Mitchell Martin
Hoffmann-La Roche
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Publication
Featured researches published by Mitchell Martin.
Nature Genetics | 2002
Gayle B. Collin; Jan D. Marshall; Akihiro Ikeda; W. Venus So; Isabelle Russell-Eggitt; Pietro Maffei; Sebastian Beck; Cornelius F. Boerkoel; Nicola Sicolo; Mitchell Martin; Patsy M. Nishina; Jürgen K. Naggert
Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits. The gene involved in Alström syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alström syndrome and the common diseases that characterize it.
American Journal of Human Genetics | 2003
Inga Reynisdottir; Gudmar Thorleifsson; Rafn Benediktsson; Gunnar Sigurdsson; Valur Emilsson; Anna S. Einarsdóttir; Eyrun Edda Hjorleifsdottir; Gudbjorg Orlygsdottir; Gudrun Thora Bjornsdottir; Jona Saemundsdottir; Skarphedinn Halldorsson; Soffía M. Hrafnkelsdóttir; Steinunn Bjorg Sigurjonsdottir; Svana Steinsdottir; Mitchell Martin; Jarema Peter Kochan; Brian Rhees; Struan F. A. Grant; Michael L. Frigge; Augustine Kong; Vilmundur Gudnason; Kari Stefansson; Jeffrey R. Gulcher
We report a genomewide linkage study of type 2 diabetes (T2D [MIM 125853]) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering 763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 2.90, P=1.29 x 10(-4)) in all diabetics. Since obesity, here defined as body mass index (BMI) > or =30 kg/m(2), is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI > or =30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 3.64, P=2.12 x (10)-5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (P=3.12 x 10(-5)) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.
Translational Research | 2010
Robert Y.L. Zee; Amy J. Castonguay; Nathaniel S. Barton; Soren Germer; Mitchell Martin
Recent data have implicated leukocyte telomere length shortening as a potential risk predictor for type 2 diabetes mellitus (T2DM) and its associated phenotypes. However, to date, epidemiologic data are scarce. Using a case-control study from a community-based population sample of the Boston metropolitan area (all whites: 424 controls and 432 cases), we examined the relationship of mean leukocyte telomere repeat copy number to single gene copy number (TSR) and T2DM. Associations of log(e)-transformed TSR with age, race, sex, body mass index (BMI), current smoking status, fasting insulin levels, fasting glucose levels, and hemoglobin A1c (HbA1c) were examined by multivariable linear regression analysis. A logistic regression analysis was performed to evaluate the association of log(e)-transformed TSR with T2DM with or without adjustment for potential confounders. The log(e)-transformed TSR was significantly shorter in the white cases than the white controls (P=0.003). In a multivariable linear regression analysis, an inverse association of log(e)-transformed TSR with BMI was observed (P=0.04). Furthermore, in a multivariable logistic regression analysis, decreased log(e)-transformed TSR was significantly associated with T2DM (adjusted odds ratio=1.748; 95% confidence interval [CI]=1.015-3.012; P=0.044). In summary, the current investigation has shown an association of mean leukocyte telomere length shortening with T2DM in white subjects. If corroborated in other studies, our findings suggest the potential importance of telomere biology in T2DM.
