Ancestry-Specific Interactions Between Circulatory Folate and One-Carbon Metabolism Genes’ Haplotypes for Higher-Grade Cervical Intraepithelial Neoplasia

Abstract Objectives Determine ancestry-specific interactions between circulatory folate concentrations, haplotypes of the one-carbon (1C) pathway genes and risk of higher-grade cervical intraepithelial neoplasia (CIN2+) in the US post-folic acid fortification era. Methods Study included self-reported African American and Caucasian American women positive for high-risk human papillomavirus (HPV) genotypes and diagnosed with ≤ CIN1 (non-cases, n = 340) or CIN2+ (cases, n = 337). Plasma and red blood cell (RBC) folate, vitamins B12 (B12) and C, and total carotene levels were measured. 660 single nucleotide polymorphisms of the 1C pathway genes and 104 ancestry informative markers (AIMs) were analyzed using buffy coat DNA and customizable Illumina GoldenGate arrays. Global African ancestry (GA) was estimated using the AIMs. Ancestry-based African American (AFR) had GA ≥ 0.8 and European Americans (EA) otherwise. Common haplotype blocks (n = 50) were tested for interactions with circulatory folate using logistic regression adjusting for age, education, body mass index (BMI), body fat %, smoking, parity, hormonal contraception use, plasma total carotene, B12 and C. False discovery rate < 0.1 was considered significant. Results Some of the main findings were, increasing plasma folate (1 SD) decreases the risk of CIN2 + when homozygous for haplotype CG at (rs575425, rs586199) of BHMT gene in EA (odds ratio/OR = 0.13, CI = 0.04,0.44), and for haplotype TA at (rs559062, rs515064) of CTH in AFR (OR = 0.23, CI = 0.1,0.52); increasing RBC folate (1 SD) decreases risk of CIN2 + when homozygous for haplotypes TA at (rs559062, rs515064) of CTH (OR = 0.27, CI = 0.12,0.61), AC at (rs7706298, rs10512934) of MTRR (OR = 0.21, CI = 0.08,0.57), and AGA at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 0.4, CI = 0.18,0.90) in AFR; and increasing RBC folate (1 SD) increases the risk of CIN2 + when homozygous for haplotypes GG at (rs3856027, rs4650051) of CTH gene (OR = 3.52, CI = 1.27,9.71), and CGG at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 5.70, CI = 1.86,17.49) in AFR. Conclusions Circulatory folate differentially modulates the risk for CIN2 + by interacting with haplotypes of the 1C pathway genes according to ancestry in reproductive-aged women exposed to US folic acid fortification program. Funding Sources National Cancer Institute

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Lower Risk of Cervical Intraepithelial Neoplasia in Women with High Plasma Folate and Sufficient Vitamin B12 in the Post-Folic Acid Fortification Era

Cancer Prevention Research ◽

10.1158/1940-6207.capr-08-0175 ◽

2009 ◽

Vol 2 (7) ◽

pp. 658-664 ◽

Cited By ~ 29

Author(s):

Chandrika J. Piyathilake ◽

Maurizio Macaluso ◽

Ronald D. Alvarez ◽

Walter C. Bell ◽

Douglas C. Heimburger ◽

...

Keyword(s):

Folic Acid ◽

Vitamin B12 ◽

Cervical Intraepithelial Neoplasia ◽

Lower Risk ◽

Intraepithelial Neoplasia ◽

High Plasma ◽

Folic Acid Fortification ◽

Plasma Folate ◽

Sufficient Vitamin

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Status of plasma folate after folic acid fortification of the food supply in pregnant African American women and the influences of diet, smoking, and alcohol consumption

American Journal of Clinical Nutrition ◽

10.1093/ajcn/81.3.669 ◽

2005 ◽

Vol 81 (3) ◽

pp. 669-677 ◽

Cited By ~ 20

Author(s):

Ken D Stark ◽

Robert J Pawlosky ◽

Skadi Beblo ◽

Mahadev Murthy ◽

Vincent P Flanagan ◽

...

Keyword(s):

African American ◽

Folic Acid ◽

Alcohol Consumption ◽

African American Women ◽

Food Supply ◽

Folic Acid Fortification ◽

American Women ◽

Plasma Folate

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Abstract B01: PEG3 DNA methylation and cervical intraepithelial neoplasia in African American and European American women

10.1158/1538-7755.disp14-b01 ◽

2015 ◽

Author(s):

Adriana C. Vidal ◽

David Skaar ◽

Zhiquing Huang ◽

Fidel Valea ◽

Rex Bentley ◽

...

