Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study.
Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.
Department of Population Health, New York University School of Medicine, New York, New York, United States of America.
Tess V
TV
Clendenen
Department of Population Health, New York University School of Medicine, New York, New York, United States of America.
Wenzhen
W
Ge
Department of Population Health, New York University School of Medicine, New York, New York, United States of America; New York University Cancer Institute, New York University School of Medicine, New York, New York, United States of America.
Karen L
KL
Koenig
Department of Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Tomas
T
Axelsson
Department of Population Health, New York University School of Medicine, New York, New York, United States of America.
Mengling
M
Liu
Department of Population Health, New York University School of Medicine, New York, New York, United States of America.
Yelena
Y
Afanasyeva
Department of Oncology, Umeå University Hospital, Umeå, Sweden.
Anne
A
Andersson
Department of Population Health, New York University School of Medicine, New York, New York, United States of America; New York University Cancer Institute, New York University School of Medicine, New York, New York, United States of America; Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, United States of America.
Alan A
AA
Arslan
Department of Population Health, New York University School of Medicine, New York, New York, United States of America; New York University Cancer Institute, New York University School of Medicine, New York, New York, United States of America.
Yu
Y
Chen
Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Umeå, Sweden.
Göran
G
Hallmans
Department of Oncology, Umeå University Hospital, Umeå, Sweden.
Per
P
Lenner
Department of Population Health, New York University School of Medicine, New York, New York, United States of America.
Tomas
T
Kirchhoff
Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden.
Eva
E
Lundin
Department of Population Health, New York University School of Medicine, New York, New York, United States of America; Radiation Effects Research Foundation, Minami-ku, Hiroshima, Japan.
Roy E
RE
Shore
Department of Surgery, Umeå University Hospital, Umeå, Sweden.
Malin
M
Sund
Department of Population Health, New York University School of Medicine, New York, New York, United States of America; New York University Cancer Institute, New York University School of Medicine, New York, New York, United States of America.
Anne
A
Zeleniuch-Jacquotte
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D015331:Cohort Studies; D000072467:Cytochrome P450 Family 2; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006887:Hydroxycholecalciferols / Q000097:blood* / Q000378:metabolism; D008875:Middle Aged; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018167:Receptors, Calcitriol / Q000235:genetics*; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013548:Sweden; D014809:Vitamin D-Binding Protein / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
D006887:Hydroxycholecalciferols; D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; D014809:Vitamin D-Binding Protein; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase