Background: Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight.
Methods: We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2,651 breast cancer cases and 2,520 controls of African or European ancestry that were pooled from seven studies.
Results: We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk.
Conclusion: The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist.
Impact: The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 21(3); 552–6. ©2012 AACR.
Epidemiologic studies have reported a positive moderate association between type 2 diabetes (T2D) and breast cancer risk, independent of obesity (1). Two meta-analyses indicated relative risks of 1.15 and 1.20 for breast cancer in T2D patients compared with women without T2D (1, 2). T2D may lead to breast cancer through the effects of insulin and insulin-like growth factor in addition to the dysregulation of sex hormones (3). However, the exact mechanisms underlying the association between the 2 diseases remain unclear. Unmeasured confounding could be an alternative explanation. Here, using data from 2,651 breast cancer cases and 2,520 controls, we further examined whether genetic susceptibility to T2D is related to breast cancer risk, which is less subject to environmental confounders because of Mendelian randomization (4). We also tested for pleiotropic effect of each of 40 established T2D risk variants.
We pooled data from 7 studies to compose a large biracial sample, with 2,279 Caucasian women (1,142 cases and 1,137 controls) from the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer project (5), and a total of 2,892 women of African ancestry from the Nigerian Breast Cancer Study (681 cases and 282 controls), the Baltimore Breast Cancer Study (117 cases and 111 controls), the Barbados National Cancer Study (93 cases and 244 controls), the Northern California site of the Breast Cancer Family Registry (199 cases and 213 controls), the Racial Variability in Genotypic Determinants of Breast Cancer Risk Study (151 cases and 272 controls), and the Chicago Cancer Prone Study (268 cases and 261 controls).
Using the catalog of genome-wide association studies (GWAS; ref. 6), we chose 40 single nucleotide polymorphisms (SNP) from 40 T2D susceptibility loci. For loci with multiple index SNPs, we picked the most reproducible SNP for each locus. For Caucasian women, 25 of 40 SNPs were genotyped using Illumina HumanHap500 array in the CGEMS breast cancer project (5) and downloaded from the Database of Genotypes and Phenotypes (dbGaP). The remaining 15 SNPs were imputed using MACH (7). The imputation quality is excellent with average R2 being 0.93 (ranging from 0.71–1.00). For women of African ancestry, we genotyped the 40 T2D SNPs and 29 ancestry informative markers using Illumina GoldenGate platform; one SNP (rs13266634) failed. The genotyping successful rate was 99.8% for the remaining SNPs. Hardy–Weinberg equilibrium was assessed for each allele, separately for each study; 18 of the 274 tests were significant compared with 14 expected.
For each individual, a composite susceptibility score was constructed as the total count of risk alleles of the 39 successfully genotyped T2D SNPs. Both continuous and categorical risk scores (quartile in controls) were examined in relation to breast cancer risk using logistic regression, stratified by race and adjusted for age group (5-year interval), study site, and genetic ancestry estimate from ancestry informative markers. In addition, we tested each of the 40 T2D variants for association with breast cancer under log-additive genetic models for the 2 racial groups separately and together. The statistical analysis was conducted using SAS 9.2 package (SAS Institute).
Three T2D SNPs were positively associated with breast cancer risk at a nominal significance level, consistent with a positive association between T2D and breast cancer: rs5945326 (DUSP9) and rs12518099 (CETN3) in Caucasian women and rs7578597 (THADA) in women of African ancestry (Table 1). However, 2 T2D risk alleles (rs1111875 and rs10923931) were inversely associated with breast cancer risk in Caucasian women. Two SNPs remained nominally significant in the pooled analysis (rs7578597 and rs12518099). After Bonferroni correction, none of the above variants remained significant. Table 2 shows that the composite T2D susceptibility score was not significantly associated with breast cancer. In the pooled analysis, the OR for the fourth quartile was 1.13 compared with quartile 1 (Ptrend = 0.09).
We found that the established risk variants for T2D did not have a strong association with breast cancer risk among women of African and European ancestry. This finding is in line with a previously published study, wherein 18 common variants for T2D were examined (8). Three of the 5 nominally significant SNPs in this study were also examined by Chen and colleagues, but none were statistically significant in their study (8). A GWAS found an association between breast cancer risk and SNP rs1011970 on 9p21 (9), which is 67 kb upstream of SNP rs7020996 examined in this study. However, these 2 SNPs are not in linkage disequilibrium. Another study, based on moderate sample size, found that SNPs in the FTO gene were associated with breast cancer risk (10). Our study found no association with rs8050136 (FTO). In conclusion, this study provides no evidence that the association between T2D and breast cancer risk (if it does exist) can be explained by the pleiotropic effects of known T2D risk alleles.
Disclosure of Potential Conflicts of Interest
The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR.
Timothy R. Rebbeck is the Editor-in-Chief of Cancer Epidemiology, Biomarkers & Prevention. In keeping with the AACR's Editorial Policy, the paper was peer reviewed and a member of the AACR's Publications Committee rendered the decision concerning acceptability.
This work was supported by National Cancer Institute (NCI) grant R01CA141712 and P01CA82707; support also was given by the Breast Cancer Research Foundation. The Northern California site of the Breast Cancer Family Registry (BCFR) was supported by the U.S. NCI, NIH under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators, including the Northern California Cancer Center (U01CA69417) and Georgetown University Medical Center Informatics Support Center (HHSN261200900010C).
Part of the data used in the work was provided by the Cancer Genetic Markers of Susceptibility (CGEMS) project, a NCI initiative, and samples from the Northern California site were processed and distributed by the Coriell Institute for Medical Research.
Note: N. Hou and Y. Zheng are co-first authors of the article.
- Received October 14, 2011.
- Accepted December 20, 2011.
- ©2012 American Association for Cancer Research.