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.
Feigelson
Heather Spencer
HS
Department of Epidemiology and Surveillance Research, American Cancer Society, National Home Office, Atlanta, Georgia 30329, USA. heather.feigelson@cancer.org
Cox
David G
DG
Cann
Howard M
HM
Wacholder
Sholom
S
Kaaks
Rudolf
R
Henderson
Brian E
BE
Albanes
Demetrius
D
Altshuler
David
D
Berglund
Goran
G
Berrino
Franco
F
Bingham
Sheila
S
Buring
Julie E
JE
Burtt
Noel P
NP
Calle
Eugenia E
EE
Chanock
Stephen J
SJ
Clavel-Chapelon
Francoise
F
Colditz
Graham
G
Diver
W Ryan
WR
Freedman
Matthew L
ML
Haiman
Christopher A
CA
Hankinson
Susan E
SE
Hayes
Richard B
RB
Hirschhorn
Joel N
JN
Hunter
David
D
Kolonel
Laurence N
LN
Kraft
Peter
P
LeMarchand
Loic
L
Linseisen
Jakob
J
Modi
William
W
Navarro
Carmen
C
Peeters
Petra H
PH
Pike
Malcolm C
MC
Riboli
Elio
E
Setiawan
V Wendy
VW
Stram
Daniel O
DO
Thomas
Gilles
G
Thun
Michael J
MJ
Tjonneland
Anne
A
Trichopoulos
Dimitrios
D
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