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Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma.

Kelemen LE, Wang Q, Dinu I, Vierkant RA, Tsai YY, Cunningham JM, Phelan CM, Fridley BL, Amankwah EK, Iversen ES, Berchuck A, Schildkraut JM, Goode EL, Sellers TA - Front Genet (2012)

Bottom Line: In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6-0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1-2.0).The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users.The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the hypothesis of no association.

View Article: PubMed Central - PubMed

Affiliation: Department of Population Health Research, Alberta Health Services-Cancer Care Calgary, AB, Canada.

ABSTRACT
ATIC, SHMT2, and SLC46A1 have essential roles in one-carbon (1-C) transfer. The authors examined whether associations between ovarian carcinoma and 15 variants in these genes are modified by regular multivitamin use, a source of 1-C donors, among Caucasian participants from two US case-control studies. Using a phased study design, variant-by-multivitamin interactions were tested, and associations between variants and ovarian carcinoma were reported stratified by multivitamin supplement use. Per-allele risk associations were modified by multivitamin use at six variants among 655 cases and 920 controls (Phase 1). In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6-0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1-2.0). The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. A multi-variant analysis was also performed by comparing the observed likelihood ratio test statistic from adjusted models with and without the two ATIC variant-by-multivitamin interaction terms with a distribution of test statistics generated by permuting case status 10,000 times. The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the hypothesis of no association. In summary, there is little statistical evidence that the 15 variants are independently associated with risk of ovarian carcinoma. However, the statistical interaction of ATIC variants with regular multivitamin intake, when evaluated at both the SNP and gene level, may support these findings as relevant to ovarian health and disease processes.

No MeSH data available.


Related in: MedlinePlus

Linkage disequilibrium plot for tagSNPs in AITC using 2,233 Caucasian subjects, Mayo Clinic, and Duke University. Numbers in squares indicate the correlation (r2) between SNPs.
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FA1: Linkage disequilibrium plot for tagSNPs in AITC using 2,233 Caucasian subjects, Mayo Clinic, and Duke University. Numbers in squares indicate the correlation (r2) between SNPs.

Mentions: In haplotype analyses, only the ATIC gene was statistically significantly associated with ovarian carcinoma among regular multivitamin supplement users (Table 4: global haplotype test P = 0.01; data not shown for SHMT2 and SLC46A1). The two ATIC SNPs, rs7586969, and rs16853834, whose minor alleles showed opposing risks, did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. Haplotype #1 accounted for 24% of all estimated haplotypes, comprised the minor allele of ATIC rs7586969 and was associated with a 24% decreased risk. Haplotype #9 accounted for 13% of all estimated haplotypes, comprised the minor allele of ATIC rs16853834 and was associated with a 39% increased risk. A third haplotype, haplotype #10, with 8% frequency, comprised common alleles for ATIC rs7586969 and rs16853834 and was associated with a 42% increased risk. Among non-users, haplotype #5 was associated with a 27% decreased risk, but the global haplotype test was not statistically significant. None of the associations were statistically significant in the unstratified data. Squared correlations among the SNPs are shown in Figure A1 in Appendix.


Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma.

Kelemen LE, Wang Q, Dinu I, Vierkant RA, Tsai YY, Cunningham JM, Phelan CM, Fridley BL, Amankwah EK, Iversen ES, Berchuck A, Schildkraut JM, Goode EL, Sellers TA - Front Genet (2012)

Linkage disequilibrium plot for tagSNPs in AITC using 2,233 Caucasian subjects, Mayo Clinic, and Duke University. Numbers in squares indicate the correlation (r2) between SNPs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3306919&req=5

FA1: Linkage disequilibrium plot for tagSNPs in AITC using 2,233 Caucasian subjects, Mayo Clinic, and Duke University. Numbers in squares indicate the correlation (r2) between SNPs.
Mentions: In haplotype analyses, only the ATIC gene was statistically significantly associated with ovarian carcinoma among regular multivitamin supplement users (Table 4: global haplotype test P = 0.01; data not shown for SHMT2 and SLC46A1). The two ATIC SNPs, rs7586969, and rs16853834, whose minor alleles showed opposing risks, did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. Haplotype #1 accounted for 24% of all estimated haplotypes, comprised the minor allele of ATIC rs7586969 and was associated with a 24% decreased risk. Haplotype #9 accounted for 13% of all estimated haplotypes, comprised the minor allele of ATIC rs16853834 and was associated with a 39% increased risk. A third haplotype, haplotype #10, with 8% frequency, comprised common alleles for ATIC rs7586969 and rs16853834 and was associated with a 42% increased risk. Among non-users, haplotype #5 was associated with a 27% decreased risk, but the global haplotype test was not statistically significant. None of the associations were statistically significant in the unstratified data. Squared correlations among the SNPs are shown in Figure A1 in Appendix.

Bottom Line: In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6-0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1-2.0).The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users.The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the hypothesis of no association.

View Article: PubMed Central - PubMed

Affiliation: Department of Population Health Research, Alberta Health Services-Cancer Care Calgary, AB, Canada.

ABSTRACT
ATIC, SHMT2, and SLC46A1 have essential roles in one-carbon (1-C) transfer. The authors examined whether associations between ovarian carcinoma and 15 variants in these genes are modified by regular multivitamin use, a source of 1-C donors, among Caucasian participants from two US case-control studies. Using a phased study design, variant-by-multivitamin interactions were tested, and associations between variants and ovarian carcinoma were reported stratified by multivitamin supplement use. Per-allele risk associations were modified by multivitamin use at six variants among 655 cases and 920 controls (Phase 1). In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6-0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1-2.0). The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. A multi-variant analysis was also performed by comparing the observed likelihood ratio test statistic from adjusted models with and without the two ATIC variant-by-multivitamin interaction terms with a distribution of test statistics generated by permuting case status 10,000 times. The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the hypothesis of no association. In summary, there is little statistical evidence that the 15 variants are independently associated with risk of ovarian carcinoma. However, the statistical interaction of ATIC variants with regular multivitamin intake, when evaluated at both the SNP and gene level, may support these findings as relevant to ovarian health and disease processes.

No MeSH data available.


Related in: MedlinePlus