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A6322 - A Recurrent Hemizygous Deletion at the MHC Region Impacting MICA, LINC01149, HCP5, HCG26 Associates with Idiopathic Pulmonary Hemosiderosis
Author Block: G. Vazquez Garcia1, F. Mentch2, X. Chang2, A. Zuppa1, S. B. Goldfarb1, H. Hakonarson1; 1Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States, 2Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Idiopathic pulmonary hemosiderosis (IPH) is a rare disease with yearly incidence of 0.24 that occurs mainly in childhood. This disease is characterized by recurrent episodes of diffuse alveolar hemorrhage (DAH). DAH can be triggered by conditions such as infections, pulmonary hypertension, or rheumatologic disease. IPH is diagnosed when there is no underlying cause of DAH. Several pathophysiologic pathways have been suggested. Prior pathology studies described diffuse fibrosis, hemosiderosis, and degeneration of elastic fibers. This suggests that structural defects in the alveolar capillaries basement membrane may be a predisposing factor of IPH. The response to immunosuppressive therapies suggests an immune-mediated process. Additionally, several reports show familial clustering, suggesting a genetic predisposition to IPH. The purpose of this study was to determine if genetic factors predispose to varying IPH phenotype and whether such information can be used to guide treatment. We recruited and thoroughly phenotyped 10 patients with IPH and genotyped them using the Illumina GSA SNP array genotyping platform. Genome-wide association study (GWAS) was conducted on all 10 cases, including 7 African-American children with IPH and 200 ancestry-matched healthy controls, as well as 3 European-American children with IPH and 200 healthy controls. As expected, the GWAS analysis did not identify a SNP having a P-value less than 10e-5 in either population. We performed a meta-analysis to combine the association results from two studies, and identified two SNPs with a P-value less than 10e-5 (rs7530150, 2.14e10-6 ; rs17064334, 4.16e10-6). rs7530150 is located 1p31.3 within the gene PDE4B. rs17064334 is located at 4q34.3 near gene NEIL3. We performed a genome-wide copy number variation (CNV) analysis on the same cohort and found a recurrent ~90Kb hemizygous deletion at the MHC region (chr6: 31360389-31451476; Gene: MICA, LINC01149, HCP5, HCG26). The CNV was found in one Caucasian and one African-American case, and in two Caucasian and two African-American controls. Fisher’s exact test suggests this deletion may confer risk to IPH (P-value = 0.0076). In conclusion, we have conducted both GWAS and CNV analysis in IPH patients. Although the sample size is small, this is the first effort to explore potential genes underlying IPH using GWAS. We found a ~90Kb hemizygous deletion located at the MHC region that is significantly associated with IPH suggesting IPH may be associated with HLA genes at the MHC locus. Future direction includes recruitment of 20-30 subjects for phenotype-genotype analysis, characterization of the cohort response to steroids in relation with this deletion.