G I Bell

Harvard University, Cambridge, Massachusetts, United States

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Publications (483)4107.98 Total impact

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    ABSTRACT: IMPORTANCE Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14 276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10-7) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.
    Journal of the American Medical Association 06/2014; 22:2305-2314.
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    ABSTRACT: Mutations in pancreatic duodenal homeobox (PDX1) are associated with diabetes in humans. Pdx1-haploinsufficient mice develop diabetes due to an increase in β-cell death leading to reduced β-cell mass. In order to define the molecular link between Pdx1 deficiency and β-cell death, Pdx1 haploinsufficient mice in which the genes for the BH3-only molecules Bim and Puma had been ablated were studied on a high fat diet. Compared to Pdx1(+/-) mice, animals haploinsufficient for both Pdx1 and Bim or Puma genes showed improved glucose tolerance, enhanced β-cell mass and reduction in the number of TUNEL positive cells in islets. These results suggest that Bim and Puma ablation improves β-cell survival in Pdx1(+/-) mice. To explore the mechanisms responsible for these findings Pdx1 gene expression was knocked down in mouse MIN6 insulinoma cells resulting in apoptotic cell death that was found to be associated with increased expression of BH3-only molecules Bim and Puma. If the upregulation of Bim and Puma that occurs during Pdx1 suppression was prevented, apoptotic β-cell death was reduced in vitro. These results suggest that Bim and Puma play important role in β-cell apoptosis in Pdx1-deficient diabetes.
    Diabetes 03/2014; · 7.90 Impact Factor
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    ABSTRACT: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
    Nature Genetics 03/2014; · 35.21 Impact Factor
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    ABSTRACT: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
    Nature Genetics 03/2014; 46(3):234-244. · 35.21 Impact Factor
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    ABSTRACT: The identification and validation of gene-gene interactions is a major challenge in human studies. Here, we explore an approach for studying epistasis in humans using a Drosophila melanogaster model of neonatal diabetes mellitus. Expression of the mutant preproinsulin (hINS(C96Y)) in the eye imaginal disc mimics the human disease: it activates conserved stress response pathways and leads to cell death (reduction in eye area). Dominant-acting variants in wild-derived inbred lines from the Drosophila Genetics Reference Panel produce a continuous, highly heritable distribution of eye degeneration phenotypes in a hINS(C96Y) background. A genome-wide association study (GWAS) in 154 sequenced lines identified a sharp peak on chromosome 3L, which mapped to a 400bp linkage block within an intron of the gene sulfateless (sfl). RNAi knock-down of sfl enhanced the eye degeneration phenotype in a mutant-hINS-dependent manner. RNAi against two additional genes in the heparan sulfate (HS) biosynthetic pathway (ttv and botv), in which sfl acts, also modified the eye phenotype in a hINS(C96Y)-dependent manner, strongly suggesting a novel link between HS-modified proteins and cellular responses to misfolded proteins. Finally, we evaluated allele-specific expression difference between the two major sfl-intronic haplotypes in heterozygtes. The results showed significant heterogeneity in marker-associated gene expression, thereby leaving the causal mutation(s) and its mechanism unidentified. In conclusion, the ability to create a model of human genetic disease, map a QTL by GWAS to a specific gene, validate its contribution to disease with available genetic resources, and the potential to experimentally link the variant to a molecular mechanism, demonstrate the many advantages Drosophila holds in determining the genetic underpinnings of human disease.
    Genetics 02/2014; 196(2):557-567. · 4.39 Impact Factor
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    ABSTRACT: Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10−13; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10−4; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
    Nature 12/2013; · 38.60 Impact Factor
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    ABSTRACT: Drosophila melanogaster has been widely used as models of human Mendelian disease, but its value in modeling complex disease has received little attention. Fly models of complex disease would enable high-resolution mapping of disease-modifying loci and the identification of novel targets for therapeutic intervention. Here, we describe a fly model of permanent neonatal diabetes mellitus and explore the complexity of this model. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINS(C96Y), which is a cause of permanent neonatal diabetes. When expressed in fly imaginal discs, hINS(C96Y) causes a reduction of adult structures, including the eye, wing and notum. Eye imaginal discs exhibit defects in both the structure and arrangement of ommatidia. In the wing, expression of hINS(C96Y) leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild type signaling processes regulating cell fates. These readily measurable "disease" phenotypes are sensitive to temperature, gene dose and sex. Mutant (but not wild type) proinsulin expression in the eye imaginal disc induces IRE1-mediated XBP1 alternative splicing, a signal for endoplasmic reticulum (ER) stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel (DGRP) produce F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease has, therefore, its own distinct signature. The genetic dominance of disease-specific phenotypic variability in our model of misfolded human proinsulin makes this approach amenable to genome-wide association study (GWAS) in a simple F1 screen of natural variation.
