Estimating Genetic Influences and Identifying the Genetic Susceptibility Loci For Uterine Cervix HPV infection Status In Korean Women

Abstract

Background: Cervical cancer is the most common cancer in women in some Africa and Asia and the third most common cancer in women worldwide. Human papillomavirus (HPV) infection is the leading cause of cervical lesions and cancers and has a crucial role in the progression of cervical cancers. The burden of HPV infection itself is very substantial in women worldwide. It was reported that approximately 610,000 new patients came out every year worldwide in 2012 and the prevalence of HPV infection was 10.4% in 863 sexually active females aged ranging 20–74 years old in Korea. HPV infection could be heritable because the patterns of progression of HPV infection are different depending on host genetic susceptibility and environmental factors. Most infections are cured, but 10–20% of women have persistent infections and they could become cervical intraepithelial neoplasm (CINs). 30–40% of CINs are progressed to invasive cancer of the cervix (ICC).

Objective: The aims of this study were to estimate genetic influences and to identify the genetic susceptibility loci with the latest and optimal method to analyze dichotomous trait based on the fact that there is a significant genetic influence on HPV infection status for uterine cervix HPV infection status in Korean Women.

Methods: The 910 study participants aged 25-79 were recruited from the females in the Healthy Twin Study. Prevalence of HPV infected host and odds ratios of HPV infection status by potential risk factors were estimated with a univariate logistic regression analysis. To estimate genetic influences, Intraclass correlation (ICC) and SOLAR were used and to identify the genetic susceptibility loci, GWAF was used, which is the latest and appropriate method to analyze dichotomous trait.

Results: Among epidemiological factors, only oral contraceptive use was significantly associated with HPV infection status. The ICC coefficient of monozygotic (MZ) twin pairs were higher than mother and daughter pairs and dizygotic (DZ) twin and sibling pairs. Genetic influences also exist moderately (h2=0.34) in AE model of HPV infection status. In addition, Genetic susceptibility loci of HPV infection status were rs13386094, rs13393102, rs10187756, rs13006868, rs28479291, rs12694475, and rs10165222 in additive model and rs7595290 in general model. They were significantly associated with the phenotype with p-value, 5.4E-7 and 8.0E-8 respectively.After analysis, several visualization methods were used to explain the results.

Discussion: Genetic influences of HPV infection status are not that high but significantly heritable. Among the genes from the results in additive model, BROX, CNTN5, GRM8, HMCN1, NEB, PDE4B, PRKAG2, PTPRJ, RHEB, STRC, VNN1,ZBTB7C, ZC3H15, ZNF680, DPP6, RAD51B, and WWOX were statistically associated with diseases such as endometrial cancer and uterine tumor and function of binding of ovarian cancer cell lines (Table 5). In addition, ADAM12, CNTN4, DPP6, GRM8, LRP1B, OBSCN, PDE4D, PLEKHH2, PRKAG2, PTPRJ, RHEB,STRC, STXBP6, VNN1, ZBTB7C, ZC3H15, ZNF680, PDE4D, WWOX, LEPR, and DTD1 were significantly related with the diseases such as endometrial cancer, uterine tumor and the functions in G1/S phase transition of cervical cancer cell lines, early or advanced stage endometriosis, and apoptosis of endometrial cancer cell lines