Publications by authors named "Maegan Harden"

21 Publications

  • Page 1 of 1

Using viral load and epidemic dynamics to optimize pooled testing in resource-constrained settings.

Sci Transl Med 2021 04 22;13(589). Epub 2021 Feb 22.

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Virological testing is central to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containment, but many settings face severe limitations on testing. Group testing offers a way to increase throughput by testing pools of combined samples; however, most proposed designs have not yet addressed key concerns over sensitivity loss and implementation feasibility. Here, we combined a mathematical model of epidemic spread and empirically derived viral kinetics for SARS-CoV-2 infections to identify pooling designs that are robust to changes in prevalence and to ratify sensitivity losses against the time course of individual infections. We show that prevalence can be accurately estimated across a broad range, from 0.02 to 20%, using only a few dozen pooled tests and using up to 400 times fewer tests than would be needed for individual identification. We then exhaustively evaluated the ability of different pooling designs to maximize the number of detected infections under various resource constraints, finding that simple pooling designs can identify up to 20 times as many true positives as individual testing with a given budget. Crucially, we confirmed that our theoretical results can be translated into practice using pooled human nasopharyngeal specimens by accurately estimating a 1% prevalence among 2304 samples using only 48 tests and through pooled sample identification in a panel of 960 samples. Our results show that accounting for variation in sampled viral loads provides a nuanced picture of how pooling affects sensitivity to detect infections. Using simple, practical group testing designs can vastly increase surveillance capabilities in resource-limited settings.
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http://dx.doi.org/10.1126/scitranslmed.abf1568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099195PMC
April 2021

Efficient prevalence estimation and infected sample identification with group testing for SARS-CoV-2.

medRxiv 2020 May 6. Epub 2020 May 6.

Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.

The ongoing pandemic of SARS-CoV-2, a novel coronavirus, caused over 3 million reported cases of coronavirus disease 2019 (COVID-19) and 200,000 reported deaths between December 2019 and April 2020. Cases and deaths will increase as the virus continues its global march outward. In the absence of effective pharmaceutical interventions or a vaccine, wide-spread virological screening is required to inform where restrictive isolation measures should be targeted and when they can be lifted. However, limitations on testing capacity have restricted the ability of governments and institutions to identify individual clinical cases, appropriately measure community prevalence, and mitigate transmission. Group testing offers a way to increase efficiency, by combining samples and testing a small number of pools. Here, we evaluate the effectiveness of group testing designs for individual identification or prevalence estimation of SARS-CoV-2 infection when testing capacity is limited. To do this, we developed mathematical models for epidemic spread, incorporating empirically measured individual-level viral kinetics to simulate changing viral loads in a large population over the course of an epidemic. We used these to construct representative populations and assess pooling strategies for community screening, accounting for variability in viral load samples, dilution effects, changing prevalence and resource constraints. We confirmed our group testing framework through pooled tests on de-identified human nasopharyngeal specimens with viral loads representative of the larger population. We show that group testing designs can both accurately estimate overall prevalence using a small number of measurements and substantially increase the identification rate of infected individuals in resource-limited settings.
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http://dx.doi.org/10.1101/2020.05.01.20086801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273255PMC
May 2020

Interaction Between Type 2 Diabetes Prevention Strategies and Genetic Determinants of Coronary Artery Disease on Cardiometabolic Risk Factors.

Diabetes 2020 01 21;69(1):112-120. Epub 2019 Oct 21.

Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.

