vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations

Veronika Fedirko; Hannah B. Mandle; Wanzhe Zhu; David J. Hughes; Afshan Siddiq; Pietro Ferrari; Isabelle Romieu; Elio Riboli; Bas Bueno-de-Mesquita; Fränzel J.B. Van Duijnhoven; Peter D. Siersema; Anne Tjønneland; Anja Olsen; Vittorio Perduca; Franck Carbonnel; Marie Christine Boutron-Ruault; Tilman Kühn; Theron Johnson; Aleksandrova Krasimira; Antonia Trichopoulou; Periklis Makrythanasis; Dimitris Thanos; Salvatore Panico; Vittorio Krogh; Carlotta Sacerdote; Guri Skeie; Elisabete Weiderpass; Sandra Colorado-Yohar; Núria Sala; Aurelio Barricarte; Maria Jose Sanchez; Ramón Quirós; Pilar Amiano; Björn Gylling; Sophia Harlid; Aurora Perez-Cornago; Alicia K. Heath; Konstantinos K. Tsilidis; Dagfinn Aune; Heinz Freisling; Neil Murphy; Marc J. Gunter; Mazda Jenab

doi:10.3390/nu11081954

vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations

Veronika Fedirko, Hannah B. Mandle, Wanzhe Zhu, David J. Hughes, Afshan Siddiq, Pietro Ferrari, Isabelle Romieu, Elio Riboli, Bas Bueno-de-Mesquita, Fränzel J.B. Van Duijnhoven, Peter D. Siersema, Anne Tjønneland, Anja Olsen, Vittorio Perduca, Franck Carbonnel, Marie Christine Boutron-Ruault, Tilman Kühn, Theron Johnson, Aleksandrova Krasimira, Antonia TrichopoulouPeriklis Makrythanasis, Dimitris Thanos, Salvatore Panico, Vittorio Krogh, Carlotta Sacerdote, Guri Skeie, Elisabete Weiderpass, Sandra Colorado-Yohar, Núria Sala, Aurelio Barricarte, Maria Jose Sanchez, Ramón Quirós, Pilar Amiano, Björn Gylling, Sophia Harlid, Aurora Perez-Cornago, Alicia K. Heath, Konstantinos K. Tsilidis, Dagfinn Aune, Heinz Freisling, Neil Murphy, Marc J. Gunter, Mazda Jenab

Research output: Contribution to journal › Article › peer-review

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Abstract

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β(TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (P_BH = 0.008) and SMAD3 (P_BH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.

Original language	English (US)
Article number	1954
Journal	Nutrients
Volume	11
Issue number	8
DOIs	https://doi.org/10.3390/nu11081954
State	Published - Aug 2019

Keywords

Colorectal neoplasms
Incidence
Single nucleotide polymorphism (SNP)
Vitamin D

ASJC Scopus subject areas

Food Science
Nutrition and Dietetics

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10.3390/nu11081954

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Fedirko, V., Mandle, H. B., Zhu, W., Hughes, D. J., Siddiq, A., Ferrari, P., Romieu, I., Riboli, E., Bueno-de-Mesquita, B., Van Duijnhoven, F. J. B., Siersema, P. D., Tjønneland, A., Olsen, A., Perduca, V., Carbonnel, F., Boutron-Ruault, M. C., Kühn, T., Johnson, T., Krasimira, A., ... Jenab, M. (2019). vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations. Nutrients, 11(8), Article 1954. https://doi.org/10.3390/nu11081954

Fedirko, V, Mandle, HB, Zhu, W, Hughes, DJ, Siddiq, A, Ferrari, P, Romieu, I, Riboli, E, Bueno-de-Mesquita, B, Van Duijnhoven, FJB, Siersema, PD, Tjønneland, A, Olsen, A, Perduca, V, Carbonnel, F, Boutron-Ruault, MC, Kühn, T, Johnson, T, Krasimira, A, Trichopoulou, A, Makrythanasis, P, Thanos, D, Panico, S, Krogh, V, Sacerdote, C, Skeie, G, Weiderpass, E, Colorado-Yohar, S, Sala, N, Barricarte, A, Sanchez, MJ, Quirós, R, Amiano, P, Gylling, B, Harlid, S, Perez-Cornago, A, Heath, AK, Tsilidis, KK, Aune, D, Freisling, H, Murphy, N, Gunter, MJ & Jenab, M 2019, 'vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations', Nutrients, vol. 11, no. 8, 1954. https://doi.org/10.3390/nu11081954

