Common NOS1AP genetic variation and QT interval duration in African Americans

Sara TribuneSara TribuneTougaloo CollegeTougaloo College

Summer Research Program in Summer Research Program in GenomicsGenomics

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Sudden cardiac death

300,000 deaths/yr US

Risk factors inadequate

Prolonged QT intervals

Increased risk of Sudden Cardiac Death Long QT Syndrome and Short QT Syndrome Drug-induced arrhythmias

Electrocardiograms

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

QT-Interval is Heritable

Framingham Heart Study (FHS) European descent (ED) 35% heritable

Jackson Heart Study (JHS) African descent (AD) 40-41% heritable

.

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.

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?

Distribution of NOS1AP haplotypes The structure of haplotype blocks in the human genome.

Courtesy of Pardis SabetiGabriel, S. B. et al. The Structure of Haplotype Blocks in the Human Genome. Science 296, 2225-2229 (2002).

Replication of the NOS1AP association in African Americans.

1st Step Selection of SNPs2nd Step Genotyping of SNPs Determine locus-specific ancestry Interim analysis Final Step Final data analysis

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

CEU Data

37 SNPs were correlated to rs10494366 in CEU (European data)

Study Design

YRI Data

rs10494366 rs4657140 rs6696160 rs1415262 rs885148 rs7548169 rs16847548 rs7550692 rs2225845

rs6696160 rs1415262 rs885148

Study Design

rs12071519rs12071519    rs10800303 rs4657140 0.919

rs12076589    rs945706 rs6696160 0.966

rs945707rs945707    rs6672881 rs4657140 1.0

rs7525891rs7525891    

rs12085258rs12085258    rs3922867 rs4657140 0.882

rs4422984rs4422984     

rs4278353rs4278353     

rs4256791rs4256791     rs1572498 rs10494366 1.0

rs1415260 rs4657140 0.863

rs1415259 rs10494366 1.0

rs10494366 rs10494366 1.0

Tagger software selected 14 SNPs with r2 ≥0.8 in YRI (West African data).

African Descent

European Descent

Locus-specific Locus-specific ancestryancestry

{ } NOS1AP Locus { } NOS1AP Locus { }

Afr-Afr

67.24 %

Afr-Eur

29.52 %

Eur-Eur

3.24 %

Locus-Specific Ancestry Increases Locus-Specific Ancestry Increases Statistical PowerStatistical Power

GenotypingGenotyping

Initial genotyping in 4605 JHS Individuals

Table 1.1 Genotypes of NOS1AP Variants

SNP Genotype Call Rate Minor Allele Minor Allele

Frequency

YRI

Frequency

CEU Frequency Expected Allele

Frequencies

rs10494366 G/T 0.982 T 0.39 0.34 0.63 0.39

rs7550692 C/T 0.965 C 0.50 0.42 0.73 0.47

rs10918740 C/T 0.975 C 0.13 0.04 0.63 0.15

rs4657140 C/T 0.974 C 0.27 0.15 0.63 0.24

rs6696160 Failed

rs7513365 Failed

Possible Outcomes

Result Effect expected Implication

1. None of the 14 SNPs will be associated withQT.

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 GGTT GT GGIncrease in QT durationIncrease in QT duration

Narrowed the region likely to contain functional QT influencing variant.

Progress

Study Design Selection of SNPs Selection and formation of assay

pools Genotyped SNPs Interim analysis (In Progress) Final data analysis (August 15)

AcknowledgmentsChristopher Newton-ChehShawna YoungNeal LearnerBruce BirrenDavid Reich

Funding supportBroad Summer Research Program in GenomicsDoris Duke Charitable Foundation (Newton-Cheh)