Consistent association of type 2 diabetes risk variants found in europeans in diverse racial and ethnic groups.

It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10(-4)) and similar in all populations (odds ratios 1.09-1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; P(het) = 3.8×10(-4)). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding "synthetic associations" of rare mutations in T2D.

Fine mapping of the association with obesity at the FTO locus in African-derived populations.

Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 x 10(-6) and 3.61 x 10(-6) in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.

Randomized control trial of opioid- versus nonopioid-based analgesia after thyroidectomy.

BACKGROUND: Opioid-based analgesia is the most common method for pain control in the postoperative period. Limited data exist to compare the adequacy of pain control in the post thyroidectomy period with nonopioid-based analgesia. We aimed to evaluate the efficacy of nonopioid-based, postoperative analgesia. METHODS: After institutional review board approval, patients were randomized to 1 of 2 pain control regimens. Sample size was calculated to assess for a pain score difference of 1 based on a visual analog scale. The control group received opioid-based, postoperative analgesia, whereas the study group received nonopioid-based analgesia of acetaminophen and ibuprofen. Pain scores (measured on visual analog scale) and opioid use (converted to morphine equivalent dose) were measured after completion of the operation. RESULTS: The sample sizes for the study and control groups were 49 and 46 patients, respectively. The pain score for the study and control groups 1 hour after the operation (3.3 vs 3.9, P = .35), 6 hours after the operation (2.8 vs 3.0, P = .08), on postoperative day 1 (1.6 vs 2.4, P = .08) and on the first office visit (0.2 vs 0.1, P = .82) did not have a statistically significant difference. Morphine equivalent opioid requirement for pain control in the postoperative period was 0.8 vs 6.9 mg (P < .01), respectively. CONCLUSION: In a randomized control trial, we showed that patients treated with nonopioid analgesia had similar pain scores to those treated with opioids, with the benefit of having lower opioid exposure in the perioperative period.

Revised management of advanced primary colon cancer: Case series of 2 patients.

BACKGROUND: The resection of a primary colon cancer has the opportunity to cure the patient of cancer by complete clearance and absolute containment of disease. Alternatively, if the cancer resection does not provide clearance and containment it will eventuate in local recurrence and peritoneal dissemination. METHODS: Culpability of recurrence of colorectal cancer is difficult to determine. Are the management strategies of the primary cancer evaluation and treatment at fault or is the underlying disease process is to be held responsible? The clinical and radiologic findings that could have been evaluated by a multidisciplinary team (MDT) were critically evaluated in 2 patients with right colon adenocarcinoma. Strategies to accomplish complete clearance and absolute containment of the primary malignancy as resectable for cure were suggested. RESULTS: Clinical evaluation of these 2 patients suggested that more knowledgeable preoperative evaluation by the multidisciplinary team (MDT) should have placed them in a high risk group for local recurrence and/or peritoneal dissemination. High carcinoembryonic antigen (CEA) tumor marker and by CT a large primary cancer infiltrating adjacent structures can be used to select advanced pre- and intraoperative treatment strategies. CONCLUSIONS: Two patients who had an approximately 50% possibility of long-term survival with optimal preoperative evaluation and expert surgical resection techniques may have been converted to a greatly reduced survival because of tumor dissemination and positive margins of resection at the time of primary cancer resection. Neither patient was evaluated by an MDT preoperatively. It is possible that these two patients entered the operating room with a contained malignancy but as result of suboptimal pre- and intraoperative management left the operating room with disseminated intraperitoneal disease.

Gender difference in NASH susceptibility: Roles of hepatocyte Ikkß and Sult1e1.

Myeloid cell and hepatocyte IKKß may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of non-alcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKKß deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKKß deficiency (IkbkbΔhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male IkbkbΔhep mice having worst NASH and lowest plasma estradiol levels. LXRα is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbΔhep mice with NASH, and a Sult1e1 promoter activity is increased by LXRα and its ligand and augmented by expression of a S32A mutant of IκBα. These results demonstrate striking gender differences in regulation by IKKß of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKß is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients.

Automated technique for angiographic determination of coronary blood flow and lumen volume.

RATIONALE AND OBJECTIVES: Visual interpretation of angiographic images has been shown to be inadequate for assessing the severity of intermediate coronary stenoses. An approach for evaluating both the anatomic and functional impact of a stenosis is needed. An automated technique for determining both coronary blood flow and lumen volume based on a first-pass analysis (FPA) of coronary angiograms and a template matching algorithm was evaluated. MATERIALS AND METHODS: Coronary angiograms of a swine animal model were obtained during power injections of contrast material into the left coronary ostium. Background anatomy was subtracted with an automated phase matching program. A template matching algorithm and first-pass analysis were then used to quantify coronary blood flow and lumen volume. Coronary blood flow and lumen volume measurements were validated with a transit-time ultrasound flow probe and a polymer cast of the coronary arteries, respectively. RESULTS: In 14 independent comparisons, the mean coronary blood flow measured with FPA showed strong correlation with the mean flow measured with the ultrasound flow probe (Q(FPA) = 0.88Q(probe) - 1.99; r = 0.977; standard error of estimate = 3.23 mL/minute). The lumen volumes determined with FPA and cast measurements demonstrated excellent correlation and can be related to each other by V(FPA) = 0.95V(C) - 0.01 (r = 0.997; standard error of estimate = 0.01 mL). CONCLUSIONS: The proposed automated method for accurate determination of coronary blood flow and lumen volume can supplement visual evaluation of coronary anatomy with quantitative physiologic data. This automated technique potentially offers a clinically feasible method of quantifying coronary blood flow and lumen volume in conjunction with routine cardiac catheterization.

A genome-wide association meta-analysis identifies new childhood obesity loci.

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).