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Aim: To identify differential methylation related to prescribed opioid use. Methods: This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting. Results: Differential methylation (false discovery rate

OBJECTIVE Environmental exposures may have greater predictive power for type 2 diabetes than polygenic scores (PGS). Studies examining environmental risk factors, however, have included only individuals with European ancestry, limiting the applicability of results. We conducted an exposome-wide association study in the multiancestry Personalized Environment and Genes Study to assess the effects of environmental factors on type 2 diabetes. RESEARCH DESIGN AND METHODS Using logistic regression for single-exposure analysis, we identified exposures associated with type 2 diabetes, adjusting for age, BMI, household income, and self-reported sex and race. To compare cumulative genetic and environmental effects, we computed an overall clinical score (OCS) as a weighted sum of BMI and prediabetes, hypertension, and high cholesterol status and a polyexposure score (PXS) as a weighted sum of 13 environmental variables. Using UK Biobank data, we developed a multiancestry PGS and calculated it for participants. RESULTS We found 76 significant associations with type 2 diabetes, including novel associations of asbestos and coal dust exposure. OCS, PXS, and PGS were significantly associated with type 2 diabetes. PXS had moderate power to determine associations, with larger effect size and greater power and reclassification improvement than PGS. For all scores, the results differed by race. CONCLUSIONS Our findings in a multiancestry cohort elucidate how type 2 diabetes odds can be attributed to clinical, genetic, and environmental factors and emphasize the need for exposome data in disease-risk association studies. Race-based differences in predictive scores highlight the need for genetic and exposome-wide studies in diverse populations.

Mutation is a phenomenon inescapable for all life-forms, including bacteria. While bacterial mutation rates are generally low due to the operation of error-avoidance systems, sometimes they are elevated by many orders of magnitude. Such a state, known as a hypermutable state, can result from exposure to stress or to harmful environments. Studies of bacterial mutation frequencies and analysis of the precise types of mutations can provide insights into the mechanisms by which mutations occur and the possible involvement of error-avoidance pathways. Several approaches have been used for this, like reporter assays involving non-essential genes or mutation accumulation over multiple generations. However, these approaches give an indirect estimation, and a more direct approach for determining mutations is desirable. With the recent development of a DNA sequencing technique known as Duplex Sequencing, it is possible to detect rare variants in a population at a frequency of 1 in 107base pairs or less. Here, we have applied Duplex Sequencing to study spontaneous mutations inE. coli. We also investigated the production of replication errors by using a mismatch-repair defective (mutL) strain as well as oxidative-stress associated mutations using amutT-defective strain. For DNA from a wild-type strain we obtained mutant frequencies in the range of 10-7to 10-8depending on the specific base-pair substitution, but we argue that these mutants merely represent a background of the system, rather than mutations that occurredin vivo. In contrast, bona-fidein vivomutations were identified for DNA from both themutLandmutTstrains, as indicated by specific increases in base substitutions that are fully consistent with their establishedin vivoroles. Notably, the data reproduce the specific context effects ofin vivomutations as well as the leading vs. lagging strand bias among DNA replication errors.

Some, but not all, women develop hypothalamic amenorrhea (HA) in association with exercise and/or food restriction. We hypothesized that variants in genes associated with the more severe hypogonadotropic disorder, idiopathic hypogonadotropic hypogonadism (IHH), may contribute to a given woman’s susceptibility to HA when she is faced with a physiologic stressor. Indeed, rare sequence variants (RSVs) in IHH-associated genes were previously identified in women with HA that were absent in controls1. This study, however, used a variant-level, as opposed to the now preferred gene-level, approach and only examined 7 genes. To build upon these earlier findings and provide more definitive support for our hypothesis, we screened 106 women with HA and 477 controls for RSVs in a much larger IHH-gene panel (n=54 genes) using exome sequencing. Healthy controls were a convenience sample drawn from the ClinSeq Project2 who had originally been selected for a range of atherosclerosis risk phenotypes, but were unselected for reproductive phenotypes. We compared the frequency of RSVs (moderate- to high-impact, minor allele frequency [MAF] < 1%) across all 54 genes in HA compared with controls using a rare variant burden test (Fisher’s exact test. We identified 54 heterozygous RSVs (51 missense, 1 nonsense, 2 frameshift; 27.4% of alleles) in 46 HA women (1-3 RSVs/woman, 58 total RSVs, 12 subjects with >1 RSV) and 149 heterozygous RSVs (141 missense, 1 nonsense, 4 frameshift, 3 inframe indels; 18.8%) in 146 control women (1-4 RSVs/woman, 179 total RSVs, 28 subjects with >1 RSV) which represents a significantly increased burden of RSVs in HA (P = 0.006). A slightly greater proportion of RSVs in the HA group were considered damaging/deleterious by both Polyphen2 and SIFT vs controls (41.1% vs 36.0%), but this was not statistically significant. Thus, women with HA are significantly enriched for RSVs in genes that cause IHH as compared with controls. These results indicate that the risk of developing HA with exposure to physiologic stressors may indeed be increased in the presence of heterozygous protein-altering variants in genes related to the regulation of GnRH neuronal development and function. 1 Caronia LM, et al. N Engl J Med. 2011;364:215-25. 2 Biesecker LG, et al. Genome Res. 2009;19:1665-74. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Background Current capsule endoscopy (CE) provides minimally invasive technology for GI imaging but has limited ability to discriminate different types of polyps. Near infrared fluorescent (NIRF) probes activated by biomarkers upregulated in adenomas (eg, cathepsin B) are potentially powerful tools to distinguish premalignant or malignant lesions from benign or inflammatory lesions. Objectives To examine whether CE can be integrated with NIRF probes to detect adenomas and whether cathepsin B–activated NIRF probes are activated by benign or inflammatory lesions. Design Mouse models of adenomas, hyperplactic/lymphoid polyps, and acute or chronic intestinal inflammation were injected intravenously with a cathepsin B–activated probe (Prosense 680). Dissected intestine was imaged with CE under white or NIRF light. For NIRF excitation (680 nm), dichroic and emission (700 nm) filters were combined with CE when images were recorded. Prosense 680 samples with or without protease were used as positive and negative controls. CE-based imaging data were verified by using and independent imaging system (Xenogen IVIS system). Main Outcome Measurements Proof of principal that CE integrated with NIRF probes can detect and discriminate adenomas from other lesions. Results CE-based NIRF imaging with Prosense 680 readily visualized adenomas, including in the colitis model. NIRF signals of different intensities were detected. Prosense 680 was not activated by benign or inflammatory lesions. Limitation Optical filters external to the capsule were used. Conclusions We demonstrate proof of the principle that biochromoendoscopy—CE combined with molecular probes––provides a novel approach that differentiates adenomas from benign polyps and inflammatory lesions.