Haplotype-based analysis of common variation in the acetyl-coA carboxylase alpha gene and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition.
A key fatty acid synthesis enzyme, acetyl-CoA carboxylase alpha (ACC-alpha), has been shown to be highly expressed in human breast cancer and other tumor types and also to specifically interact with the protein coded by one of two major breast cancer susceptibility genes BRCA1. We used a comprehensive haplotype analysis to examine the contribution of the ACC-alpha common genetic variation (allele frequency >5%) to breast cancer in a case-control study (1,588 cases/2,600 controls) nested within the European Prospective Investigation into Cancer and Nutrition. We identified 21 haplotype-tagging polymorphisms efficiently capturing common variation within 325 kb of ACC-alpha and surrounding sequences using genotype data from the HapMap project and our resequencing data. We found an effect on overall risk of breast cancer in homozygous carriers of one common haplotype [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.03-2.94]. When the data were subdivided by menopausal status, we found statistical evidence of heterogeneity for two other common haplotypes (P value for heterogeneity = 0.016 and 0.045). In premenopausal women, the carriers of these haplotypes, compared with noncarriers, had an altered risk of breast cancer (OR, 0.70; 95% CI, 0.53-0.92 and OR, 1.35; 95% CI, 1.04-1.76). These findings were not significant after adjustment for multiple testing and therefore should be considered as preliminary and evaluated in larger independent studies. However, they suggest a possible role of the ACC-alpha common sequence variants in susceptibility to breast cancer and encourage studies of other genes involved in fatty acid synthesis.
Sinilnikova
Olga M
OM
IARC, Lyon, France.
McKay
James D
JD
Tavtigian
Sean V
SV
Canzian
Federico
F
DeSilva
Deepika
D
Biessy
Carine
C
Monnier
Stéphanie
S
Dossus
Laure
L
Boillot
Catherine
C
Gioia
Lydie
L
Hughes
David J
DJ
Jensen
Majken K
MK
Overvad
Kim
K
Tjonneland
Anne
A
Olsen
Anja
A
Clavel-Chapelon
Françoise
F
Chajès
Véronique
V
Joulin
Virginie
V
Linseisen
Jakob
J
Chang-Claude
Jenny
J
Boeing
Heiner
H
Dahm
Stephan
S
Trichopoulou
Antonia
A
Trichopoulos
Dimitrios
D
Koliva
Maria
M
Khaw
Kay-Tee
KT
Bingham
Sheila
S
Allen
Naomi E
NE
Key
Timothy
T
Palli
Domenico
D
Panico
Salvatore
S
Berrino
Franco
F
Tumino
Rosario
R
Vineis
Paolo
P
Bueno-de-Mesquita
H Bas
HB
Peeters
Petra H
PH
van Gils
Carla H
CH
Lund
Eiliv
E
Pera
Guillem
G
Quirós
José Ramón
JR
Dorronsoro
Miren
M
Martínez García
Carmen
C
Tormo
María-José
MJ
Ardanaz
Eva
E
Hallmans
Goran
G
Lenner
Per
P
Berglund
Göran
G
Manjer
Jonas
J
Riboli
Elio
E
Lenoir
Gilbert M
GM
Kaaks
Rudolf
R
D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005060:Europe; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D012307:Risk Factors
D000103:Acetyl-CoA Carboxylase