Association of the progesterone receptor gene with breast cancer risk: a single-nucleotide polymorphism tagging approach.
Association studies on susceptibility to breast cancer using single nucleotide polymorphisms (SNP) in the progesterone receptor (PGR) gene have been previously published, but the results have been inconclusive. We used a comprehensive SNP-tagging approach to search for low-penetrance susceptibility alleles in a study of up to 4,647 cases and 4,564 controls, in a two-stage study design. We identified seven tagging SNPs using genotype data from the National Institute of Environmental Health Sciences (NIEHS) Environmental Genome Project and typed these, and an additional three SNPs, in 2,345 breast cancer cases and 2,284 controls (set 1). Three SNPs showed no evidence for association and were not studied further, whereas seven SNPs (rs11571171, rs7116336, rs660149, rs10895068, rs500760, rs566351, and rs1042838) exhibited significant associations at P < 0.1 using either a heterogeneity or trend test and progressed to be genotyped in set 2. After both stages, only one SNP was significantly associated with an increased risk of breast cancer - the PGR-12 (rs1042638) V660L valine to leucine polymorphism [VL heterozygotes (odds ratio, 1.13; 95% confidence interval, 1.03-1.24) and the LL homozygotes (odds ratio, 1.30; 95% confidence interval, 0.98-1.73), P(het) = 0.008, P(trend) = 0.002]. Similar estimates were obtained in a combined analysis of our data with those from three other published studies. We conclude that the 660L allele may be associated with a moderately increased risk of breast cancer, but that other common SNPs in the PGR gene are unlikely to be associated with a substantial risk of breast cancer.
Pooley
Karen A
KA
Department of Oncology, Cancer Research UK, University of Cambridge, Strangeways Research Laboratory. karen.pooley@srl.cam.ac.uk
Healey
Catherine S
CS
Smith
Paula L
PL
Pharoah
Paul D P
PD
Thompson
Deborah
D
Tee
Louise
L
West
Judith
J
Jordan
Clare
C
Easton
Douglas F
DF
Ponder
Bruce A J
BA
Dunning
Alison M
AM
D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D012306:Risk; D016324:Sequence Tagged Sites; D006113:United Kingdom; D014633:Valine / Q000235:genetics
D011980:Receptors, Progesterone; D014633:Valine