According to our results certain HLA-G alleles appears to have the impact on father-child HPV concordance and prevalence in perinatal period. However, HLA-G genotypes did not show to influence the HPV concordance among the father-child dyads. The acquisition of HPV infection in early life is supposed to be facilitated by many complex immunological, genetical and epigenetical co-factors . The father’s role in child’s early life exposure for HPV infection remains unclear. Only few studies have evaluated the father’s role in perinatal HPV infection with controversial results [8, 9, 30]. The study with the Polish family cohort (146 parental couples and their newborns) showed that father’s oral HPV16/18 infection increased the newborn’s oral HPV16/18 infection at birth . With our Finnish Family cohort, Rintala and colleagues showed that the newborn’s genital HPV positivity associated with mother’s oral HR-HPV detected before delivery whereas the newborn’s oral HPV positivity at the age of six months associated with father’s oral HR-HPV detected before delivery . In both studies, type-specific concordance was not analyzed. In addition, another recent study with our Finnish Family cohort showed that the incident oral HR-HPV infection for a child were predicted by HR-HPV seropositivity of the father . In contrast, Smith and coworkers showed HPV transmission from parents to newborn to be rare in American population in Iowa, as only one of 574 mother-child dyads and none of 68 father-child dyads had concordant HPV type .
The role of HLA-G in vertical HPV transmission is even less studied. To our knowledge there is only one previous study with the same Finnish Family HPV cohort that has evaluated the HLA-G and vertical mother-to-child HPV transmission . In that study HLA-G allele or genotype concordance did not show any impact to mother-to-child genotype specific HPV transmission . To date, no studies on HLA-G in father-child HPV concordance or transmission have been reported. HLA-G in vertical human immunodeficiency virus (HIV) transmission is more studied than HLA-G in vertical HPV transmission. Several studies have shown HLA-G polymorphism to influence the risk of mother-to-child HIV transmission [31–36]. With regard of mother-child HLA-G concordance the data is controversial and sparse. One small prospective cohort study (N = 34) run in New York City suggested that mother-child discordance in exon 2 associate with a reduced risk of perinatal HIV infection . However, two larger studies have not found association between HLA-G allele concordance and vertical mother-to-child HIV transmission [32, 36]. To best of our knowledge no studies with HLA-G and father-to-child transmission of HIV nor other viruses have been published before.
In this study with our cohort of fathers and their newborns we identified only nine different HLA-G alleles. To date overall 94 HLA-G alleles have been identified (IPD-IMGT/HLA Database) . Relatively low number of different HLA-G alleles we found was expected considering that Finnish population has a quite restricted and homogenous gene pool due to historical isolation. The most common allele observed among both fathers and their offspring in our cohort was the wildtype G*01:01:01 as it was in other studies with Canadian, Black South African and Kenyan populations [32, 36, 38].
We showed HLA-G concordance with certain specific alleles to have an impact on HPV father-child concordance (in any-, LR- and HR-HPV groups) but if it indicates HPV transmission from father to child, is questionable. At least we showed that the type-specific father-child HPV concordance associated with HLA-G allele G*01:04:01. HLA- G*01:04:01 father-child concordance was related to the father’s oral and child’s postpartum oral any- and HR-HPV concordance. In this case, HPV type-specific concordance was seen in two father-child dyads with HR-HPV genotypes 33 and 70 (50% of concordant dyads had HR-HPV genotype specific concordance, data not shown). Further evaluations showed that if the mother’s oral HPV status were also taken into account, the adjusted OR’s for G*01:04:01 father-child concordance and the father’s oral and child’s postpartum oral any- and HR-HPV concordance remained statistically significant; adjusted OR:s 11.50 (95% CI 1.77–74.87) and 9.86 (95% CI 1.49–65.12), respectively (data not shown). This finding is suggestive for vertical father-to-child HPV transmission in this case. Interestingly, in the study of the same Finnish Family cohort with mother-child dyads, discordant mother-child HLA-G allele G*01:04:01 increased the risk for child’s oral LR-HPV infection at birth .
According to our results HLA-G G*01:01:03 allele father-child concordance relates to father’s urethral and child’s oral HR-HPV concordance at birth. Controversially, when child’s oral HPV status was determined at postpartum, association between G*01:01:03 allele discordance and father’s urethral and child’s oral HR-HPV concordance was seen. Moreover, HLA-G allele G*01:01:03 discordance seems to increase the risk of father’s urethral and/or child’s oral any- and HR-HPV positivity at birth, whereas G*01:01:03 concordance was associated with the higher risk of father’s oral and/or child’s oral HR-HPV positivity at birth. This contradiction remains unexplainable assuming that biologically HLA-G allele discordance is supposed to reduce risk of infection at any anatomical site. Therefore, we investigated separately the fathers’ HPV prevalence at baseline (before birth) and children’s HPV prevalence at birth; G*01:01:03 allele discordance seemed to increase solely the father’s urethral any- and HR-HPV positivity but not child’s oral HPV positivity at birth (data not shown). G*01:01:03 allele concordance lost the statistical significance when fathers’ oral HR-HPV prevalence and children’s oral HR-HPV prevalence at birth were explored separately, thus it did not show an impact on one or the other’s oral HR-HPV prevalence alone (data not shown). Interestingly in our recently published study we found the presence of men’s allele G*01:01:03 to associate with an increased risk for urethral HR-HPV infections .
Allele G*01:06 concordance associated with the LR-HPV prevalence of fathers’ semen as urethral and/or children’s oral HPV at birth. When explored this association by fathers’ and children’s prevalence alone, G*01:06 concordance did not associate with alone father’s semen or child’s oral LR-HPV positivity at birth. However, G*01:06 concordance increased the father’s urethral LR-HPV positivity, but not child’s oral LR-HPV positivity at birth, when prevalence of fathers and children were analyzed separately (data not shown). Interestingly, the study of the Finnish Family cohort with mother-child dyads showed that G*01:06 mother-child discordance increased the child’s oral LR-HPV positivity but had not impact on the mother’s site .
The main limitation of this study is that we could not stratify analyses by HPV genotype due to relatively low sample size of fathers and newborns. A small sample size of fathers and children with uncommon HLA-G alleles may reduce the detection rate of significant associations between father-child HLA-G allele concordance and father-child HPV concordance.
For many it is still questionable whether child’s HPV status at birth represent passive HPV contamination or a true infection. However, recently published study with the FFHPV cohort showed that part of the newborns born to seronegative mothers had a seroconversion to HPV6, HPV11, HPV16 and HPV18 recorded after birth . According to this finding, there is a reason to suggest that newborns had acquired HPV infection somewhere in their body as they had created an immune response for HPV already in early infancy. In fact our previous findings by Koskimaa et al showed that HPV16-specific immune response exists among these unvaccinated and sexually naïve children [41–43]. The oral infection with LR HPV6 and HPV11 types is known to cause juvenile-onset recurrent respiratory papillomatosis . Even if the JoRRP is rare, and the lesions it causes are benign, recurrent disease need repeated surgery and can persist into adulthood . Given that, the consequences of newborn’s exposure for HPV infection should not be ignored. Furthermore, the risk of genital precancerous lesions in adolescents and young adults based on vertical transmission is not fully understood. Better knowledge of natural history of HPV in early childhood is crucial to create the most effective preventive strategies for HPV-infections related diseases as to determine the optimal timing of the prophylactic HPV vaccination.