PT433 Rheumatic Rescue: Genetic basis for elevated rheumatic heart disease susceptibility in Samoa

Introduction: Pathogenesis of Rheumatic Heart Disease (RHD) is complex. Environmental and genetic factors are contributing factors. Estimated heritability from a metaanalysis of twin studies was 60%. Rates of RHD are elevated in Samoa, and ecent data suggests that within Samoa there are geographic regions with significantly higher rates of RHD than others. Objectives: We analyzed prevalence data from screening efforts by the Rheumatic Rescue organization to determine statistically significant regional variation in rates of RHD. Families in Samoa with multiple affected individuals and patterns of inheritance indicative of elevated genetic risk for disease were identified. Exome sequencing was performed to search for the variant(s) responsible for this elevated risk. Methods: We compared the number of unaffected and affected individuals in each school to coresponding numbers in all other schools screened using Fisher’s Exact test. P-values were adjusted for multiple tests using a Bonferroni correction. For pedigree identification we contacted the parents of individuals who screened positive to assess the number and relatedness of other known RHD cases. When multiple affected individuals were identified we obtained consent, conducted a full RHD screening, and collected DNA via saliva samples from all available family members. Results: We identified a significantly higher rate of RHD at two schools (P1⁄40.0046, P1⁄40.0013). Two other schools showed an excess in RHD rates but were smaller in size; therefore, the differences were not statistically significant. We characterized one family with multiple affected individuals (fig 1). Thirteen individuals were available for screening and DNA collection. Four of the nine offspring, ranging in age from 7 years to 27 years, screened positive for RHD. DNA from all 13 individuals in this pedigree has been extracted and is being sequenced. We plan to report the results of this analysis at the conference. Conclusion: The prevalence of RHD in Samoa is known to be elevated. Our findings show that even within Samoa, there are small geographic regions (school boundaries), which have further elevated rates of RHD. We have identified a large pedigree that likely harbors RHD risk variants. While environmental factors clearly contribute to elevated rates of RHD in Samoa, our data suggest that is also a genetic contribution to RHD risk. We anticipate that our exome sequencing efforts will lead to the identification of genetic variants in this pedigree that alter risk for RHD. Disclosure of Interest: None Declared