Coronary artery disease (CAD) is more frequent among individuals with dysglycemia. Preventive interventions for diabetes can improve cardiometabolic risk factors (CRFs), but it is unclear whether the benefits on CRFs are similar for individuals at different genetic risk for CAD. We built a 201-variant polygenic risk score (PRS) for CAD and tested for interaction with diabetes prevention strategies on 1-year changes in CRFs in 2,658 Diabetes Prevention Program (DPP) participants. We also examined whether separate lifestyle behaviors interact with PRS and affect changes in CRFs in each intervention group. Participants in both the lifestyle and metformin interventions had greater improvement in the majority of recognized CRFs compared with placebo ( < 0.001) irrespective of CAD genetic risk ( > 0.05). We detected nominal significant interactions between PRS and dietary quality and physical activity on 1-year change in BMI, fasting glucose, triglycerides, and HDL cholesterol in individuals randomized to metformin or placebo, but none of them achieved the multiple-testing correction for significance. This study confirms that diabetes preventive interventions improve CRFs regardless of CAD genetic risk and delivers hypothesis-generating data on the varying benefit of increasing physical activity and improving diet on intermediate cardiovascular risk factors depending on individual CAD genetic risk profile.
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http://dx.doi.org/10.2337/db19-0097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925585PMC
January 2020

A Polygenic Lipodystrophy Genetic Risk Score Characterizes Risk Independent of BMI in the Diabetes Prevention Program.

J Endocr Soc 2019 Sep 24;3(9):1663-1677. Epub 2019 Jun 24.

Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts.

Context: There is substantial heterogeneity in insulin sensitivity, and genetics may suggest possible mechanisms by which common variants influence this trait.

Objectives: We aimed to evaluate an 11-variant polygenic lipodystrophy genetic risk score (GRS) for association with anthropometric, glycemic and metabolic traits in the Diabetes Prevention Program (DPP). In secondary analyses, we tested the association of the GRS with cardiovascular risk factors in the DPP.

Design: In 2713 DPP participants, we evaluated a validated GRS of 11 common variants associated with fasting insulin-based measures of insulin sensitivity discovered through genome-wide association studies that cluster with a metabolic profile of lipodystrophy, conferring high metabolic risk despite low body mass index (BMI).

Results: At baseline, a higher polygenic lipodystrophy GRS was associated with lower weight, BMI, and waist circumference measurements, but with worse insulin sensitivity index (ISI) values. Despite starting at a lower weight and BMI, a higher GRS was associated with less weight and BMI reduction at one year and less improvement in ISI after adjusting for baseline values but was not associated with diabetes incidence. A higher GRS was also associated with more atherogenic low-density lipoprotein peak-particle-density at baseline but was not associated with coronary artery calcium scores in the Diabetes Prevention Program Outcomes Study.

Conclusions: In the DPP, a higher polygenic lipodystrophy GRS for insulin resistance with lower BMI was associated with diminished improvement in insulin sensitivity and potential higher cardiovascular disease risk. This GRS helps characterize insulin resistance in a cohort of individuals at high risk for diabetes, independent of adiposity.
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http://dx.doi.org/10.1210/js.2019-00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694040PMC
September 2019

Outcomes of patient self-referral for the diagnosis of several rare inherited kidney diseases.

Genet Med 2020 01 24;22(1):142-149. Epub 2019 Jul 24.

Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Purpose: To evaluate self-referral from the Internet for genetic diagnosis of several rare inherited kidney diseases.

Methods: Retrospective study from 1996 to 2017 analyzing data from an academic referral center specializing in autosomal dominant tubulointerstitial kidney disease (ADTKD). Individuals were referred by academic health-care providers (HCPs) nonacademic HCPs, or directly by patients/families.

Results: Over 21 years, there were 665 referrals, with 176 (27%) directly from families, 269 (40%) from academic HCPs, and 220 (33%) from nonacademic HCPs. Forty-two (24%) direct family referrals had positive genetic testing versus 73 (27%) families from academic HCPs and 55 (25%) from nonacademic HCPs (P = 0.72). Ninety-nine percent of direct family contacts were white and resided in zip code locations with a mean median income of $77,316 ± 34,014 versus US median income $49,445.

Conclusion: Undiagnosed families with Internet access bypassed their physicians and established direct contact with an academic center specializing in inherited kidney disease to achieve a diagnosis. Twenty-five percent of all families diagnosed with ADTKD were the result of direct family referral and would otherwise have been undiagnosed. If patients suspect a rare disorder that is undiagnosed by their physicians, actively pursuing self-diagnosis using the Internet can be successful. Centers interested in rare disorders should consider improving direct access to families.
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http://dx.doi.org/10.1038/s41436-019-0617-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946861PMC
January 2020

Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial.

Nature 2019 01 19;565(7738):234-239. Epub 2018 Dec 19.

Oncovir Inc, Washington, DC, USA.

Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses and can function as bona fide antigens that facilitate tumour rejection. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load and an immunologically 'cold' tumour microenvironment. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4 and CD8 T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.
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http://dx.doi.org/10.1038/s41586-018-0792-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546179PMC
January 2019

Noninvasive Immunohistochemical Diagnosis and Novel Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease.

J Am Soc Nephrol 2018 09 2;29(9):2418-2431. Epub 2018 Jul 2.

Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.

Background: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene () mutations (ADTKD-) is characterized by progressive kidney failure. Genetic evaluation for ADTKD- specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel mutations in individuals with positive immunohistochemical staining for the MUC1fs protein.

Methods: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify frameshift mutations.

Results: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel frameshift mutations that all predict production of the identical MUC1fs protein.

Conclusions: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-.
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http://dx.doi.org/10.1681/ASN.2018020180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115665PMC
September 2018

A Loss-of-Function Splice Acceptor Variant in Is Protective for Type 2 Diabetes.

Diabetes 2017 11 24;66(11):2903-2914. Epub 2017 Aug 24.

Department of Genetics, Harvard Medical School, Boston, MA.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of isoform 2. In individuals who do not carry the protective allele, expression of isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
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http://dx.doi.org/10.2337/db17-0187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652606PMC
November 2017

An immunogenic personal neoantigen vaccine for patients with melanoma.

Nature 2017 07 5;547(7662):217-221. Epub 2017 Jul 5.

Center for Immuno-Oncology (CIO), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.

Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4 and CD8 T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
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http://dx.doi.org/10.1038/nature22991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577644PMC
July 2017

Catechol-O-methyltransferase association with hemoglobin A1c.

Metabolism 2016 07 14;65(7):961-967. Epub 2016 Apr 14.

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes.

Methods: We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women's Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment.

Results: COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (β=-0.032% [0.012], p=0.008) and borderline significant in MAGIC (β=-0.006% [0.003], p=0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR=0.98 [0.96-0.998], p=0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR=0.81 [0.65-1.00], p=0.05).

Conclusions: COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD.
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http://dx.doi.org/10.1016/j.metabol.2016.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924514PMC
July 2016

Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials.

Diabetes 2015 Dec 7;64(12):4312-21. Epub 2015 Aug 7.

Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Malmö, Sweden Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA

Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2-4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism×treatment interaction (P = 4.3 × 10(-3)). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 × 10(-4)). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.
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http://dx.doi.org/10.2337/db15-0441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657576PMC
December 2015

African Ancestry Analysis and Admixture Genetic Mapping for Proliferative Diabetic Retinopathy in African Americans.

Invest Ophthalmol Vis Sci 2015 Jun;56(6):3999-4005

Institute for Translational Genomics and Population Sciences, LABiomed and Department of Pediatrics, Harbor-UCLA, Torrance, California, United States.

Purpose: To examine the relationship between proportion of African ancestry (PAA) and proliferative diabetic retinopathy (PDR) and to identify genetic loci associated with PDR using admixture mapping in African Americans with type 2 diabetes (T2D).

Methods: Between 1993 and 2013, 1440 participants enrolled in four different studies had fundus photographs graded using the Early Treatment Diabetic Retinopathy Study scale. Cases (n = 305) had PDR while controls (n = 1135) had nonproliferative diabetic retinopathy (DR) or no DR. Covariates included diabetes duration, hemoglobin A1C, systolic blood pressure, income, and education. Genotyping was performed on the Affymetrix platform. The association between PAA and PDR was evaluated using logistic regression. Genome-wide admixture scanning was performed using ANCESTRYMAP software.

Results: In the univariate analysis, PDR was associated with increased PAA (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.16-1.59, P = 0.0002). In multivariate regression adjusting for traditional DR risk factors, income and education, the association between PAA and PDR was attenuated and no longer significant (OR = 1.21, 95% CI = 0.59-2.47, P = 0.61). For the admixture analyses, the maximum genome-wide score was 1.44 on chromosome 1.

Conclusions: In this largest study of PDR in African Americans with T2D to date, an association between PAA and PDR is not present after adjustment for clinical, demographic, and socioeconomic factors. No genome-wide significant locus (defined as having a locus-genome statistic > 5) was identified with admixture analysis. Further analyses with even larger sample sizes are needed to definitively assess if any admixture signal for DR is present.
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http://dx.doi.org/10.1167/iovs.15-16674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477259PMC
June 2015

Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation.

Cancer Immunol Res 2015 Aug 26;3(8):855-63. Epub 2015 May 26.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527885PMC
August 2015

The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes.

PLoS One 2015 26;10(3):e0121553. Epub 2015 Mar 26.

Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.

Objective: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future.

Methods: All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured.

Results: Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels.

Conclusions: SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes.

Trial Registration: ClinicalTrials.gov NCT01762046.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374872PMC
March 2016

The cancer-associated FGFR4-G388R polymorphism enhances pancreatic insulin secretion and modifies the risk of diabetes.

Cell Metab 2013 Jun;17(6):929-940

Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.

The fibroblast growth factor receptor 4 (FGFR4)-R388 single-nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant that preferentially promotes STAT3/5 signaling. This STAT activation transcriptionally induces Grb14 in pancreatic endocrine cells to promote insulin secretion. Knockin mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion and enhanced with FGF19 administration. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link underlying cancer and hyperinsulinemia.
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http://dx.doi.org/10.1016/j.cmet.2013.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005358PMC
June 2013

Close association of olfactory placode precursors and cranial neural crest cells does not predestine cell mixing.

Dev Dyn 2012 Jul 22;241(7):1143-54. Epub 2012 May 22.

Department of Molecular Biology and Genetics, 445/449 Biotechnology Building, Cornell University, Ithaca, New York, USA.

Vertebrate sensory organs originate from both cranial neural crest cells (CNCCs) and placodes. Previously, we have shown that the olfactory placode (OP) forms from a large field of cells extending caudally to the premigratory neural crest domain, and that OPs form through cell movements and not cell division. Concurrent with OP formation, CNCCs migrate rostrally to populate the frontal mass. However, little is known about the interactions between CNCCs and the placodes that form the olfactory sensory system. Previous reports suggest that the OP can generate cell types more typical of neural crest lineages such as neuroendocrine cells and glia, thus marking the OP as an unusual sensory placode. One possible explanation for this exception is that the neural crest origin of glia and neurons has been overlooked due to the intimate association of these two fields during migration. Using molecular markers and live imaging, we followed the development of OP precursors and of dorsally migrating CNCCs in zebrafish embryos. We generated a six4b:mCherry line (OP precursors) that, with a sox10:EGFP line (CNCCs), was used to follow cell migration. Our analyses showed that CNCCs associate with and eventually surround the forming OP with limited cell mixing occurring during this process.
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http://dx.doi.org/10.1002/dvdy.23797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240535PMC
July 2012

Olfactory imprinting is correlated with changes in gene expression in the olfactory epithelia of the zebrafish.

J Neurobiol 2006 Nov;66(13):1452-66

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.

Odors experienced as juveniles can have significant effects on the behavior of mature organisms. A dramatic example of this occurs in salmon, where the odors experienced by developing fish determine the river to which they return as adults. Further examples of olfactory memories are found in many animals including vertebrates and invertebrates. Yet, the cellular and molecular bases underlying the formation of olfactory memory are poorly understood. We have devised a series of experiments to determine whether zebrafish can form olfactory memories much like those observed in salmonids. Here we show for the first time that zebrafish form and retain olfactory memories of an artificial odorant, phenylethyl alcohol (PEA), experienced as juveniles. Furthermore, we demonstrate that exposure to PEA results in changes in gene expression within the olfactory sensory system. These changes are evident by in situ hybridization in the olfactory epithelium of the developing zebrafish. Strikingly, our analysis by in situ hybridization demonstrates that the transcription factor, otx2, is up regulated in the olfactory sensory epithelia in response to PEA. This increase is evident at 2-3 days postfertilization and is maintained in the adult animals. We propose that the changes in otx2 gene expression are manifest as an increase in the number of neuronal precursors in the cells olfactory epithelium of the odor-exposed fish. Thus, our results reveal a role for the environment in controlling gene expression in the developing peripheral nervous system.
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http://dx.doi.org/10.1002/neu.20328DOI Listing
November 2006

UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/lamellipodin.

Curr Biol 2006 May 23;16(9):845-53. Epub 2006 Mar 23.

Department of Pathology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.

Background: Axon migrations are guided by extracellular cues that can act as repellants or attractants. However, the logic underlying the manner through which attractive and repulsive responses are determined is unclear. Many extracellular guidance cues, and the cellular components that mediate their signals, have been implicated in both types of responses.

Results: Genetic analyses indicate that MIG-10/RIAM/lamellipodin, a cytoplasmic adaptor protein, functions downstream of the attractive guidance cue UNC-6/netrin and the repulsive guidance cue SLT-1/slit to direct the ventral migration of the AVM and PVM axons in C. elegans. Furthermore, overexpression of MIG-10 in the absence of UNC-6 and SLT-1 induces a multipolar phenotype with undirected outgrowths. Addition of either UNC-6 or SLT-1 causes the neurons to become monopolar. Moreover, the ability of UNC-6 or SLT-1 to direct the axon ventrally is enhanced by the MIG-10 overexpression. We also demonstrate that an interaction between MIG-10 and UNC-34, a protein that promotes actin-filament extension, is important in the response to guidance cues and that MIG-10 colocalizes with actin in cultured cells, where it can induce the formation of lamellipodia.

Conclusions: We conclude that MIG-10 mediates the guidance of AVM and PVM axons in response to the extracellular UNC-6 and SLT-1 guidance cues. The attractive and repulsive guidance cues orient MIG-10-dependant axon outgrowth to cause a directional response.
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http://dx.doi.org/10.1016/j.cub.2006.03.025DOI Listing
May 2006

A role for foxd3 and sox10 in the differentiation of gonadotropin-releasing hormone (GnRH) cells in the zebrafish Danio rerio.

Development 2005 Dec 16;132(24):5491-502. Epub 2005 Nov 16.

Department of Molecular Biology and Genetics, 445 Biotechnology Building, Cornell University, Ithaca, NY 14853, USA.

Gonadotropin-releasing hormone (GnRH) is found in a wide range of vertebrate tissues, including the nervous system. In general, GnRH has two functions: endocrine, acting as a releasing hormone; and neuromodulatory, affecting neural activity in the peripheral and central nervous system. The best understood population of GnRH cells is that of the hypothalamus, which is essential for reproduction. Less well understood are the populations of GnRH cells found in the terminal nerve and midbrain, which appear to be neuromodulatory in function. The GnRH-containing cells of the midbrain are proposed to arise from the mesencephalic region of the neural tube. Previously, we showed that neuromodulatory GnRH cells of the terminal nerve arise from cranial neural crest. To test the hypothesis that neuromodulatory GnRH cells of the midbrain also arise from neural crest, we used gene knockdown experiments in zebrafish to disrupt neural crest development. We demonstrate that decrement of the function of foxd3 and/or sox10, two genes important for the development and specification of neural crest, resulted in a reduction and/or loss of GnRH cells of the midbrain, as well as a reduction in the number of terminal nerve GnRH cells. Therefore, our data support a neural crest origin for midbrain GnRH cells. Additionally, we demonstrate that knockdown of kallmann gene function resulted in the loss of endocrine GnRH cells of the hypothalamus, but not of neuromodulatory GnRH cells of the midbrain and terminal nerve, thus providing additional evidence for separate pathways controlling the development of neuromodulatory and endocrine GnRH cells.
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http://dx.doi.org/10.1242/dev.02158DOI Listing
December 2005