The proposed project will address significant limitations in our understanding of the etiopathogenesis of idiopathic inflammatory myopathy associated interstitial lung disease (IIM- ILD) and disparities in IIM-ILD disease expression among different racial/ethnic groups. ILD is an important cause of morbidity and mortality in patients with IIM. Unfortunately, the rarity of IIM and clinical heterogeneity of IIM-ILD has limited adequately powered clinical studies of IIM-ILD risk factors and long-term outcomes. Additionally, there remains a major lack of understanding of the role of genetics in African Americans with IIM-ILD. Access to a large existing database of HLA typing in European Americans and African Americans from the NIH in addition to a large highly characterized cohort of patients from the Johns Hopkins Myositis Center offers a unique opportunity for our research team to successfully investigate this problem now. We plan to explore how HLA class I and II associations in IIM-ILD, racial/ethnic background, and myositis specific autoantibodies influence clinical phenotypes and outcomes in IIM-ILD. One overall goal and three specific aims will be pursed through this effort. Project goal: To identify genetic, serological, and clinical predictors of IIM-ILD development, morbidity, and mortality. Overall hypothesis: Patients with IIM who develop ILD differ significantly from patients with IIM who do not develop ILD in regard to their genetic risk factors, ancestry, and myositis specific autoantibodies.
Specific Aim 1 : To test the hypothesis that the HLA region harbors major genetic determinants of risk to IIM-ILD among European Americans. We will first perform an unbiased assessment of all HLA alleles observed within the NIH cohort of 138 European American cases (IIM-ILD) and 404 European American myositis controls (IIM alone). We will then test for replication of all significant associations identified in our discovery cohort relying on an independent set of 225 European American IIM-ILD cases and 525 European American myositis controls from the Johns Hopkins Myositis Center replication cohort.
Specific Aim 2 : To test the hypothesis that the HLA region harbors major genetic determinants of IIM- ILD among African Americans, but that the specific alleles that determine risk within this group are different from those identified in European Americans. We will first perform an unbiased assessment of all HLA alleles observed in the NIH cohort of 51 African American cases (IIM- ILD) and 91 African American myositis controls (IIM alone). We will then test for replication of all significant associations identified in our discovery cohort relying on an independent set of 51 African American IIM-ILD cases and 120 African American myositis controls from the Johns Hopkins Myositis Center replication cohort. Finally, we will test for heterogeneity in these genetic associations between European Americans (Aim 1) and African Americans (Aim 2).
Specific Aim 3 : To test the hypothesis that pulmonary physiology, high resolution computed tomography, and mortality patterns in patients with IIM-ILD differ by race/ethnicity, and myositis specific autoantibody type relying on the existing extensive clinical phenotype data available from the Johns Hopkins Myositis Center database on 225 European Americans and 51 African Americans with IIM-ILD. Additionally, we will also evaluate the role that HLA alleles identified in Aims 1 and 2 play in the determining pulmonary physiology, high resolution computed tomography, and mortality patterns.
Idiopathic inflammatory myopathy associated interstitial lung disease (IIM-ILD) is a significant cause of excess morbidity and mortality in patients with IIM. Accurate quantifiable measures that predict IIM-ILD development do not exist. This research will lead to a better understanding of why some patients with IIM develop ILD while others remain free of ILD.
