These results demonstrate a high prevalence of medical findings in community-dwelling women with anorexia nervosa. Therefore, women with anorexia nervosa should be carefully followed up with regular physical examinations and laboratory assessments. In addition, low weight, particularly in conjunction with the abnormalities reported, should prompt the consideration of a diagnosis of anorexia nervosa.

We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry, in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative, identifying a new association with prostate cancer risk on chromosome 8q24 (rs620861, p=1.3×10-10, heterozygote OR = 1.17, 95% CI 1.10 – 1.24; homozygote OR = 1.33; 95% CI 1.21 – 1.45). This defines a new prostate locus on 8q24, Region 4, previously associated with breast cancer.

Anorexia nervosa (AN) is characterized by low weight and self-imposed caloric restriction and leads to severe bone loss. Although amenorrhea due to acquired GnRH deficiency is nearly universal in AN, a subset of patients maintains menses despite low weight. The mechanisms underlying continued GnRH secretion despite low weight in these patients and the impact of gonadal hormone secretion on bone mineral density (BMD) in such eumenorrheic, low-weight patients remain unknown. We hypothesized that 1) eumenorrheic women with AN would have higher body fat and levels of nutritionally dependent hormones, including leptin and IGF-I, than amenorrheic women with AN and comparable body mass index; and 2) BMD would be higher in these women. We also investigated whether the severity of eating disorder symptomatology differed between the groups. We studied 116 women: 1) 42 lowweight women who fulfilled all Diagnostic and Statistical Manual of Mental Disorders (fourth edition) diagnostic criteria for AN, except for amenorrhea; and 2) 74 women with AN and amenorrhea for at least 3 months. The two groups were similar in body mass index (17.1 ؎ 0.2 vs. 16.8 ؎ 0.2 kg/m 2 ), percent ideal body weight (78.2 ؎ 0.8% vs. 76.7 ؎ 0.8%), duration of eating disorder (70 ؎ 13 vs. 59 ؎ 9 months), age of menarche (13.2 ؎ 0.3 vs. 13.5 ؎ 0.2 yr), and exercise (4.5 ؎ 1.0 vs. 4.2 ؎ 0.5 h/wk). As expected, eumenorrheic patients had a higher mean estradiol level (186.6 ؎ 19.0 vs. 59.4 ؎ 2.5 nmol/ liter; P < 0.0001) than amenorrheic subjects. Mean percent body fat, total body fat mass, and truncal fat were higher in eumenorrheic than amenorrheic patients [20.9 ؎ 0.9% vs. 16.7 ؎ 0.6% (P ‫؍‬ 0.0001); 9.8 ؎ 0.5 vs. 7.8 ؎ 0.3 kg (P ‫؍‬ 0.0009); 3.4 ؎ 0.2 vs. 2.7 ؎ 0.1 kg (P ‫؍‬ 0.006)]. The mean leptin level was higher in the eumenorrheic compared with the amenorrheic group (3.7 ؎ 0.3 vs. 2.8 ؎ 0.2 ng/ml; P ‫؍‬ 0.04). Serum IGF-I levels were also higher in the eumenorrheic than in the amenorrheic group (41.8 ؎ 3.7 vs. 30.8 ؎ 2.3 nmol/liter; P ‫؍‬ 0.02). There were only minor differences in severity of eating disorder symptomatology, as measured by the Eating Disorders Inventory, and where differences were observed, eumenorrheic subjects manifested more severe symptomatology than amenorrheic subjects. Mean BMD at the posterior-anterior and lateral spine were low in both groups, but were higher in patients with eumenorrhea than in those with amenorrhea [posterioranterior spine T-score, ؊0.9 ؎ 0.1 vs. ؊1.9 ؎ 0.1 (P < 0.0001); lateral spine T-score, ؊1.2 ؎ 0.1 vs. ؊2.3 ؎ 0.2 (P < 0.0001)]. In contrast, preservation of menstrual function was not protective at the total hip (total hip T-score, ؊0.9 ؎ 0.1 vs. ؊1.1 ؎ 0.1; P ‫؍‬ 0.27), trochanter, or femoral neck. In summary, patients with eumenorrhea had more body fat and higher serum leptin levels than their amenorrheic counterparts of similar weight. Moreover, reduced bone density was observed in both groups, but was less severe at the spine, but not the hip, in women with undernutrition and preserved menstrua...

Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.

Background: Heart failure (HF) is a major public health problem that is associated with substantial morbidity, impaired quality of life, and diminished survival. Despite the considerable prevalence of HF in the United States, there are limited published data describing the contemporary long-term prognosis of patients hospitalized with decompensated HF. Methods: A total of 2445 residents in the Worcester metropolitan area discharged from 11 greater Worcester hospitals after confirmed acute HF during 2000 comprised the study sample. Follow-up of discharged hospital survivors was carried out through 2005. Results: The mean age of the study population was 76 years, 43.4% were men, and approximately three quarters had been previously diagnosed as having HF. Among discharged hospital patients, 37.3% died during the first year after hospital discharge, while 78.5% died during the 5-year follow-up period. Several subgroups of patients were at significantly increased risk for dying during the first year after hospital discharge. This included older persons (Ն85 years) (adjusted odds ratio [OR], 2.11; 95% confidence interval [CI], 1.35-3.29), patients with a history of chronic obstructive pulmonary disease (OR, 1.39; 95% CI, 1.15-1.69) or HF (OR, 1.26; 95% CI, 1.00-1.59), and patients with elevated serum urea nitrogen levels during hospitalization (OR, 1.02; 95% CI, 1.01-1.03). Conclusions: The results of our communitywide study demonstrate the poor long-term prognosis of patients surviving hospitalization for decompensated HF. Despite advances in the therapeutic management of these patients, their long-term survival remains guarded. Efforts are needed to improve the long-term survival of patients with this clinical syndrome.

In summary, we identified regions in AR and CYP19A1 that are of interest for further evaluation in relation to endometrial cancer risk in future haplotype and subsequent fine mapping studies in larger study populations.

Many popular methods for exploring gene-gene interactions, including the case-only approach, rely on the key assumption that physically distant loci are in linkage equilibrium in the underlying population. These methods utilize the presence of correlation between unlinked loci in a disease-enriched sample as evidence of interactions among the loci in the etiology of the disease. We use data from the CGEMS case-control genome-wide association study of breast cancer to demonstrate empirically that the case-only and related methods have the potential to create large-scale false positives because of the presence of population stratification (PS) that creates long-range linkage disequilibrium in the genome. We show that the bias can be removed by considering parametric and nonparametric methods that assume gene-gene independence between unlinked loci, not in the entire population, but only conditional on population substructure that can be uncovered based on the principal components of a suitably large panel of PS markers. Applications in the CGEMS study as well as simulated data show that the proposed methods are robust to the presence of population stratification and are yet much more powerful, relative to standard logistic regression methods that are also commonly used as robust alternatives to the case-only type methods.

Recent genome-wide association studies have identified independent susceptibility loci for prostate cancer that could influence risk through interaction with other, possibly undetected, susceptibility loci. We explored evidence of interaction between pairs of 13 known susceptibility loci and single nucleotide polymorphisms (SNP) across the genome to generate hypotheses about the functionality of prostate cancer susceptibility regions. We used data from Cancer Genetic Markers of Susceptibility: Stage I included 523,841 SNPs in 1,175 cases and 1,100 controls; Stage II included 27,383 SNPs in an additional 3,941 cases and 3,964 controls. Power calculations assessed the magnitude of interactions our study is likely to detect. Logistic regression was used with alternative methods that exploit constraints of gene-gene independence between unlinked loci to increase power. Our empirical evaluation demonstrated that an empirical Bayes (EB) technique is powerful and robust to possible violation of the independence assumption. Our EB analysis identified several noteworthy interacting SNP pairs, although none reached genome-wide significance. We highlight a Stage II interaction between the major prostate cancer susceptibility locus in the subregion of 8q24 that contains POU5F1B and an intronic SNP in the transcription factor EPAS1, which has potentially important functional implications for 8q24. Another noteworthy result involves interaction of a known prostate cancer susceptibility marker near the prostate protease genes KLK2 and KLK3 with an intronic SNP in PRXX2. Overall, the interactions we have identified merit follow-up study, particularly the EPAS1 interaction, which has implications not only in prostate cancer but also in other epithelial cancers that are associated with the 8q24 locus. Cancer Res; 71(9); 3287-95. Ó2011 AACR.