PD-1 Genetic risk factors for high-risk human papillomavirus (HPV) infections and persistence among African women

Abstract

Background: Genetic factors may influence the susceptibility to high-risk human papillomavirus (hrHPV) infection and persistence. We conducted a genome-wide association study (GWAS) to identify variants associated with hrHPV infection and persistence among women of African ancestry. Methods: Participants were 522 Nigerian women evaluated at baseline and 6 months follow-up visits for HPV. HPV was characterized using SPF25/LiPA10. hrHPV infection was positive if at least one carcinogenic HPV genotype was detected in a sample provided at the baseline visit and persistent if at least one carcinogenic HPV genotype was detected in each of the samples provided at the baseline and follow-up visits. Genotyping was done using the Illumina Multi-Ethnic Genotyping Array (MEGA) and imputation was done using the African Genome Resources Haplotype Reference Panel. Association analysis was done under additive genetic models adjusted for age, HIV status and the first 3 principal components of the genotypes. Results: The mean (±SD) age of the study participants was 38 (±8) years, 46% were HIV negative, 24% were hrHPV positive and 10% had persistent hrHPV infections. The GWAS yielded 71 and 107 variants associated with hrHPV infection and persistence, respectively, with suggestive genome-wide significance [P value <1.0 × 10−5]. The top variants (rs149473200, rs147344426, rs151071053 and rs572823632) associated with hrHPV infections are in or near KLF12 [all P = 1.5 × 10−6]. KLF12 is an important regulator of gene expression during carcinogenesis, and it is highly expressed by human immune cells. In several studies, it was associated with HPV and cervical cancer. The top variants associated with persistent hrHPV infections were 3 variants upstream of AL450244 (rs143668247, rs12740341, rs2502139), a cluster of 5 intronic variants in JPH2 (rs116834259, rs74358070, rs11452236, rs79032354, rs6130527) and 2 intronic variants in GPR39 (rs16832308, rs62167448) [all P < 7.0 × 10−7]. These variants are in enhancer histone marks in several tissues and alter the motifs Ets, GATA, NR4A, RXRA, which have been associated with several cancers of the female reproductive system and leiomyosarcomas. Conclusions: This exploratory GWAS yielded risk loci that provide clues to the pathogenesis of hrHPV infection and persistence in women of African ancestry. Given the limited sample, larger discovery and replication studies are under way to further characterize the reported associations.