Michelle S Cespedes1, Sarah L Kerns2, Robert S Holzman1, Paul J McLaren3, Harry Ostrer4, Judith A Aberg1. 1. New York University School of Medicine, New York, New York. 2. Mount Sinai School of Medicine, New York, New York. 3. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 4. Albert Einstein College of Medicine, Bronx, New York.
Abstract
OBJECTIVE: To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. DESIGN: Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naïve studies in the AIDS Clinical Trials Group (ACTG). METHODS: Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10(-8) for genome-wide associations. RESULTS: No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). CONCLUSIONS: These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.
OBJECTIVE: To examine genome-wide associations in HIV-infectedwomen with a history of cervical dysplasia compared with HIV-infectedwomen with no history of abnormal Papanicolaou (Pap) tests. DESIGN: Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naïve studies in the AIDS Clinical Trials Group (ACTG). METHODS: Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10(-8) for genome-wide associations. RESULTS: No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). CONCLUSIONS: These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infectedwomen. Given the small sample size, the results need to be validated in a separate cohort.
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Jennifer S Daly; Benjamin T Davis; Kristine Davis; Sheila M Davod; Edwin DeJesus; Craig A Dietz; Eleanor Dunham; Michael E Dunn; Todd B Ellerin; Joseph J Eron; John J W Fangman; Claire E Farel; Helen Ferlazzo; Sarah Fidler; Anita Fleenor-Ford; Renee Frankel; Kenneth A Freedberg; Neel K French; Jonathan D Fuchs; Jon D Fuller; Jonna Gaberman; Joel E Gallant; Rajesh T Gandhi; Efrain Garcia; Donald Garmon; Joseph C Gathe; Cyril R Gaultier; Wondwoosen Gebre; Frank D Gilman; Ian Gilson; Paul A Goepfert; Michael S Gottlieb; Claudia Goulston; Richard K Groger; T Douglas Gurley; Stuart Haber; Robin Hardwicke; W David Hardy; P Richard Harrigan; Trevor N Hawkins; Sonya Heath; Frederick M Hecht; W Keith Henry; Melissa Hladek; Robert P Hoffman; James M Horton; Ricky K Hsu; Gregory D Huhn; Peter Hunt; Mark J Hupert; Mark L Illeman; Hans Jaeger; Robert M Jellinger; Mina John; Jennifer A Johnson; Kristin L Johnson; Heather Johnson; Kay Johnson; Jennifer Joly; Wilbert C Jordan; Carol A Kauffman; Homayoon Khanlou; 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