Cancer Research | 2012
Fei Su; William D. Bradley; Qiongqing Wang; Hong Yang; Lizhong Xu; Brian Higgins; Kenneth Kolinsky; Kathryn Packman; Min Jung Kim; Kerstin Trunzer; Richard J. Lee; Kathleen Schostack; Jade Carter; Thomas J. Albert; Soren Germer; Jim Rosinski; Mitchell Martin; Mary Ellen Simcox; Brian Lestini; David C. Heimbrook; Gideon Bollag
A high percentage of patients with BRAF(V600E) mutant melanomas respond to the selective RAF inhibitor vemurafenib (RG7204, PLX4032) but resistance eventually emerges. To better understand the mechanisms of resistance, we used chronic selection to establish BRAF(V600E) melanoma clones with acquired resistance to vemurafenib. These clones retained the V600E mutation and no second-site mutations were identified in the BRAF coding sequence. Further characterization showed that vemurafenib was not able to inhibit extracellular signal-regulated kinase phosphorylation, suggesting pathway reactivation. Importantly, resistance also correlated with increased levels of RAS-GTP, and sequencing of RAS genes revealed a rare activating mutation in KRAS, resulting in a K117N change in the KRAS protein. Elevated levels of CRAF and phosphorylated AKT were also observed. In addition, combination treatment with vemurafenib and either a MAP/ERK kinase (MEK) inhibitor or an AKT inhibitor synergistically inhibited proliferation of resistant cells. These findings suggest that resistance to BRAF(V600E) inhibition could occur through several mechanisms, including elevated RAS-GTP levels and increased levels of AKT phosphorylation. Together, our data implicate reactivation of the RAS/RAF pathway by upstream signaling activation as a key mechanism of acquired resistance to vemurafenib, in support of clinical studies in which combination therapy with other targeted agents are being strategized to combat resistance.
Endocrine | 2007
Xuxia Wu; Jelai Wang; Xiangqin Cui; Lidia Maianu; Brian Rhees; James Andrew Rosinski; W. Venus So; Steven M. Willi; Michael V. Osier; Helliner S. Hill; Grier P. Page; David B. Allison; Mitchell Martin; W. Timothy Garvey
To study the insulin effects on gene expression in skeletal muscle, muscle biopsies were obtained from 20 insulin sensitive individuals before and after euglycemic hyperinsulinemic clamps. Using microarray analysis, we identified 779 insulin-responsive genes. Particularly noteworthy were effects on 70 transcription factors, and an extensive influence on genes involved in both protein synthesis and degradation. The genetic program in skeletal muscle also included effects on signal transduction, vesicular traffic and cytoskeletal function, and fuel metabolic pathways. Unexpected observations were the pervasive effects of insulin on genes involved in interacting pathways for polyamine and S-adenoslymethionine metabolism and genes involved in muscle development. We further confirmed that four insulin-responsive genes, RRAD, IGFBP5, INSIG1, and NGFI-B (NR4A1), were significantly up-regulated by insulin in cultured L6 skeletal muscle cells. Interestingly, insulin caused an accumulation of NGFI-B (NR4A1) protein in the nucleus where it functions as a transcription factor, without translocation to the cytoplasm to promote apoptosis. The role of NGFI-B (NR4A1) as a new potential mediator of insulin action highlights the need for greater understanding of nuclear transcription factors in insulin action.
PLOS ONE | 2010
Claudia H. T. Tam; Janice Sin Ka Ho; Ying Wang; Heung Man Lee; Vincent K. L. Lam; Soren Germer; Mitchell Martin; Wing Yee So; Ronald C.W. Ma; Juliana C.N. Chan; M. C. Y. Ng
Background Previous studies identified melatonin receptor 1B (MTNR1B), islet-specific glucose 6 phosphatase catalytic subunit-related protein (G6PC2), glucokinase (GCK) and glucokinase regulatory protein (GCKR) as candidate genes for type 2 diabetes (T2D) acting through elevated fasting plasma glucose (FPG). We examined the associations of the reported common variants of these genes with T2D and glucose homeostasis in three independent Chinese cohorts. Methodology/Principal Findings Five single nucleotide polymorphisms (SNPs), MTNR1B rs10830963, G6PC2 rs16856187 and rs478333, GCK rs1799884 and GCKR rs780094, were genotyped in 1644 controls (583 adults and 1061 adolescents) and 1342 T2D patients. The G-allele of MTNR1B rs10830963 and the C-alleles of both G6PC2 rs16856187 and rs478333 were associated with higher FPG (0.0034<P<6.6×10−5) in healthy controls. In addition to our previous report for association with FPG, the A-allele of GCK rs1799884 was also associated with reduced homeostasis model assessment of beta-cell function (HOMA-B) (P = 0.0015). Together with GCKR rs780094, the risk alleles of these SNPs exhibited dosage effect in their associations with increased FPG (P = 2.9×10−9) and reduced HOMA-B (P = 1.1×10−3). Meta-analyses strongly supported additive effects of MTNR1B rs10830963 and G6PC2 rs16856187 on FPG. Conclusions/Significance Common variants of MTNR1B, G6PC2 and GCK are associated with elevated FPG and impaired insulin secretion, both individually and jointly, suggesting that these risk alleles may precipitate or perpetuate hyperglycemia in predisposed individuals.
