Ovarian cancer risk and common variation in the sex hormone-binding globulin gene: a population-based case-control study

BACKGROUND: The sex hormone-binding globulin (SHBG) is a carrier protein that modulates the bio-availability of serum sex steroid hormones, which may be involved in ovarian cancer. We evaluated whether common genetic variation in SHBG and its 3' neighbor ATP1B2, in linkage disequilibrium, is associated with the risk of epithelial ovarian cancer. METHODS: The study population included 264 women with ovarian carcinoma and 625 controls participating in a population-based case-control study in Poland. Five common single nucleotide polymorphisms (SNPs) in SHGB and five in ATP1B2 were selected to capture most common variation in this region. RESULTS: None of the SNPs evaluated was significantly associated with ovarian cancer risk, including the putative functional SNPs SHBG D356N (rs6259) and -67G>A 5'UTR (rs1799941). However, our data were consistent with a decreased ovarian cancer risk associated with the variant alleles for these two SNPs, which have been previously associated with increased circulating levels of SHBG. CONCLUSION: These data do not support a substantial association between common genetic variation in SHBG and ovarian cancer risk

A comparison of phenotype definitions for diabetes mellitus

OBJECTIVE: This study compares the yield and characteristics of diabetes cohorts identified using heterogeneous phenotype definitions. MATERIALS AND METHODS: Inclusion criteria from seven diabetes phenotype definitions were translated into query algorithms and applied to a population (n=173 503) of adult patients from Duke University Health System. The numbers of patients meeting criteria for each definition and component (diagnosis, diabetes-associated medications, and laboratory results) were compared. RESULTS: Three phenotype definitions based heavily on ICD-9-CM codes identified 9–11% of the patient population. A broad definition for the Durham Diabetes Coalition included additional criteria and identified 13%. The electronic medical records and genomics, NYC A1c Registry, and diabetes-associated medications definitions, which have restricted or no ICD-9-CM criteria, identified the smallest proportions of patients (7%). The demographic characteristics for all seven phenotype definitions were similar (56–57% women, mean age range 56–57 years).The NYC A1c Registry definition had higher average patient encounters (54) than the other definitions (range 44–48) and the reference population (20) over the 5-year observation period. The concordance between populations returned by different phenotype definitions ranged from 50 to 86%. Overall, more patients met ICD-9-CM and laboratory criteria than medication criteria, but the number of patients that met abnormal laboratory criteria exclusively was greater than the numbers meeting diagnostic or medication data exclusively. DISCUSSION: Differences across phenotype definitions can potentially affect their application in healthcare organizations and the subsequent interpretation of data. CONCLUSIONS: Further research focused on defining the clinical characteristics of standard diabetes cohorts is important to identify appropriate phenotype definitions for health, policy, and research

Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10−13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10−5, 10−8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10−4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment