; phenotype (4) obstructive lung function and majority Scadding stage 2/3; phenotype (5) restrictive lung function and majority Scadding stage 2/3; phenotype (6) mixed obstructive and restrictive lung function and mostly Scadding stage 4. Although there were differences in the percentages, all Scadding stages were encompassed by all of the phenotypes, except for phenotype 1, in which none were Scadding stage 4. Clusters 4, 5, 6 were significantly more likely to have ever been on immunosuppressive treatment and had higher Wasfi disease severity scores.
Conclusions
Cluster analysis produced 6 sarcoidosis phenotypes that demonstrated less severe and severe phenotypes. Phenotypes 1, 2, 3 have less lung function abnormalities, a lower percentage on immunosuppressive treatment and lower Wasfi severity scores. Phenotypes 4, 5, 6 were characterized by lung function abnormalities, more parenchymal abnormalities, an increased percentage on immunosuppressive treatment and higher Wasfi severity scores. These data support using cluster analysis as an objective and clinically useful way to phenotype sarcoidosis subjects and to empower clinicians to identify those with more severe disease versus those who have less severe disease, independent of Scadding stage.
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