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title = "vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations",

abstract = "Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β(TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.",

keywords = "Colorectal neoplasms, Incidence, Single nucleotide polymorphism (SNP), Vitamin D",

author = "Veronika Fedirko and Mandle, {Hannah B.} and Wanzhe Zhu and Hughes, {David J.} and Afshan Siddiq and Pietro Ferrari and Isabelle Romieu and Elio Riboli and Bas Bueno-de-Mesquita and {Van Duijnhoven}, {Fr{\"a}nzel J.B.} and Siersema, {Peter D.} and Anne Tj{\o}nneland and Anja Olsen and Vittorio Perduca and Franck Carbonnel and Boutron-Ruault, {Marie Christine} and Tilman K{\"u}hn and Theron Johnson and Aleksandrova Krasimira and Antonia Trichopoulou and Periklis Makrythanasis and Dimitris Thanos and Salvatore Panico and Vittorio Krogh and Carlotta Sacerdote and Guri Skeie and Elisabete Weiderpass and Sandra Colorado-Yohar and N{\'u}ria Sala and Aurelio Barricarte and Sanchez, {Maria Jose} and Ram{\'o}n Quir{\'o}s and Pilar Amiano and Bj{\"o}rn Gylling and Sophia Harlid and Aurora Perez-Cornago and Heath, {Alicia K.} and Tsilidis, {Konstantinos K.} and Dagfinn Aune and Heinz Freisling and Neil Murphy and Gunter, {Marc J.} and Mazda Jenab",

note = "Publisher Copyright: {\textcopyright} 2019 by the authors.",

year = "2019",

month = aug,

doi = "10.3390/nu11081954",

language = "English (US)",

volume = "11",

journal = "Nutrients",

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T1 - vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations

AU - Fedirko, Veronika

AU - Mandle, Hannah B.

AU - Zhu, Wanzhe

AU - Hughes, David J.

AU - Siddiq, Afshan

AU - Ferrari, Pietro

AU - Romieu, Isabelle

AU - Riboli, Elio

AU - Bueno-de-Mesquita, Bas

AU - Van Duijnhoven, Fränzel J.B.

AU - Siersema, Peter D.

AU - Tjønneland, Anne

AU - Olsen, Anja

AU - Perduca, Vittorio

AU - Carbonnel, Franck

AU - Boutron-Ruault, Marie Christine

AU - Kühn, Tilman

AU - Johnson, Theron

AU - Krasimira, Aleksandrova

AU - Trichopoulou, Antonia

AU - Makrythanasis, Periklis

AU - Thanos, Dimitris

AU - Panico, Salvatore

AU - Krogh, Vittorio

AU - Sacerdote, Carlotta

AU - Skeie, Guri

AU - Weiderpass, Elisabete

AU - Colorado-Yohar, Sandra

AU - Sala, Núria

AU - Barricarte, Aurelio

AU - Sanchez, Maria Jose

AU - Quirós, Ramón

AU - Amiano, Pilar

AU - Gylling, Björn

AU - Harlid, Sophia

AU - Perez-Cornago, Aurora

AU - Heath, Alicia K.

AU - Tsilidis, Konstantinos K.

AU - Aune, Dagfinn

AU - Freisling, Heinz

AU - Murphy, Neil

AU - Gunter, Marc J.

AU - Jenab, Mazda

PY - 2019/8

Y1 - 2019/8

N2 - Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β(TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.

AB - Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β(TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.

KW - Colorectal neoplasms

KW - Incidence

KW - Single nucleotide polymorphism (SNP)

KW - Vitamin D

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DO - 10.3390/nu11081954

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JO - Nutrients

JF - Nutrients

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ER -

vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations

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ASJC Scopus subject areas

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