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A2130 - The United States Pulmonary Hypertension Scientific Registry (USPHSR): Preliminary Genomic Data
Author Block: R. L. Benza1, W. Chung2, G. Elliott3, A. E. Frost4, M. Pauciulo5, E. D. Austin6, H. W. Farber7, D. B. Badesch8, J. Badlam9, C. Yu10, A. Poms11, K. feldkircher12, W. C. Nichols13; 1Allegheny General Hosp, Pittsburgh, PA, United States, 2Columbia University, New York, NY, United States, 3Intermountain Med Ctr, Murray, UT, United States, 4Smith Tower, Suite 1001, Houston Methodist Lung Center, Houston, TX, United States, 5Cincinnati Children's Hospital, Cincinnati, OH, United States, 6Vanderbilt Univ, Nashville, TN, United States, 7Boston Univ Sch of Med, Boston, MA, United States, 8Leprino Office Bldg, Univ of Colorado Denver, Aurora, CO, United States, 9Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, United States, 10Vanderbilt University, Nashville, TN, United States, 11E Squared Trials, Chapel Hill, NC, United States, 12E Squared Trials, Half Moon Bay, CA, United States, 13Division of Human Genetics, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH, United States.
Rationale: Diagnostic Group 1 Pulmonary Arterial Hypertension (PAH) is a progressive and fatal disorder. Past observational registries provided important insights into PAH; including recognition of a strong predominance of idiopathic PAH (IPAH) in women. However, past registries did not include genomic data. The United States Pulmonary Hypertension Scientific Registry (USPHSR) aims to characterize 500 patients newly diagnosed with PAH; and to characterize relationships between environmental exposures, hormone exposures, genomics, and PAH. Methods: We have enrolled 143 individuals diagnosed with PAH after confirmation by cardiac catheterization. We extracted DNA and generated genomic data, including coding sequence data for ABCC8, BMPR2, ACVRL1, ENG, CAV1, SMAD4, SMAD9, KCNK3, KCNA5, TBX4 and EIF2AK4, for 143 subjects. We have administered a questionnaire to characterize environmental and hormone exposures. Results: To date, the 143 USPHSR subjects (median age 56 years) include 114 (80%) women; 60 (42%) IPAH; 74 (52%) PAH associated with other disorders (APAH), and 8 (5%) familial PAH (FPAH) and 1 PVOD. For women, the mean age of menarche was 12.5 years and the mean number of pregnancies before diagnostic catheterization was 2. More than 80% of the women used hormonal contraceptives before the diagnosis of PAH. 114 of the 143 subjects were sequenced for 7 PAH genes (BMPR2, ENG, ACVRL1, EIF2K4, CAV1, KNCK3, SMAD9), and 56 were sequenced for 5 more genes (ABCC8, TBX4, KCNA5, SMAD4, GDF2). Five subjects demonstrated pathogenic variants (2 missense, 2 nonsense, 1 splice site) in BMPR2 (4 FPAH, 1 IPAH). One subject had a suspected pathogenic variant (missense) in BMPR2 (APAH). 5 subjects had 5 missense variants of unknown significance (VUS) in BMPR2 (1, IPAH and 1, APAH), ACVRL1 (1, IPAH and 1, APAH) and KCNA5 (1, IPAH). We found one intronic VUS in EIF2AK4 in an IPAH patient. All other variants were considered benign, located mostly in EIF2AK4 (missense and insertion/deletion) and ABCC8 (missense). In addition, whole exome sequencing data are available for 112 patients and OMNI5 SNP data for 108 patients to enable identification of genetic variants outside of the 12 genes already sequenced. Conclusions: PAH remains a disorder disproportionately affecting women in midlife. Estrogen exposure is common prior to diagnosis and may represent an environmental factor, underlying PAH in genetically susceptible individuals. Our future studies will attempt to define a relationship between genomic variants and estrogen exposure in PAH.