Polymorphisms associated with circulating sex hormone levels in postmenopausal women.
BACKGROUND
Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate them.


METHODS
We assayed circulating levels of estradiol, testosterone, estrone, androstenedione, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these postmenopausal women and in a breast cancer case-control study. Associations of genotypes with breast cancer risk were evaluated in the case-control study and with hormone levels in the postmenopausal women using multiple linear regression with assay batch, body mass index, parity, peri- or postmenopausal status, and age band as covariates.


RESULTS
CYP19 SNPs (rs10046 and [TCT]+/-) were associated with differences in estradiol level (P =.0006 and P =.0003, respectively) and the estradiol : testosterone ratio (P =.000001() and P =.002). SNP rs10046 explained 1.6% of the variance (r2) in the estradiol : testosterone ratio. SHBG SNPs (5' untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels (P<10(-6) and P =.005) and the estradiol : SHBG ratio (P =().000008() and P =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels, respectively. SNPs in the other genes were not associated with differences in any hormone levels, and none were statistically significantly associated with breast cancer risk.


CONCLUSIONS
Genetic variation in CYP19 and SHBG contributes to variance in circulating hormone levels between postmenopausal women, but low r2 values may explain why these genes have given inconclusive results in breast cancer case-control studies.
Dunning
Alison M
AM
Cancer Research UK, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. alisond@srl.cam.ac.uk
Dowsett
Mitch
M
Healey
Catherine S
CS
Tee
Louise
L
Luben
Robert N
RN
Folkerd
Elizabeth
E
Novik
Karen L
KL
Kelemen
Livia
L
Ogata
Saeko
S
Pharoah
Paul D P
PD
Easton
Douglas F
DF
Day
N E
NE
Ponder
Bruce A J
BA
D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000368:Aged; D000735:Androstenedione / Q000097:blood; D001141:Aromatase / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004739:England; D004958:Estradiol / Q000097:blood; D004970:Estrone / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000097:blood* / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000097:blood / Q000235:genetics; D012738:Sex Hormone-Binding Globulin / Q000235:genetics* / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013739:Testosterone / Q000097:blood
D012739:Gonadal Steroid Hormones; D012738:Sex Hormone-Binding Globulin; D004970:Estrone; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D019326:17-alpha-Hydroxyprogesterone; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D013254:Steroid 17-alpha-Hydroxylase; D002394:Catechol O-Methyltransferase