👤 Dermot P McGovern

Elevated circulating branched-chain amino acids (BCAA) have been linked with the severity of insulin resistance across numerous populations, implicating heightened BCAA metabolism as a potential therapy for insulin resistance. Recently, the angiotensin II type 1 receptor (AT1R) inhibitor Valsartan (VAL) was identified as a potent inhibitor of branched-chain alpha-keto acid dehydrogenase kinase (BCKDK), a negative regulator of BCAA metabolism. This work investigated the effect of VAL on myotube metabolism and insulin sensitivity under both insulin sensitive and insulin resistant conditions. C2C12 myotubes were treated with or without VAL at 8 µM for 24 h, both with and without hyperinsulinemic-induced insulin resistance. Oxygen consumption and extracellular acidification were used to measure mitochondrial and glycolytic metabolism, respectively. Gene expression was assessed via qRT-PCR, and insulin sensitivity was assessed via Western blot. Insulin resistance significantly reduced both basal and peak mitochondrial function which were rescued to control levels by concurrent VAL. Changes in mitochondrial function occurred without substantial changes in mitochondrial content or related gene expression. Insulin sensitivity and glycolytic metabolism were unaffected by VAL, as was lipogenic signaling and lipid content. Additionally, both VAL and insulin resistance depressed Bckdha expression. Interestingly, an interaction effect was observed for extracellular isoleucine, valine, and total BCAA (but not leucine), suggesting VAL may alter BCAA utilization in an insulin sensitivity-dependent manner. Insulin resistance appears to suppress mitochondrial function in a myotube model which can be rescued by VAL. Further research will be required to explore the implications of these findings in more complex models. Show less

Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event. Show less

The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10 We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10 We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry. Show less

Interindividual variation in response to anti-TNFalpha therapy may be explained by genetic variability in disease pathogenesis or mechanism of action. Recent genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) have increased our understanding of the genetic susceptibility to IBD. The aim was to test associations of known IBD susceptibility loci and novel "pharmacogenetic" GWAS identified loci with primary nonresponse to anti-TNFalpha in pediatric IBD patients and develop a predictive model of primary nonresponse. Primary nonresponse was defined using the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and partial Mayo score for ulcerative colitis (UC). Genotyping was performed using the Illumina Infinium platform. Chi-square analysis tested associations of phenotype and genotype with primary nonresponse. Genetic associations were identified by testing known IBD susceptibility loci and by performing a GWAS for primary nonresponse. Stepwise multiple logistic regression was performed to build predictive models. Nonresponse occurred in 22 of 94 subjects. Six known susceptibility loci were associated with primary nonresponse (P < 0.05). Only the 21q22.2/BRWDI loci remained significant in the predictive model. The most predictive model included 3 novel "pharmacogenetic" GWAS loci, the previously identified BRWD1, pANCA, and a UC diagnosis (R(2) = 0.82 and area under the curve [AUC] = 0.98%). The relative risk of nonresponse increased 15-fold when number of risk factors increased from 0-2 to > or =3. The combination of phenotype and genotype is most predictive of primary nonresponse to anti-TNFalpha in pediatric IBD. Defining predictors of response to anti-TNFalpha may allow the identification of patients who will not benefit from this class of therapy. Show less