American Journal of Physiology-endocrinology and Metabolism | 2010
Jiarong Liu; Xuxia Wu; John L. Franklin; Joseph L. Messina; Helliner S. Hill; Douglas R. Moellering; R. Grace Walton; Mitchell Martin; W. Timothy Garvey
Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes.
Diabetes | 2009
Claudia H. T. Tam; Ronald C.W. Ma; Wing Yee So; Ying Wang; Vincent K. L. Lam; Soren Germer; Mitchell Martin; Juliana C.N. Chan; Maggie C.Y. Ng
OBJECTIVE— Recent studies in European populations have reported a reciprocal association of glucokinase regulatory protein (GCKR) gene with triglyceride versus fasting plasma glucose (FPG) levels and type 2 diabetes risk. GCKR is a rate-limiting factor of glucokinase (GCK), which functions as a key glycolytic enzyme for maintaining glucose homeostasis. We examined the associations of two common genetic polymorphisms of GCKR and GCK with metabolic traits in healthy Chinese adults and adolescents. RESEARCH DESIGN AND METHODS— Two single nucleotide polymorphisms (SNPs), rs780094 at GCKR and rs1799884 at GCK, were genotyped in 600 healthy adults and 986 healthy adolescents. The associations of these SNPs with metabolic traits were assessed by linear regression adjusted for age, sex, and/or BMI. We also tested for the epistasis between these two SNPs and performed a meta-analysis among European and Asian populations. RESULTS— The T-allele of GCKR rs780094 was associated with increased triglycerides (P = 5.4 × 10−7), while the A-allele of GCK rs1799884 was associated with higher FPG (P = 3.1 × 10−7). A novel interaction effect between the two SNPs on FPG was also observed (P = 0.0025). Meta-analyses strongly supported the additive effects of the two SNPs on FPG and triglycerides, respectively. CONCLUSIONS— In support of the intimate relationship between glucose and lipid metabolisms, GCKR and GCK genetic polymorphisms interact to increase FPG in healthy adults and adolescents. These risk alleles may contribute to increased diabetes risk in subjects who harbor other genetic or environmental/lifestyle risk factors.
BMJ Open | 2013
Jianmei Wang; Adam Platt; Ruchi Upmanyu; Soren Germer; Guiyuan Lei; Christina Rabe; Ryma Benayed; Andrew Kenwright; Andrew Hemmings; Mitchell Martin; Olivier Harari
Objectives To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab. Design Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response. Results Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response. Conclusions Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.
Pharmacogenomics Journal | 2013
Jun Wang; A T Bansal; Mitchell Martin; Soren Germer; Ryma Benayed; Laurent Essioux; Jin Soo Lee; A Begovich; Andrew Hemmings; A. Kenwright; K E Taylor; Ruchi Upmanyu; P Cutler; Olivier Harari; Jonathan Marchini; L A Criswell; Adam Platt
Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting the joints. A heterogeneous response to available therapies demonstrates the need to identify those patients likely to benefit from a particular therapy. Our objective was to identify genetic factors associated with response to tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor, recently approved for treating RA. We report the first genome-wide association study on the response to tocilizumab in 1683 subjects with RA from six clinical studies. Putative associations were identified with eight loci, previously unrecognized as linked to the IL-6 pathway or associated with RA risk. This study suggests that it is unlikely that a major genetic determinant of response exists, and it illustrates the complexity of performing genome-wide association scans in clinical trials.