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Background: Cervical cancer is one of the most important cancers worldwide with a high incident and mortality rate and is caused by the human papilloma virus (HPV). Among sexually active women who get infected with human papillomavirus (HPV), a small fraction progresses to cervical cancer disease pointing to possible roles of additional risk factors in development of the disease which include host genetic factors and other infections such as HSV-2. Since cellular apoptosis plays a role in controlling the spread of virus-infections in cells, gene variants altering the function of proteins involved in cell death pathways might be associated with the clearing of virus infections. Activity altering polymorphisms in FasR (-1377G > A and -670A > G), FasL (-844 T > C) and CASP8 (-652 6 N ins/del) genes have been shown to alter the mechanism of apoptosis by modifying the level of expression of their correspondent proteins. In the present study, we set out to investigate the combined risks of CASP8, FasR, and FasL polymorphisms in cervical cancer, pre-cancerous lesions, HPV infection and HSV-2 infection., Methods: Participants were 442 South African women of black African and mixed-ancestry origin with invasive cervical cancer and 278 control women matched by age, ethnicity and domicile status. FasR and FasL polymorphisms were genotyped by TaqMan and CASP8 polymorphism by PCR-RFLP. The results were analysed with R using haplo.stats software version 1.5.2., Results: CASP8 -652 6 N del + FasR-670A was associated with a reduced risk (P = 0.019, Combined Polymorphism Score (CPS) = -2.34) and CASP8 -652 6 N ins + FasR-1377G was associated with a marginal increased risk (P = 0.047, CPS = 1.99) of cervical cancer among black Africans. When compared within the control group, CASP8 -652 6 N ins + FasR-1377A showed a reduced risk (P = 0.023, CPS = -2.28) of HSV-2 infection in both black African and mixed-ancestry population., Conclusions: Our results show that the combined risks of variants in cell death pathway genes are associated with the cervical cancer as well as the HSV-2 infection in the black African and mixed-ancestry population.

Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted infection (STI) worldwide that causes genital infection. Among several factors responsible, host genetic factors may play an important role in susceptibility to HSV-2 infection. Apoptosis is a vital mechanism in eliminating virus-infected cells and controlling viral infections. Apoptosis can be regulated and triggered by the interaction between Fas and Fas Ligand (FasL). Polymorphisms in genes encoding Fas and FasL might result in altered apoptosis and contribute in susceptibility to viral infections. Two polymorphisms in Fas gene (FasR-1377G > A, FasR-670A > G) and one in FasL gene (FasL-844T > C) have been well studied and associated with different diseases. These polymorphisms were investigated in 407 South African women of black African and mixed-ancestry origin to determine if they were associated with HSV-2 seropositivity. Two hundred sixty-five women were HSV-2 infected and 142 were non-infected. HSV-2 was detected using HerpeSelect ELISA test and genotyping was performed using TaqMan assay. FasR-1377A allele showed a statistically significant association (P = 0.008) with reduced risk of HSV-2 infection. Analyzing the FasR haplotypes also showed a statistically significant association (P = 0.0001) with FasR-1377/FasR-670 AG haplotype and reduced risk of HSV-2 infection. There was no significant association found with FasR-670A > G and FasL-844T > C polymorphisms and risk of HSV-2 infection. This is, to our knowledge, the first time a non-HLA genetic link with HSV-2 infection has been reported.