    Genetics 11/2013; · 4.39 Impact Factor
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    ABSTRACT: Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.
    Pediatric Diabetes 10/2013; · 2.08 Impact Factor
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    ABSTRACT: Objective To evaluate the cost-effectiveness of a genetic testing policy for HNF1A, HNF4A and GCK-MODY in a hypothetical cohort of type 2 diabetes patients 25-40 years old with a MODY prevalence of 2%.Research Design and Methods We used a simulation model of type 2 diabetes complications based on UKPDS data, modified to account for the natural history of disease by genetic subtype, to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of -1.5%, compared to usual care. GCK-MODY received no therapy. Main outcome measures were costs and quality-adjusted life years (QALYs), based on lifetime risk of complications and treatments, expressed as the incremental cost-effectiveness ratio (ICER, $/QALY).ResultsThe testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of $205,000. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼$50,000. If MODY prevalence was >30%, the testing policy was cost-saving. Reducing genetic testing costs to $700 also resulted in an ICER of ∼$50,000.Conclusions Our simulated model suggests a policy of testing for MODY in selected populations is cost-effective for the United States based on contemporary ICER thresholds. Higher prevalence of MODY in the tested population or decreased testing costs would enhance cost-effectiveness. Our results make a compelling argument for routine coverage of genetic testing in patients with high clinical suspicion of MODY.
    Diabetes care 09/2013; · 7.74 Impact Factor
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    ABSTRACT: Here we use Drosophila melanogaster to create a genetic model of human permanent neonatal diabetes mellitus and present experimental results describing dimensions of this complexity. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINSC96Y, which is a cause of the disease. When expressed in fly imaginal discs, hINSC96Y causes a reduction of adult structures, including the eye, wing and notum. Eye imaginal discs exhibit defects in both the structure and arrangement of ommatidia. In the wing, expression of hINSC96Y leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild type signaling processes regulating cell fates. These readily measurable disease phenotypes are sensitive to temperature, gene dose and sex. Mutant (but not wild type) proinsulin expression in the eye imaginal disc induces IRE1-mediated Xbp1 alternative splicing, a signal for endoplasmic reticulum stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel produces F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease thus has its own distinct signature. The genetic dominance of disease-specific phenotypic variability makes this approach amenable to genome-wide association study (GWAS) in a simple F1 screen of natural variation.
    05/2013;
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    ABSTRACT: AIMSHYPOTHESIS: Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes. In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass. Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery. CONCLUSIONSINTERPRETATION: These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.
    PLoS ONE 01/2013; 8(6):e65777. · 3.73 Impact Factor
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    ABSTRACT: Aims/Introduction: Mutations in hepatocyte nuclear factor-4α (HNF4α) lead to various diseases, among which C-terminal deletions of HNF4α are exclusively responsible for maturity onset diabetes of the young 1 (MODY1). MODY is an autosomal dominant disease characterized by a primary defect in insulin response to glucose, suggesting that the C-terminus of HNF4α is important for pancreatic β-cell function. To clarify the role of the C-terminus of HNF4α, changes in cellular localization and the binding ability to its regulator were examined, specifically in the region containing Q268, which deletion causes MODY1. Materials and Methods: Cellular localization of mutant HNF4α were examined in monkey kidney 7 (COS7), Chinese hamster ovary, rat insulinoma and mouse insulinoma cells, and their binding activity to other proteins were examined by fluorescence resonance energy transfer (FRET) in COS7 cells. Results: Although wild-type HNF4α was localized in the nucleoplasm in transfected cultured cells, Q268X-HNF4α was located predominantly in the nucleolus. Deletion analysis of the C-terminus of HNF4α showed that the S337X-HNF4α mutant, and other mutants with shorter amino acid sequences (S337-K194), were mostly localized in the nucleolus. HNF4α mutants with amino acid sequences shorter than the W192X-HNF4α mutant gradually spread to the nucleoplasm in accordance with their lengths. The A250X-HNF4α mutant was capable of causing the accumulation of HNF4α or the small heterodimer partner (SHP), one of the HNF4α regulators, in the nucleolus. However, the R154X-HNF4α mutant did not have binding ability to wild-type HNF4α or SHP, and thus was seen in the nucleus. Conclusions: The C-terminus sites might play a key role in facilitating the nucleolar and subnucleolar localization of HNF4α. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00210.x, 2012).
