Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies.
The 17beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.
Department of Epidemiology and Surveillance Research, American Cancer Society, National Home Office, Atlanta, Georgia 30329, USA. heather.feigelson@cancer.org
Heather Spencer
HS
Feigelson
David G
DG
Cox
Howard M
HM
Cann
Sholom
S
Wacholder
Rudolf
R
Kaaks
Brian E
BE
Henderson
Demetrius
D
Albanes
David
D
Altshuler
Goran
G
Berglund
Franco
F
Berrino
Sheila
S
Bingham
Julie E
JE
Buring
Noel P
NP
Burtt
Eugenia E
EE
Calle
Stephen J
SJ
Chanock
Francoise
F
Clavel-Chapelon
Graham
G
Colditz
W Ryan
WR
Diver
Matthew L
ML
Freedman
Christopher A
CA
Haiman
Susan E
SE
Hankinson
Richard B
RB
Hayes
Joel N
JN
Hirschhorn
David
D
Hunter
Laurence N
LN
Kolonel
Peter
P
Kraft
Loic
L
LeMarchand
Jakob
J
Linseisen
William
W
Modi
Carmen
C
Navarro
Petra H
PH
Peeters
Malcolm C
MC
Pike
Elio
E
Riboli
V Wendy
VW
Setiawan
Daniel O
DO
Stram
Gilles
G
Thomas
Michael J
MJ
Thun
Anne
A
Tjonneland
Dimitrios
D
Trichopoulos
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000368:Aged; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies
D015067:17-Hydroxysteroid Dehydrogenases