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

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

doi:10.1093/ije/dyw207

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

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

Department of Clinical Medicine

65 Citations (Scopus)

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.

Original language	English
Journal	International Journal of Epidemiology
Volume	45
Issue number	5
Pages (from-to)	1619-1630
ISSN	0300-5771
DOIs	https://doi.org/10.1093/ije/dyw207
Publication status	Published - Oct 2016

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Ong, J.-S., Cuellar-Partida, G., Lu, Y., Ovarian Cancer Study, A., Fasching, P. A., Hein, A., Burghaus, S., Beckmann, M. W., Lambrechts, D., Van Nieuwenhuysen, E., Vergote, I., Vanderstichele, A., Anne Doherty, J., Anne Rossing, M., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M. T., ... MacGregor, S. (2016). Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. International Journal of Epidemiology, 45(5), 1619-1630. https://doi.org/10.1093/ije/dyw207

Ong, J-S, Cuellar-Partida, G, Lu, Y, Ovarian Cancer Study, A, Fasching, PA, Hein, A, Burghaus, S, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Vanderstichele, A, Anne Doherty, J, Anne Rossing, M, Chang-Claude, J, Eilber, U, Rudolph, A, Wang-Gohrke, S, Goodman, MT, Bogdanova, N, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, Antonenkova, N, Butzow, R, Leminen, A, Nevanlinna, H, Pelttari, LM, Edwards, RP, Kelley, JL, Modugno, F, Moysich, KB, Ness, RB, Cannioto, R, Høgdall, E , Høgdall, CK, Jensen, A, Giles, GG, Bruinsma, F, Kjaer, SK, Hildebrandt, MA, Liang, D, Lu, KH, Wu, X, Bisogna, M, Dao, F, Levine, DA, Cramer, DW, Terry, KL, Tworoger, SS, Stampfer, M, Missmer, S, Bjorge, L, Salvesen, HB, Kopperud, RK, Bischof, K, Aben, KK, Kiemeney, LA, Massuger, LF, Brooks-Wilson, A, Olson, SH, McGuire, V, Rothstein, JH, Sieh, W, Whittemore, AS, Cook, LS, Le, ND, Blake Gilks, C, Gronwald, J, Jakubowska, A, Lubiński, J, Kluz, T, Song, H, Tyrer, JP, Wentzensen, N, Brinton, L, Trabert, B, Lissowska, J, McLaughlin, JR, Narod, SA, Phelan, C, Anton-Culver, H, Ziogas, A, Eccles, D, Campbell, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Ramus, SJ, Wu, AH, Dansonka-Mieszkowska, A, Kupryjanczyk, J, Timorek, A, Szafron, L, Cunningham, JM, Fridley, BL, Winham, SJ, Bandera, EV, Poole, EM, Morgan, TK, Risch, HA, Goode, EL, Schildkraut, JM, Pearce, CL, Berchuck, A, Pharoah, PD, Chenevix-Trench, G, Gharahkhani, P, Neale, RE, Webb, PM & MacGregor, S 2016, 'Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study', International Journal of Epidemiology, vol. 45, no. 5, pp. 1619-1630. https://doi.org/10.1093/ije/dyw207

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title = "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.",

author = "Jue-Sheng Ong and Gabriel Cuellar-Partida and Yi Lu and {Ovarian Cancer Study}, Australian and Fasching, {Peter A} and Alexander Hein and Stefanie Burghaus and Beckmann, {Matthias W} and Diether Lambrechts and {Van Nieuwenhuysen}, Els and Ignace Vergote and Adriaan Vanderstichele and {Anne Doherty}, Jennifer and {Anne Rossing}, Mary and Jenny Chang-Claude and Ursula Eilber and Anja Rudolph and Shan Wang-Gohrke and Goodman, {Marc T} and Natalia Bogdanova and Thilo D{\"o}rk and Matthias D{\"u}rst and Peter Hillemanns and Runnebaum, {Ingo B} and Natalia Antonenkova and Ralf Butzow and Arto Leminen and Heli Nevanlinna and Pelttari, {Liisa M} and Edwards, {Robert P} and Kelley, {Joseph L} and Francesmary Modugno and Moysich, {Kirsten B} and Ness, {Roberta B} and Rikki Cannioto and Estrid H{\o}gdall and H{\o}gdall, {Claus K} and Allan Jensen and Giles, {Graham G} and Fiona Bruinsma and Kjaer, {Susanne K} and Hildebrandt, {Michelle At} and Dong Liang and Lu, {Karen H} and Xifeng Wu and Maria Bisogna and Fanny Dao and Levine, {Douglas A} and Cramer, {Daniel W} and Terry, {Kathryn L} and Tworoger, {Shelley S} and Meir Stampfer and Stacey Missmer and Line Bjorge and Salvesen, {Helga B} and Kopperud, {Reidun K} and Katharina Bischof and Aben, {Katja Kh} and Kiemeney, {Lambertus A} and Massuger, {Leon Fag} and Angela Brooks-Wilson and Olson, {Sara H} and Valerie McGuire and Rothstein, {Joseph H} and Weiva Sieh and Whittemore, {Alice S} and Cook, {Linda S} and Le, {Nhu D} and {Blake Gilks}, C and Jacek Gronwald and Anna Jakubowska and Jan Lubi{\'n}ski and Tomasz Kluz and Honglin Song and Tyrer, {Jonathan P} and Nicolas Wentzensen and Louise Brinton and Britton Trabert and Jolanta Lissowska and McLaughlin, {John R} and Narod, {Steven A} and Catherine Phelan and Hoda Anton-Culver and Argyrios Ziogas and Diana Eccles and Ian Campbell and Gayther, {Simon A} and Aleksandra Gentry-Maharaj and Usha Menon and Ramus, {Susan J} and Wu, {Anna H} and Agnieszka Dansonka-Mieszkowska and Jolanta Kupryjanczyk and Agnieszka Timorek and Lukasz Szafron and Cunningham, {Julie M} and Fridley, {Brooke L} and Winham, {Stacey J} and Bandera, {Elisa V} and Poole, {Elizabeth M} and Morgan, {Terry K} and Risch, {Harvey A} and Goode, {Ellen L} and Schildkraut, {Joellen M} and Pearce, {Celeste L} and Andrew Berchuck and Pharoah, {Paul Dp} and Georgia Chenevix-Trench and Puya Gharahkhani and Neale, {Rachel E} and Webb, {Penelope M} and Stuart MacGregor",

year = "2016",

month = oct,

doi = "10.1093/ije/dyw207",

language = "English",

volume = "45",

pages = "1619--1630",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "5",

}

TY - JOUR

T1 - Association of vitamin D levels and risk of ovarian cancer

T2 - a Mendelian randomization study

AU - Ong, Jue-Sheng

AU - Cuellar-Partida, Gabriel

AU - Lu, Yi

AU - Ovarian Cancer Study, Australian

AU - Fasching, Peter A

AU - Hein, Alexander

AU - Burghaus, Stefanie

AU - Beckmann, Matthias W

AU - Lambrechts, Diether

AU - Van Nieuwenhuysen, Els

AU - Vergote, Ignace

AU - Vanderstichele, Adriaan

AU - Anne Doherty, Jennifer

AU - Anne Rossing, Mary

AU - Chang-Claude, Jenny

AU - Eilber, Ursula

AU - Rudolph, Anja

AU - Wang-Gohrke, Shan

AU - Goodman, Marc T

AU - Bogdanova, Natalia

AU - Dörk, Thilo

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Runnebaum, Ingo B

AU - Antonenkova, Natalia

AU - Butzow, Ralf

AU - Leminen, Arto

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M

AU - Edwards, Robert P

AU - Kelley, Joseph L

AU - Modugno, Francesmary

AU - Moysich, Kirsten B

AU - Ness, Roberta B

AU - Cannioto, Rikki

AU - Høgdall, Estrid

AU - Høgdall, Claus K

AU - Jensen, Allan

AU - Giles, Graham G

AU - Bruinsma, Fiona

AU - Kjaer, Susanne K

AU - Hildebrandt, Michelle At

AU - Liang, Dong

AU - Lu, Karen H

AU - Wu, Xifeng

AU - Bisogna, Maria

AU - Dao, Fanny

AU - Levine, Douglas A

AU - Cramer, Daniel W

AU - Terry, Kathryn L

AU - Tworoger, Shelley S

AU - Stampfer, Meir

AU - Missmer, Stacey

AU - Bjorge, Line

AU - Salvesen, Helga B

AU - Kopperud, Reidun K

AU - Bischof, Katharina

AU - Aben, Katja Kh

AU - Kiemeney, Lambertus A

AU - Massuger, Leon Fag

AU - Brooks-Wilson, Angela

AU - Olson, Sara H

AU - McGuire, Valerie

AU - Rothstein, Joseph H

AU - Sieh, Weiva

AU - Whittemore, Alice S

AU - Cook, Linda S

AU - Le, Nhu D

AU - Blake Gilks, C

AU - Gronwald, Jacek

AU - Jakubowska, Anna

AU - Lubiński, Jan

AU - Kluz, Tomasz

AU - Song, Honglin

AU - Tyrer, Jonathan P

AU - Wentzensen, Nicolas

AU - Brinton, Louise

AU - Trabert, Britton

AU - Lissowska, Jolanta

AU - McLaughlin, John R

AU - Narod, Steven A

AU - Phelan, Catherine

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Eccles, Diana

AU - Campbell, Ian

AU - Gayther, Simon A

AU - Gentry-Maharaj, Aleksandra

AU - Menon, Usha

AU - Ramus, Susan J

AU - Wu, Anna H

AU - Dansonka-Mieszkowska, Agnieszka

AU - Kupryjanczyk, Jolanta

AU - Timorek, Agnieszka

AU - Szafron, Lukasz

AU - Cunningham, Julie M

AU - Fridley, Brooke L

AU - Winham, Stacey J

AU - Bandera, Elisa V

AU - Poole, Elizabeth M

AU - Morgan, Terry K

AU - Risch, Harvey A

AU - Goode, Ellen L

AU - Schildkraut, Joellen M

AU - Pearce, Celeste L

AU - Berchuck, Andrew

AU - Pharoah, Paul Dp

AU - Chenevix-Trench, Georgia

AU - Gharahkhani, Puya

AU - Neale, Rachel E

AU - Webb, Penelope M

AU - MacGregor, Stuart

PY - 2016/10

Y1 - 2016/10

N2 - 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.

AB - 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.

U2 - 10.1093/ije/dyw207

DO - 10.1093/ije/dyw207

M3 - Journal article

C2 - 27594614

SN - 0300-5771

VL - 45

SP - 1619

EP - 1630

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 5

ER -

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

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