    Journal of diabetes investigation. 10/2012; 3(5):449-56.
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    ABSTRACT: AIMS/HYPOTHESIS: Recent functional characterisations of genome-wide association study (GWAS) loci suggest that cis-regulatory variation may be a common paradigm for complex disease susceptibility. Several studies point to a similar mechanism at the transcription factor 7-like 2 (TCF7L2) GWAS locus for type 2 diabetes. To address this possibility, we carried out an in vitro scan of this diabetes-associated locus to fine-map cis-regulatory sequences within this genomic interval. METHODS: A systematic cell-based enhancer strategy was employed to interrogate all sequences within the 92 kb type-2-diabetes-association interval for cis-regulatory activity in a panel of cell lines (HCT-116, Neuro-2a, C2C12, U2OS, MIN6 and HepG2). We further evaluated chromatin state at a subset of these regions in HCT-116 and U2OS cells and examined allelic-specific enhancer properties at the type-2-diabetes-associated single nucleotide polymorphism (SNP) rs7903146. RESULTS: In total, we assigned cis-regulatory activity to approximately 30% (9/28) of constructs tested. Notably, a subset of enhancers was active across multiple cell lines and overlapped with key epigenetic markers suggestive of cis-regulatory sequences. We further replicated the allelic-specific properties for SNP rs7903146 in pancreatic beta cells and additionally demonstrate identical allelic-specific enhancer effects in other cell lines. CONCLUSIONS: These results provide a detailed map of cis-regulatory elements within the TCF7L2 GWAS locus and support the hypothesis of cis-regulatory variation leading to type 2 diabetes predisposition. The detection of allelic-specific effects for SNP rs7903146 in multiple cell lines further alludes to the likelihood of a peripheral defect in disease aetiology.
    Diabetologia 09/2012; · 6.49 Impact Factor
  • Anita S Chong, Graeme I Bell
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    ABSTRACT: New research shows that in a mouse model of type 1 diabetes, it may be possible to abrogate autoimmunity and then exploit the ability of pancreatic β cells to regenerate, thereby restoring blood glucose regulation.
    Science translational medicine 05/2012; 4(133):133fs12. · 10.76 Impact Factor
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    ABSTRACT: Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0-4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.
    PLoS ONE 01/2012; 7(5):e38050. · 3.73 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D), implicating a role for cis-regulatory variation within this locus in disease etiology. Supporting this hypothesis, we previously localized complex regulatory activity to the TCF7L2 T2D-associated interval using an in vivo bacterial artificial chromosome (BAC) enhancer-trapping reporter strategy. To follow-up on this broad initial survey of the TCF7L2 regulatory landscape, we performed a fine-mapping enhancer scan using in vivo mouse transgenic reporter assays. We functionally interrogated approximately 50% of the sequences within the T2D-associated interval, utilizing sequence conservation within this 92-kb interval to determine the regulatory potential of all evolutionary conserved sequences that exhibited conservation to the non-eutherian mammal opossum. Included in this study was a detailed functional interrogation of sequences spanning both protective and risk alleles of single nucleotide polymorphism (SNP) rs7903146, which has exhibited allele-specific enhancer function in pancreatic beta cells. Using these assays, we identified nine segments regulating various aspects of the TCF7L2 expression profile and that constitute nearly 70% of the sequences tested. These results highlight the regulatory complexity of this interval and support the notion that a TCF7L2 cis-regulatory disruption leads to T2D predisposition.
    PLoS ONE 01/2012; 7(5):e36501. · 3.73 Impact Factor
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    ABSTRACT: To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians. The coding and bordering intron-exon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non-diabetic subjects who historically were thought to be of South Asian Indian ancestry as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region. We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo-Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098). Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population.
    The West Indian medical journal 12/2011; 60(6):604-7. · 0.32 Impact Factor
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    ABSTRACT: There has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causes accounting for the majority of cases are mutations in the genes encoding the two subunits of the ATP-sensitive potassium channel (K(ATP)), KCNJ11 and ABCC8, and the insulin gene (INS), as well as abnormalities in chromosome 6q24. Patients with activating mutations in KCNJ11 and ABCC8 can be treated with oral sulfonylureas in lieu of insulin injections. This compelling example of personalized genetic medicine leading to improved glucose regulation and quality of life may-with continued research-be repeated for other forms of neonatal diabetes in the future.
    Current Diabetes Reports 12/2011; 11(6):519-32. · 3.17 Impact Factor
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    Stefan S Fajans, Graeme I Bell
    Diabetes care 08/2011; 34(8):1878-84. · 7.74 Impact Factor

Publication Stats

25k Citations
4,107.98 Total Impact Points

Institutions

  • 2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2004–2012
    • University of Bergen
      • • Department of Clinical Medicine
      • • The Gade Institute
      Bergen, Hordaland Fylke, Norway
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 1988–2012
    • University of Chicago
      • • Department of Surgery
      • • Department of Medicine
      • • Department of Biochemistry & Molecular Biology
      • • Department of Obstetrics & Gynecology
      Chicago, IL, United States
    • Roswell Park Cancer Institute
      • Department of Human Genetics
      Buffalo, New York, United States
  • 1987–2012
    • University of Illinois at Chicago
      • • Department of Medicine (Chicago)
      • • Department of Biochemistry and Molecular Genetics (Chicago)
      • • Department of Obstetrics and Gynecology (Chicago)
      Chicago, Illinois, United States
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, CA, United States
  • 2010–2011
    • Aarhus University Hospital
      • Department of Endocrinology and Internal Medicine
      Århus, Central Jutland, Denmark
  • 1997–2011
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
    • Steno Diabetes Center
      Gjentofte, Capital Region, Denmark
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2009
    • University of British Columbia - Vancouver
      • Department of Cellular and Physiological Sciences
      Vancouver, British Columbia, Canada
  • 2004–2009
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 2004–2006
    • Whitehead Institute for Biomedical Research
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 2004–2005
    • The University of the West Indies, Trinidad and Tobago
      City of Port-of-Spain, City of Port of Spain, Trinidad and Tobago
  • 2002–2005
    • Tokyo Women's Medical University
      • Diabetes Center
      Edo, Tōkyō, Japan
  • 1986–2005
    • Howard Hughes Medical Institute
      Maryland, United States
  • 2003–2004
    • The Chinese University of Hong Kong
      • Prince of Wales Hospital
      Hong Kong, Hong Kong
  • 1997–2001
    • University of Exeter
      • Peninsula College of Medicine and Dentistry
      Exeter, England, United Kingdom
  • 1994–2001
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Stony Brook University
      • Department of Physiology and Biophysics
      Stony Brook, NY, United States
  • 1999
    • Institut Universitaire de France
      Lutetia Parisorum, Île-de-France, France
  • 1998
    • Gunma University
      • Department of Anatomy and Cell Biology
      Maebashi-shi, Gunma-ken, Japan
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1988–1997
    • University of Iowa
      • • Department of Pediatrics
      • • Department of Internal Medicine
      Iowa City, IA, United States
  • 1996
    • University of Texas Health Science Center at Houston
      • Human Genetics Center
      Houston, TX, United States
  • 1995–1996
    • Virginia Mason Medical Center
      Seattle, Washington, United States
    • Institut Louis Bachelier
      Lutetia Parisorum, Île-de-France, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • University of Oxford
      Oxford, England, United Kingdom
  • 1993–1995
    • University of Pennsylvania
      • • Department of Medicine
      • • Department of Pharmacology
      Philadelphia, PA, United States
    • Kyoto University
      • Graduate School of Medicine / Faculty of Medicine
      Kyoto, Kyoto-fu, Japan
  • 1992–1995
    • Hospital of the University of Pennsylvania
      • Department of Pharmacology
      Philadelphia, PA, United States
    • Wakayama Medical University
      Wakayama, Wakayama, Japan
  • 1976–1994
    • University of California, San Francisco
      San Francisco, California, United States
  • 1991–1992
    • Oxford University Hospitals NHS Trust
      • Department of Haematology
      Oxford, ENG, United Kingdom
  • 1990–1991
    • University of Glasgow
      • Division of Biochemistry
      Glasgow, SCT, United Kingdom
  • 1989
    • Karolinska University Hospital
      • Department of Clinical Genetics
      Stockholm, Stockholm, Sweden
  • 1988–1989
    • Wayne State University
      • School of Medicine
      Detroit, Michigan, United States