Genetic predictors of cervical dysplasia in African American HIV-infected women: ACTG DACS 268

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.

Keywords: GWAS; cervical dysplasia; risk markers.

Figure 1

Plot of –log₁₀ P values from allelic chi-square tests for association of each of the 613,335 single nucleotide polymorphisms (SNPs) with the development of high-grade cervical dysplasia in HIV-infected (A) women of all races, (B) African American women only, and (C) African American cases compared to their 3 closest genetic matches determined by principal component analysis. Line represents the cutoff for genome-wide significance. SNPs with the highest significance are highlighted with a halo.

Figure 2

Ancestry distributions using principal component analysis. (A) Subjects of all races with any grade of dysplasia (including CIN I) and normal controls; (B) African American (AA) high-grade dysplagia cases vs African American controls; and (C) proportional ancestry for AA high-grade cases vs AA normal controls. Included for reference are 90 HapMap individuals from the respective reference populations: Asian, African, and European.