Monica McGrath

The Functional UGT1A1 Promoter Polymorphism Decreases Endometrial Cancer Risk

UDP-glucuronosyltransferase (UGT) 1A1 is involved in the inactivation of estradiol (E2) and its oxidized metabolites. These metabolites have been shown to contribute to the development of endometrial cancer in animal studies. Thus UGT1A1 represents a candidate gene in endometrial carcinogenesis. In this study, we established the substrate specificity of UGT1A1 for E2 and its 2- and 4-hydroxylated metabolites. Intrinsic clearances indicated that UGT1A1 had a preference for the glucuronidation of 2-hydroxyestradiol, a metabolite associated with antiproliferative activity. Expression analysis demonstrated that UGT1A1 is present in the nonmalignant endometrium. Subsequently, we sought to determine whether the common UGT1A1 promoter allele, UGT1A1*28 [A(TA)7TAA], which decreases gene transcription, was associated with endometrial cancer risk in a case-control study nested within the Nurses’ Health Study (222 cases, 666 matched controls). Conditional logistic regression demonstrated a significant inverse association with the UGT1A1*28 allele and endometrial cancer risk. Compared with women homozygous for the UGT1A1*1 [A(TA)6TAA] allele, the adjusted odds ratio (OR) was 0.81 [95% confidence interval (CI), 0.56–1.16] for the UGT1A1*1/*28 genotype and 0.40 (95% CI, 0.21–0.75) for the homozygous UGT1A1*28 genotype (Ptrend = 0.007). There was a suggestion of an interaction by menopausal status [OR = 0.39 (95% CI, 0.18–0.85) for premenopausal women and OR = 0.79 (95% CI, 0.55–1.13) for postmenopausal women who carry the UGT1A1*28 allele (Pinteraction = 0.05)]. These observations suggest that lower expression of UGT1A1 decreases the risk of endometrial cancer by reducing the excretion of 2-hydroxyestradiol, the antiproliferative metabolite of E2, in the endometrium.

Telomere length and genetic analyses in population-based studies of endometrial cancer risk

Telomeres are protective structures at the ends of linear chromosomes, regulated by a host of associated proteins. When telomeres become dysfunctional, genomic instability ensues. The vast majority of cells undergo apoptosis, although a rare cell may survive and become tumorigenic.

Telomere length and risk of Parkinson's disease

We investigated whether telomere length was associated with the risk of Parkinsons disease (PD) in a case‐control study (96 cases and 172 age‐matched controls) nested within the Health Professionals Follow‐up Study. Relative ratio of telomere repeat copy number to single‐gene copy number in peripheral blood leukocytes was determined by quantitative real time PCR. Men with shorter telomeres had a lower PD risk (multivariate adjusted relative risk for the lowest vs. the highest quartile 0.33; 95% confidence interval: 0.12–0.90). Our results suggest that, contrary to telomere attrition observed in several aging‐related diseases, shorter telomeres are not associated with an increased risk of PD.

Two estrogen-related variants in CYP19A1 and endometrial cancer risk: A pooled analysis in the epidemiology of endometrial cancer consortium

Common variants in CYP19A1 (the A alleles of rs749292 and rs727479) have been associated with a 10% to 20% increase in circulating estrogen levels in postmenopausal women. We hypothesized that the presence of one or both A alleles in these single nucleotide polymorphisms (SNP) is associated with increased endometrial cancer risk. We tested this hypothesis in a large pooled analysis of 4,998 endometrial cancer cases and 8,285 controls from 10 studies in the Epidemiology of Endometrial Cancer Consortium. The majority of women (>66%) were whites, with smaller proportions of other races and ethnic groups (blacks, Asians, and Latinas) also included in this pooled analysis. Unconditional logistic regression was used to model the association between SNPs/haplotypes and endometrial cancer risk. Carrying the A allele of either of these SNPs was associated with an increased risk of endometrial cancer, with pooled odds ratios per allele of 1.14, 95% confidence interval of 1.09-1.21, and P = 7.1 × 10-7 for rs749292, and odds ratio per allele of 1.08, 95% confidence interval of 1.02-1.14, and P = 0.009 for rs727479. For rs749292, these associations were generally stronger among women age ≥55 years. For both SNPs, risk increased with increasing body mass index, and for rs727479, this pattern seemed stronger among women age ≥55 years (P interaction = 0.007). The combination of A alleles in the two SNPs, either by direct count or by haplotype analysis, did not increase risk above that observed for the individual SNPs. Our study provides evidence that CYP19A1 genetic variation influences susceptibility to endometrial cancer, particularly among older and obese women. (Cancer Epidemiol Biomarkers Prev 2009;18(1):242–7)