Lower red blood cell folate enhances the HPV-16–associated risk of cervical intraepithelial neoplasia

Objective We previously reported that higher circulating concentrations of folate are independently associated with a lower likelihood of becoming positive for high-risk human papillomaviruses (HR-HPVs) and of having a persistent HR-HPV infection and a greater likelihood of becoming HR-HPV negative (Cancer Res 2004;64:8788–93). In the present study conducted in the same study population, we tested whether circulating folate concentrations modify the risk of cervical intraepithelial neoplasia (CIN) ≥2 associated with specific types of HR-HPV. Methods Multiple logistic regression models were used to assess associations (odds ratio with 95% confidence intervals) across HR-HPV, folate, and rigorously reviewed cervical histology of each subject. Results HPV-16–positive women with low red blood cell folate were significantly more likely to be diagnosed with CIN ≥2 than were HPV-16–negative women with higher red blood cell folate (odds ratio 9, 95% confidence interval 3.3–24.8). Conclusion To our knowledge, this is the first study reporting an independent association of folate with risk of having CIN ≥2 in a population tested extensively for HR-HPV and CIN that also adequately controlled for several other micronutrients and known risk factors for CIN. Our findings suggest that improving the folate status in HR-HPV–infected women may reduce the risk of CIN and thus the risk of cervical cancer. Folate supplementation should be tested as a means of reducing the risk of developing CIN ≥2 in women exposed to HR-HPV, especially HPV-16.