Keyword(s):

Dna Methylation ◽

African American ◽

Cervical Intraepithelial Neoplasia ◽

Intraepithelial Neoplasia ◽

European American ◽

American Women ◽

European American Women

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Abstract PR01: HPV genotype distribution and cervical intraepithelial neoplasia in African American and white women living in the Southeastern United States

10.1158/1940-6215.prev-13-pr01 ◽

2013 ◽

Author(s):

Adriana C Vidal ◽

Jennifer S Smith ◽

Edwin Iversen ◽

Fidel Valea ◽

Rex Bentley ◽

...

Keyword(s):

United States ◽

African American ◽

Cervical Intraepithelial Neoplasia ◽

White Women ◽

Southeastern United States ◽

Intraepithelial Neoplasia ◽

Genotype Distribution

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Association study of relationships of polymorphisms in the miR-21, miR-26b, miR-221/222 and miR-126 genes with cervical intraepithelial neoplasia and cervical cancer

BMC Cancer ◽

10.1186/s12885-021-08743-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jia Yang ◽

Zhiling Yan ◽

Yingying Wang ◽

Jinmei Xu ◽

Rui Li ◽

...

Keyword(s):

Cervical Cancer ◽

Cervical Intraepithelial Neoplasia ◽

Additive Model ◽

Intraepithelial Neoplasia ◽

Recessive Model ◽

Cancer Development ◽

Nucleotide Polymorphisms ◽

Mirna Genes ◽

Increased Risk ◽

Cervical Cancer Development

Abstract Background miR-21, miR-26b, miR-221/222 and miR-126 play crucial roles in cervical cancer development. Studies have shown that polymorphisms in miRNA genes can affect miRNA expression, which might be associated with cancer development. Methods Ten single-nucleotide polymorphisms (SNPs) in the miR-21, miR-26b, miR-221/222 and miR-126 genes (rs1292037, rs13137 in miR-21; rs2227255, rs2227258 in miR-26b; rs2858061, rs34678647, rs2858060, rs2745709 in miR-221/222; rs2297537, rs2297538 in miR-126) were selected, and genotyped in a total of 2176 individuals, including 435 patients with cervical intraepithelial neoplasia (CIN), 743 patients with cervical cancer (CC) and 998 healthy persons using TaqMan assays, and their associations with CIN and CC were evaluated. Results Our results showed significant differences for the rs2297538 genotypes between the CIN and CC groups (P = 0.001). In addition, our results also showed significant differences for the rs2297537 alleles between the CIN and CC groups (P = 0.003), and the C allele of rs2297537 might be associated with a decreased risk of CC (OR = 0.72, 95%CI: 0.58–0.90). At the inheritance analysis, between the CIN and control groups, the T/T-T/C genotype in rs1292037 and A/A-A/T genotype in rs13137 might be associated with an increased risk of CIN in the recessive model (OR = 1.61, 95% CI: 1.17–2.20 and OR = 1.58, 95% CI: 1.15–2.15). In addition, the C/C-T/T genotype of rs2745709 might be associated with a decreased risk of CIN in the overdominant model (OR = 0.66, 95% CI: 0.52–0.82). Between, CIN and CC group, the T/T-C/C genotype in rs1292037 and A/A-T/T genotype in rs13137 might be associated with an increased risk of CC in the overdominant model (OR = 1.43, 95% CI: 1.12–1.81 and OR = 1.42, 95% CI: 1.12–1.80). The rs2297538 G/G-A/G genotype might be associated with an increased risk of CC in the recessive model (OR = 2.83, 95% CI: 1.52–5.25). The rs2297537 2C/C + C/G genotype might be associated with a decreased risk of CC (OR = 0.71, 95% CI: 0.57–0.89) in the log-additive model. The rs2745709 T/T-C/C genotype might be associated with an increased risk of CC (OR = 1.44, 95% CI: 1.13–1.83) in the overdominant model. Conclusion Our results indicate that rs2297538 and rs2297537 in miR-126, rs1292037 and rs13137 in miR-21, and rs2745709 in miR-221/222, may have important roles in the development of CIN or CC.

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