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Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

ABSTRACT: BACKGROUND:In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS:We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS:The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20?nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS:Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

SUBMITTER: Ong JS

PROVIDER: S-EPMC5100621 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Ong Jue-Sheng JS Cuellar-Partida Gabriel G Lu Yi Y Fasching Peter A PA Hein Alexander A Burghaus Stefanie S Beckmann Matthias W MW Lambrechts Diether D Van Nieuwenhuysen Els E Vergote Ignace I Vanderstichele Adriaan A Anne Doherty Jennifer J Anne Rossing Mary M Chang-Claude Jenny J Eilber Ursula U Rudolph Anja A Wang-Gohrke Shan S Goodman Marc T MT Bogdanova Natalia N Dörk Thilo T Dürst Matthias M Hillemanns Peter P Runnebaum Ingo B IB Antonenkova Natalia N Butzow Ralf R Leminen Arto A Nevanlinna Heli H Pelttari Liisa M LM Edwards Robert P RP Kelley Joseph L JL Modugno Francesmary F Moysich Kirsten B KB Ness Roberta B RB Cannioto Rikki R Høgdall Estrid E Høgdall Claus K CK Jensen Allan A Giles Graham G GG Bruinsma Fiona F Kjaer Susanne K SK Hildebrandt Michelle At MA Liang Dong D Lu Karen H KH Wu Xifeng X Bisogna Maria M Dao Fanny F Levine Douglas A DA Cramer Daniel W DW Terry Kathryn L KL Tworoger Shelley S SS Stampfer Meir M Missmer Stacey S Bjorge Line L Salvesen Helga B HB Kopperud Reidun K RK Bischof Katharina K Aben Katja Kh KK Kiemeney Lambertus A LA Massuger Leon Fag LF Brooks-Wilson Angela A Olson Sara H SH McGuire Valerie V Rothstein Joseph H JH Sieh Weiva W Whittemore Alice S AS Cook Linda S LS Le Nhu D ND Gilks C Blake CB Gronwald Jacek J Jakubowska Anna A Lubiński Jan J Kluz Tomasz T Song Honglin H Tyrer Jonathan P JP Wentzensen Nicolas N Brinton Louise L Trabert Britton B Lissowska Jolanta J McLaughlin John R JR Narod Steven A SA Phelan Catherine C Anton-Culver Hoda H Ziogas Argyrios A Eccles Diana D Campbell Ian I Gayther Simon A SA Gentry-Maharaj Aleksandra A Menon Usha U Ramus Susan J SJ Wu Anna H AH Dansonka-Mieszkowska Agnieszka A Kupryjanczyk Jolanta J Timorek Agnieszka A Szafron Lukasz L Cunningham Julie M JM Fridley Brooke L BL Winham Stacey J SJ Bandera Elisa V EV Poole Elizabeth M EM Morgan Terry K TK Risch Harvey A HA Goode Ellen L EL Schildkraut Joellen M JM Pearce Celeste L CL Berchuck Andrew A Pharoah Paul Dp PD Chenevix-Trench Georgia G Gharahkhani Puya P Neale Rachel E RE Webb Penelope M PM MacGregor Stuart S

International journal of epidemiology 20160904 5

<h4>Background</h4>In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associat ...[more]

PMID: 27594614

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Project description:BackgroundEvidence showed the supplementation of vitamin D might have beneficial effects for migraine patients. We aimed to investigate the causal effects of serum vitamin D levels on migraine risk using two-sample Mendelian randomization (MR) method.MethodsA total of 184 independent genetic instruments for serum vitamin D levels were selected from a study in 417,580 Europeans from UK biobank. Six variants from an independent study were obtained to perform replication analysis. Summary-level data for migraine were obtained from three studies with 48,975 migraine cases, 28,852 migraine cases and 10,536 migraine cases, respectively.ResultsThe estimated odds ratios (ORs) per standard deviation increase in circulating vitamin D levels based on the three migraine datasets were 0.948 (95% CI = 0.883-1.016, p = 0.133), 0.902 (95% confidence intervals [CI] = 0.825-0.986, p = 0.023), and 0.880 (95% CI = 0.786-0.984, p = 0.025), respectively. Using pooled migraine summary data with no sample overlap, MR analysis showed per standard deviation increase in circulating vitamin D levels was significantly associated with a decreased migraine risk (OR = 0.916, 95% CI = 0.859-0.977, p = 0.008). Multivariable MR analyses, sensitivity analyses and replication analysis confirmed the association. MR analyses showed similar estimates for migraine with aura and migraine without aura but with wider 95% CIs. Mediation analysis showed the effect of vitamin D on migraine risk via pathway of serum calcium was corresponding to an OR of 1.003 (95% CI = 1.001-1.005) and a proportion mediated of 3.42%. The reverse MR analysis showed migraine might not affect vitamin D levels.ConclusionThis two-sample MR study showed genetically determined increased circulating vitamin D levels are associated with decreased migraine risk. The effect seems consistent across different migraine subtypes. In addition, the role of serum calcium in mediating the association between vitamin D and migraine is negligible. Future large well-designed randomized trials are warranted to assess the effects of vitamin D supplementation for migraine patients, especially in those with vitamin D deficiency.

Project description:BackgroundObservational studies indicated that circulating vitamin C (VitC) levels may be correlated with the risk of endometrial cancer (EC). However, the causal effects and direction between them were still unclear.MethodsIn this study, 11 single nucleotide polymorphisms (SNPs) robustly correlated with plasma VitC levels were extracted from the latest genome-wide association study (GWAS), containing 52,018 individuals. Genetic data of EC were obtained from the Endometrial Cancer Association Consortium (ECAC) (12,906 cases and 108,979 controls). An inverse-variance weighted method was utilized as the primary analysis of Mendelian randomization (MR), supplemented by the weighted median, MR Pleiotropy Residual Sum and Outlier test (MR-PRESSO), and MR-Egger methods. Additional sensitivity analyses excluding 3 SNPs with secondary phenotypes were conducted to rule out the possible pleiotropic effects. Potential impacts of several risk factors of EC, such as obesity, body mass index (BMI), hypertension, and diabetes on VitC levels, were assessed. We additionally evaluated the effects of VitC on LDL cholesterol levels, HDL cholesterol levels, and triglycerides levels to probe into the possible mediators in the VitC-EC pathway.ResultsGenetically predicted higher plasma VitC levels (per 1 SD increase, approximately 20 μmol/L) were causally associated with an increased risk of EC overall [odds ratio (OR) 1.374, 95% CI 1.128-1.674, p = 0.0016], supported by complementary sensitivity analyses. In the subgroup analyses, genetically predicted higher levels of VitC were associated with a tendency of increased risks of both endometrioid (OR SD 1.324, 95% CI 0.959-1.829, p = 0.0881) and non-endometrioid histology (OR SD 1.392, 95% CI 0.873-2.220, p = 0.1647) while without statistical significance. The association remained significant after the exclusion of the three pleiotropic SNPs (OR SD 1.394, 95% CI 1.090-1.784, p = 0.0082). The confounders and mediators were unlikely to affect the VitC-EC relationship. The causal effect of EC on VitC levels was not supported (OR 1.001, 95% CI 0.998-1.004, p = 0.4468).ConclusionsThis bi-directional MR study demonstrated a causal risk role of higher circulating VitC at physiological levels on an increased risk of EC, which was independent of confounders and mediators. Further studies are warranted to elucidate the possible mechanisms.

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Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

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Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

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