FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation.
Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate-causal single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03-1.41, P(trend) = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European (n = 7196 cases, 7275 controls) and Asian (n = 3901 cases, 3205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of < 1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to highly accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.
Udler
Miriam S
MS
Department of Public Health and Primary Care, University of Cambridge, UK.
Meyer
Kerstin B
KB
Pooley
Karen A
KA
Karlins
Eric
E
Struewing
Jeffery P
JP
Zhang
Jinghui
J
Doody
David R
DR
MacArthur
Stewart
S
Tyrer
Jonathan
J
Pharoah
Paul D
PD
Luben
Robert
R
Bernstein
Leslie
L
Kolonel
Laurence N
LN
Henderson
Brian E
BE
Le Marchand
Loic
L
Ursin
Giske
G
Press
Michael F
MF
Brennan
Paul
P
Sangrajrang
Suleeporn
S
Gaborieau
Valerie
V
Odefrey
Fabrice
F
Shen
Chen-Yang
CY
Wu
Pei-Ei
PE
Wang
Hui-Chun
HC
Kang
Daehee
D
Yoo
Keun-Young
KY
Noh
Dong-Young
DY
Ahn
Sei-Hyun
SH
Ponder
Bruce A J
BA
Haiman
Christopher A
CA
Malone
Kathleen E
KE
Dunning
Alison M
AM
Ostrander
Elaine A
EA
Easton
Douglas F
DF
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D055815:Young Adult
D002843:Chromatin; D051497:Receptor, Fibroblast Growth Factor, Type 2