No evidence for association of inherited variation in genes involved in mitosis and percent mammographic density.
BACKGROUND
Increased mammographic breast density is one of the strongest risk factors for breast cancer. While two-thirds of the variation in mammographic density appears to be genetically influenced, few variants have been identified. We examined the association of inherited variation in genes from pathways that mediate cell division with percent mammographic density (PMD) adjusted for age, body mass index (BMI) and postmenopausal hormones, in two studies of healthy postmenopausal women.


METHODS
We investigated 2,058 single nucleotide polymorphisms (SNPs) in 378 genes involved in regulation of mitosis for associations with adjusted PMD among 484 unaffected postmenopausal controls (without breast cancer) from the Mayo Clinic Breast Cancer Study (MCBCS) and replicated the findings in postmenopausal controls (n = 726) from the Singapore and Sweden Breast Cancer Study (SASBAC) study. PMD was assessed in both studies by a computer-thresholding method (Cumulus) and linear regression approaches were used to assess the association of SNPs and PMD, adjusted for age, BMI and postmenopausal hormones. A P-value threshold of 4.2 × 10-5 based on a Bonferroni correction of effective number of independent tests was used for statistical significance. Further, a pathway-level analysis was conducted of all 378 genes using the self-contained gene-set analysis method GLOSSI.


RESULTS
A variant in PRPF4, rs10733604, was significantly associated with adjusted PMD in the MCBCS (P = 2.7 × 10-7), otherwise, no single SNP was associated with PMD. Additionally, the pathway analysis provided no evidence of enrichment in the number of associations observed between SNPs in the mitotic genes and PMD (P = 0.60). We evaluated rs10733604 (PRPF4), and 73 other SNPs at P < 0.05 from 51 genes in the SASBAC study. There was no evidence of an association of rs10733604 (PRPF4) with adjusted PMD in SASBAC (P = 0.23). There were, however, consistent associations (P < 0.05) of variants at the putative locus, LOC375190, Aurora B kinase (AURKB), and Mini-chromosome maintenance complex component 3 (MCM3) with adjusted PMD, although these were not statistically significant.


CONCLUSIONS
Our findings do not support a role of inherited variation in genes involved in regulation of cell division and adjusted percent mammographic density in postmenopausal women.
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. vachon.celine@mayo.edu
Celine M
CM
Vachon
Jingmei
J
Li
Christopher G
CG
Scott
Per
P
Hall
Kamila
K
Czene
Xianshu
X
Wang
Jianjun
J
Liu
Zachary S
ZS
Fredericksen
David N
DN
Rider
Fang-Fang
FF
Wu
Janet E
JE
Olson
Julie M
JM
Cunningham
Kristen N
KN
Stevens
Thomas A
TA
Sellers
Shane V
SV
Pankratz
Fergus J
FJ
Couch
D000328:Adult; D000368:Aged; D000071060:Breast Density; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D016014:Linear Models; D042361:Mammary Glands, Human / Q000002:abnormalities; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause