Circadian clock genes and risk of fatal prostate cancer.
OBJECTIVE
Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response, and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and first morning void urinary 6-sulfatoxymelatonin levels.


METHODS
We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across 12 circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n = 24 cases), the Health Professionals Follow-Up Study (HPFS) (n = 40 cases), and the Physicians' Health Study (PHS) (n = 105 cases). We used linear regression to evaluate the association between SNPs and first morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP sets in the pathway (gene based) were associated with our outcomes.


RESULTS
None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p values = 0.01, 0.01, and 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPs in TIMELESS (four SNPs), NPAS2 (six SNPs), PER3 (two SNPs) and CSNK1E (one SNP) were nominally associated with 6-sulfatoxymelatonin levels.


CONCLUSIONS
We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.
Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115-6018, USA, sec110@mail.harvard.edu.
Sarah C
SC
Markt
Unnur A
UA
Valdimarsdottir
Irene M
IM
Shui
Lara G
LG
Sigurdardottir
Jennifer R
JR
Rider
Rulla M
RM
Tamimi
Julie L
JL
Batista
Sebastien
S
Haneuse
Erin
E
Flynn-Evans
Steven W
SW
Lockley
Charles A
CA
Czeisler
Meir J
MJ
Stampfer
Lenore
L
Launer
Tamara
T
Harris
Albert Vernon
AV
Smith
Vilmundur
V
Gudnason
Sara
S
Lindstrom
Peter
P
Kraft
Lorelei A
LA
Mucci
D000368:Aged; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007055:Iceland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics