1. Common NOS1AP genetic variation and QT interval duration in African Americans Sara Tribune Tougaloo College Summer Research Program in Genomics

2. 2 Sudden cardiac death 300,000 deaths/yr US Risk factors inadequate

3. Prolonged QT intervals Increased risk of Sudden Cardiac Death Long QT Syndrome and Short QT Syndrome Drug-induced arrhythmias

4. Electrocardiograms http://www.mercksource.com/pp/us/cns/cns_hl_adam.jspzQzpgzEzzSzppdocszSzuszSzcnszSzcontentzSzadamzSzimagepageszSz8772zPzhtm

5. QT-Interval is Heritable Framingham Heart Study (FHS) European descent (ED) 35% heritable Jackson Heart Study (JHS) African descent (AD) 40-41% heritable.

6. NOS1AP Associated with QT Interval Duration in ED Three cohorts of ED individuals Common variants (rs 10494366) NOS1AP explain approximately 1.5% of QT interval variation. Whether the association between QT interval duration and common variation in NOS1AP exists in AD individuals is unknown.

7. Why is it not accurate assume that an association exists between QT interval duration and NOS1AP in AD individuals if an association is found in in ED individuals ?

8. Distribution of NOS1AP haplotypes The structure of haplotype blocks in the human genome. Courtesy of Pardis Sabeti Gabriel, S. B. et al. The Structure of Haplotype Blocks in the Human Genome. Science 296, 2225-2229 (2002).

9. Replication of the NOS1AP association in African Americans. 1 st Step  Selection of SNPs 2 nd Step  Genotyping of SNPs  Determine locus-specific ancestry  Interim analysis Final Step  Final data analysis

10. African Variants Show Less Correlation Using Hapmap data and Haploview Correlation of SNPS in CEU (ED) and YRI (AD) data set Red=Strong Correlation White=No Correlation CEU Data YRI Data

11. CEU Data 37 SNPs were correlated to rs10494366 in CEU (European data) Study Design

12. YRI Data rs10494366 rs4657140 rs6696160 rs1415262 rs885148 rs7548169 rs16847548 rs7550692 rs2225845 rs6696160 rs1415262 rs885148 Study Design rs10800303rs46571400.919 rs12076589 rs945706rs66961600.966 rs6672881rs46571401.0 rs3922867rs46571400.882 rs1572498rs104943661.0 rs1415260rs46571400.863 rs1415259rs104943661.0 rs10494366 1.0 Tagger software selected 14 SNPs with r 2 ≥0.8 in YRI (West African data).

13. African Descent European Descent Locus-specific ancestry { } NOS1AP Locus { } NOS1AP Locus { } Afr-Afr 67.24 % Afr-Eur 29.52 % Eur-Eur 3.24 % Locus-Specific Ancestry Increases Statistical Power

14. Genotyping

15. Initial genotyping in 4605 JHS Individuals Table 1.1 Genotypes of NOS1AP Variants SNPGenotypeCall RateMinor Allele Frequency YRI Frequency CEU Frequency Expected Allele Frequencies rs10494366G/T0.982T0.390.340.630.39 rs7550692C/T0.965C0.500.420.730.47 rs10918740C/T0.975C0.130.040.630.15 rs4657140C/T0.974C0.270.150.630.24 rs6696160Failed rs7513365Failed

16. Possible Outcomes ResultEffect expectedImplication 1. None of the 14 SNPs will be associated with QT. No difference in QT by genotype QT-prolonging allele emerge after Out-of-Africa Migration. Rose to High Frequency in ED individuals. 2. One or more SNPs will associated with QT Proportional increase in QT duration with each additional copy of an allele. e.g. if G= longer QT TT GT GG TT GT GG Increase in QT duration Narrowed the region likely to contain functional QT influencing variant.

17. Progress  Study Design  Selection of SNPs  Selection and formation of assay pools  Genotyped SNPs  Interim analysis (In Progress)  Final data analysis (August 15)

18. Acknowledgments Christopher Newton-Cheh Shawna Young Neal Learner Bruce Birren David Reich Funding support Broad Summer Research Program in Genomics Doris Duke Charitable Foundation (Newton-Cheh)