A comprehensive examination of CYP19 variation and risk of breast cancer using two haplotype-tagging approaches.
BACKGROUND
Numerous studies point to a positive relationship between elevated levels of estrogens and increased risk of breast. Androgens are converted to estrogens by the aromatase enzyme, which is encoded by the CYP19 gene. We recently published resequencing data on 88 polymorphisms identified in that gene. The hypothesis tested in this study was that polymorphisms, or haplotypes, in CYP19 are related to risk of breast cancer.


METHODS
Incident cases of breast cancer were identified through the Division of Medical Oncology at the Mayo Clinic in Rochester, MN. Controls were patients visiting Mayo for an annual medical examination. Controls were frequency matched to cases based on age and region of residence. Tag-polymorphisms were selected using 2 methods: (1) 12 variants using the tag-selection method of Carlson et al. (Am J Hum Genet 74:106-120, 2004); and (2) 12 variants using the haplotype method of Stram (Genet Epidemiol 27:365-374, 2004). Six SNPs were selected by both methods. Genotyping was conducted using SNPStream, TaqMan and RFLP analyses. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Analyses were conducted among all cases and controls, or stratified by estrogen receptor alpha (ER) status and/or menopausal status.


RESULTS
A total of 750 cases (60% postmenopausal) and 732 controls (75% postmenopausal) were included. No association with breast cancer risk was detected for individual variants, selected tagSNPs or hap-tag SNPs despite 80% power to detect OR as low as 1.49 for minor allele frequency (MAF) of 0.10. Similarly, stratified analyses based on ER status or menopausal status failed to detect any association with breast cancer risk.


CONCLUSIONS
These analyses suggest that variants of CYP19 are not associated with risk of breast cancer.
Olson
Janet E
JE
Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic College of Medicine, Rochester, MN 55901, USA. olsonj@mayo.edu
Ingle
James N
JN
Ma
Cynthia X
CX
Pelleymounter
Linda L
LL
Schaid
Daniel J
DJ
Pankratz
V Shane
VS
Vierkant
Robert A
RA
Fredericksen
Zachary S
ZS
Wu
Yanhong
Y
Couch
Fergus J
FJ
Vachon
Celine M
CM
Sellers
Thomas A
TA
Weinshilboum
Richard M
RM
D000483:Alleles; D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000235:genetics; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000201:enzymology / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D009361:Neoplasm Invasiveness / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D001141:Aromatase