UPCC 36818 The Role of Mitochondrial DNA Background in HPV Infection and Cervical Cancer Precursor Risk

The analysis of HPV infection, cervical lesions, and mitochondrial haplogroup diversity will provide insights into evolutionary questions by examining how mtDNA differences that have accrued over time as a result of natural selection can affect the health of modern day people. Such an analysis will also illuminate the relationships between behavioral, socio-demographic, and clinical covariates with HPV infection and cervical cancer precursors. Thus, to clarify the role of the mtDNA in the susceptibility to HPV infection, we will pursue the following specific aims:

(1) Identify mtDNA haplogroups that confer a higher risk of HPV infection. By comparing mtDNA haplogroups in high- and low-risk HPV cases and controls, we will determine the extent to which certain maternal lineages confer a higher risk of HPV infection in women. We will specifically focus on differences between European haplogroups (H, U, T, V, J, K, X) and African haplogroups (L0, L1, L2, L3), as they have bioenergetic differences in mitochondrial coupling due to evolving in either cold or warm climates (Mishmar et al., 2003; Hancock et al., 2008, 2011; Fetterman et al., 2013; Krzywanski et al., 2016b). HPV infection risk is also increased by lifestyle factors such as smoking and an increased number of sexual partners (Palefsky et al., 1999; Winer et al., 2003; Kahn, 2007; Chelimo et al., 2013; Castellsagué et al., 2014; Foliaki et al., 2014; Trottier et al., 2015). Such risk factors will be controlled for in order to exclude them as possible confounders to an association between mtDNA haplogroup and HPV positive status.

(2) Identify mtDNA haplogroups that are associated with an overrepresentation of cervical lesions among HPV positive high-risk cases. Within the HPV positive high-risk cases, we will compare the proportion of cervical cancer lesions among them in every haplogroup background to determine whether a particular haplogroup is associated with a higher risk of cervical lesions than others once HPV infection has occurred. Co-infection with HIV or immunosuppressing factors may also increase the risk of cervical cancer progression(Delmas et al., 2000; Palefsky, 2006). For this reason, samples from patients experiencing immunosuppression for medically diagnosed reasons including HIV will be excluded from this study.

(3) Ascertain the particular geographic variants of HPV 16 and 18 that cause greater cancer risk in different mtDNA haplogroup backgrounds. Two high risk HPV genotypes, type-16 and type-18, cause the majority of cases of cervical cancer (zur Hausen, 1999; Bosch et al., 2002). However, the relative degree of carcinogenicity of specific geographic variants of these types (Ho et al., 1993; Ong et al., 1993; Xi et al., 2006) in relation to different mtDNA haplogroups has not been well characterized (Burk et al., 2013). We will therefore survey HPV positive individuals for different viral subtypes and deduce if there is any relationship between geographic variants of the two predominate types of high risk HPV and cervical cancer precursors relative to specific mtDNA haplogroup background. Phylogenetic analysis will be performed by comparison of SNPs characteristic of mtDNA haplogroups identified in the samples to the Cambridge Reference sequence and Phylotree (Anderson et al., 1981; Andrews et al., 1999; van Oven and Kayser, 2009b) using the Network program (Bandelt et al., 1999). HPV type analysis will be performed by comparison with HPV genomes deposited in the NCBI-GenBank using the BLAST program (NCBI) (Fuessel Haws et al., 2004) while geographic variants will be compared to published data on HPV 16 and 18 phylogenetic trees (Ho et al., 1993; Ong et al., 1993).

This study will compare three HPV states (HPV negative, HPV positive low risk type, and HPV positive high risk type) to different mtDNA haplogroups. A chi square test will be performed ( = 0.05) to determine whether an HPV state is independent of mtDNA haplogroup

You may be eligible for this study if you meet the following criteria:

• Conditions: Medical Research
• Age: 99 years or below
• Gender: All