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A7789 - Familial Clustering Suggests a Genetic Contribution to Risk of Chronic Thromboembolic Pulmonary Hypertension
Author Block: M. W. Dodson1, K. Allen-Brady2, L. M. Brown1, G. Elliott1, L. Cannon-Albright2; 1Intermountain Medical Center, Murray, UT, United States, 2University of Utah, Salt Lake City, UT, United States.
Rationale: Whether genetic factors influence risk for chronic thromboembolic pulmonary hypertension (CTEPH) is not currently known. Common inherited thrombophilias like the Factor V Leiden mutation are found no more frequently in patients with CTEPH than in the general healthy population, suggesting that genetic risk factors for venous thromboembolism (VTE) may not be risk factors for CTEPH. To assess whether there might be a genetic contribution to CTEPH risk, we measured familial clustering of CTEPH cases using the Utah Population Database (UPDB), which contains detailed genealogy records for 3 million Utah residents that are linked to medical records at the state’s two largest healthcare providers (the University of Utah and Intermountain Healthcare). Methods: We reviewed medical records linked to the UPDB to identify all patients meeting diagnostic criteria for CTEPH. We required that all subjects included in the UPDB analyses have genealogy records that included both parents, all four grandparents, and six of eight great-grandparents. We used the UPDB to calculate the genealogical index of familiality (GIF) of the CTEPH cohort, and compared this to the GIF of controls matched by birth year and sex. The GIF tests for excess relatedness within a cohort by assessing the pair-wise relatedness between all possible pairs of individuals in a defined group and comparing this to the average expected relatedness of individuals in the UPDB. We also used the UPDB to assess the relative risk (RR) of VTE in first degree relatives of patients with CTEPH. Results: We identified 131 Utah CTEPH cases, of which 48 met our pre-specified criteria for adequacy of genealogy information. Among these 48 CTEPH cases, the GIF was 4.8, compared to the control GIF of 1.6 (p=0.04), suggesting greater than expected relatedness among patients with CTEPH. Compared to controls, the first degree relatives of patients with CTEPH had increased incidence of VTE, with RR 2.7 (95% confidence interval 1.1-6.2, p=0.04). Conclusions: Using a large computerized genealogy database, we demonstrate that CTEPH cases cluster in families significantly more frequently than would be expected by chance, strongly arguing for a genetic contribution to CTEPH risk. Despite previous reports demonstrating no increase in the frequency of common inherited thrombophilias in patients with CTEPH, the RR of VTE is significantly increased in the first degree relatives of patients with CTEPH. This suggests that genetic risk factors that increase CTEPH risk are also likely to be associated with increased risk of VTE.