In the present study, we identified ten different HLA-G alleles and 24 different genotype combinations among the 306 women of the FFHPV-Study. We found an association with certain HLA-G alleles and genotypes with the outcomes of oral HPV-infections, but interesting enough no such associations with the outcomes of genital HPV-infections. Additionally, some HLA-G alleles and genotypes seemed to be linked with some characteristics of the women’s reproductive health. There are only a few studies available investigating the impact of HLA-G polymorphism in the natural history of HPV-infections, most of these previous studies being published on cervical HPV-induced premalignant and malignant lesions [8, 18–22]. The data on HLA-G polymorphism in oral HPV-infections are, to our knowledge, lacking, with anecdotal data on malignant lesions of the oropharynx where HLA-G polymorphism have been studied, but only using immunohistochemistry in the biopsy samples with mono-/or polyclonal antibodies for HLA-G or assessing the polymorphic sites at 5′URR (upstream regulatory region) and 3′UTR (untranslated region) by polyacrylamide gel electrophoresis (PAGE)[22–24]. In our FFHPV cohort, no oral premalignant (i.e. oral potentially malignant disorders, OPMD) or malignant oral lesions were recorded in these women.
This is the first study to report that HLA-G has a potentially an important role in the natural history of oral HPV infections in women. The findings of the present study are in agreements with our recent observations showing that HLA-G molecules are associated with the newborn's likelihood of oral HPV infection at birth. Accordingly, HLA-G*01:01:02/01:01:02 genotype concordance between mother and her child was shown to increase the risk of oral infection of the child by any HPV genotype and/or HR-HPV genotypes (OR 2.45)[23]. This raised the possibility that oral HPV infections detected in young women might be determined by their mother’s HLA-G status [25].
In the present female cohort, homozygous genotype G*01:01:01/01:01:01 was shown to increase both the clearance of any oral HPV infection (OR = 1.18) (Table 2) and having any oral HPV-infections during the follow-up (OR = 1.86) (Table 1). However, this wild-type genotype did not impact on the HPV persistence that would be needed for the progression to a premalignant lesion. A similar protective effect for oral HPV infection was seen with G*04:01+ (OR 1.87) as with genotype G*01:01:01/01:04:01 (OR 2.18). In the genital mucosa, Metcalfe and coworkers showed that allele G*01:01:01(OR = 2.23) and heterozygous genotype with G*01:01:01 (OR = 2.14) were increasing both the risks of genital LR-HPV infection and genital multiple-type infections versus single- type infections [21]. Ferguson et al. found significant associations between persistent genital HPV-16 and LR-HPV- infection with allele G*01:01:02, G*01:01:03, G*01:01:05, G*01:01:08 and G*01:03 (OR’s 1.90, 2.07, 2.52, 2.17, 2.99 respectively)[7]. Later, they also reported that the homozygous G*01:01:02 genotype increased the risk of developing invasive cervical squamous cell carcinoma (OR = 3.52)[8]. Contradictory to the later, Metcalfe et al observed that allele G*01:01:02 was significantly associated with decreased risk of any genital HPV infection (OR = 0.64) and had a protective effect against multiple type infections (OR = 0.45)[21].
In the present study, we found allele G*01:01:02 to reduce the probability of clearance of oral HPV-infection (OR = 0.50) and its combined genotype G*01:01:02/01:04:01 to increase oral HPV persistence (OR = 4.01). Protective effect against multiple-type infections was also noted with genotype G*01:01:01/01:01:02 (OR = 0.49) but not with the allele G*01:01:02. With regard allele G*01:01:03, Ferguson et al. found it to increase the risk of genital HPV infections (OR = 2.07) [20]. This finding was also observed in our study for multiple-type oral infections (OR = 3.32) but not for genital infections (Table 1). In previous studies, there seems to be some parallel trends recorded in both genital and oral infections, but interestingly, the present cohort failed to show any association between HLA-G polymorphism and genital HPV infections. The potential reasons might be that the previous studies have been somewhat larger (N = 539–636) [7, 8, 21], and importantly, focused on populations of different origin (Hispanics, Inuites)[21, 24], thus representing a larger scale of HLA-G polymorphism available as potential predictors of genital HPV infection outcomes, which might explain the divergent results[7, 8, 21, 24].
Only a few studies have assessed the associations between HLA-G polymorphism and female reproductive health [25, 26]. HLA-G seems to play a major role as a suppressor of the immune response at the maternal-fetal interface as well as in placental angiogenesis [27]. Craenmehr et al reported HLA-G over-expression in the full-term placenta of the women with a history of recurrent miscarriages (OR = 6.67)[25]. In another study, HLA-G gene alleles *0106, *010106, *01010106 and *0105N were significantly higher in patients with embryonic implantation failure on infertility treatments[26] In the present study, we could not confirm these results on HLA-G alleles, but we showed an association with HLA-G G*01:01:02/01:04:01 genotype and risk of both infertility and undergoing treatments for infertility (OR = 5.06 and OR = 9.07, respectively). In addition, genotype G*01:01:01/01:01:03 was significantly associated with an abnormal placenta (OR = 5.51). Of note, all women in our cohort were pregnant at study baseline. Thus, our cohort is not a representative series of infertility clinic patients and all the data on their reproductive health are based on the women’s self-reported statements.
This study has some potential limitations. The FFHPV cohort consists only of Caucasian Finnish women, and accordingly, the generalization to other populations is limited because Finland has its limited gene pool [28]. Cohort size of women was quite small, only 306 women, thus impeding the power to evaluate any associations of the rarest HLA-G genotypes. The main strength of this study is the vast database from a long-term prospective study that included study subjects with similar lifestyle and biological background, followed-up a for a long period of time with detailed HPV status of both the genital and oral sites.
In conclusion, we identified six clinically significant HLA-G genotypes affecting the oral HPV status and infection outcomes, and being related to some characteristics of the reproductive health of the women in the FFHPV study. The host HLA-G genotypes and certain alleles alone appear to have a potentially important impact in the outcome of oral HPV infection in women, but only a minor or no role in the natural history of genital HPV infections. Further studies on HLA-G polymorphism are warranted to confirm their impact as predictors of the natural history of HPV infections at different anatomic sites.