Patrick Concannon

Genetics and IVF Institute, N. Bethesda, Maryland, United States

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Publications (152)1346.54 Total impact

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    ABSTRACT: Despite the finding of over 40 risk loci for type 1 diabetes (T1D), the causative variants and genes remain largely unknown. Here, we sought to identify rare deleterious variants of moderate-to-large effects contributing to T1D. We deeply sequenced 301 protein-coding genes located in 49 previously reported T1D risk loci in 70 T1D cases of European ancestry. These cases were selected from putatively high-risk families that had three or more siblings diagnosed with T1D at early ages. A cluster of rare deleterious variants in PTPN22 was identified, including two novel frameshift mutations (ss538819444 and rs371865329) and two missense variants (rs74163663 and rs56048322). Genotyping in 3,609 T1D families showed that rs56048322 was significantly associated with T1D, and that this association was independent of the T1D-associated, common variant rs2476601. The risk allele at rs56048322 affects splicing of PTPN22 resulting in the production of two alternative PTPN22 transcripts and a novel isoform of LYP (the protein encoded by PTPN22). This isoform competes with the wild-type LYP for binding to CSK and results in hyporesponsiveness of CD4(+) T cells to antigen stimulation in T1D subjects. These findings demonstrate that in addition to common variants, rare deleterious variants in PTPN22 exist and can affect T1D risk.
    No preview · Article · Dec 2015 · Diabetes
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    ABSTRACT: Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease.
    Preview · Article · Oct 2015 · eLife Sciences
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    ABSTRACT: Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here we evaluated associations between common genetic variants (single nucleotide polymorphisms (SNPs) and indels) in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15,397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r(2) with rs17507066=0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1 x10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72x10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r(2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70 x 10(-8)). These data suggest that common variants at 22q11.2 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
    Full-text · Article · Oct 2015 · Carcinogenesis
  • Stephen S. Rich · Patrick Concannon
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    ABSTRACT: Objective: Type 1 diabetes (T1D) arises from the autoimmune destruction of the β-cells of the pancreas, resulting in dependence on exogenously administered insulin for survival. Key biomarkers of the autoimmune process in T1D are the occurrence of autoantibodies directed against β-cells and other antigens. The Type 1 Diabetes Genetics Consortium (T1DGC) assembled collections to 1) discover genes that modify the risk of T1D, 2) conduct phenotyping related to risk, and 3) make available biologic and genetic resources for research. The goal of the T1DGC Autoantibody Workshop was to use T1DGC phenotypic, genotypic, and autoantibody data on affected sibling pair (ASP) families to discover genes accounting for variation in presence of autoantibodies. Research design and methods: The T1DGC provided the working groups with autoantibody and genetic data on 9,976 subjects from 2,321 ASP families. Data were distributed to numerous working groups for analyses of specific autoantibody subsets and targets. Results: Seven groups analyzed the joint autoantibody and genetic data within the ASP families. Six reports are provided in this collection, ranging from candidate gene analyses of selected autoantibodies to evaluation of regions of genetic variants associated with autoimmunity on the collection of autoantibodies. Conclusions: Although selected variants in the available genes remain important genetic predictors for prevalence of T1D, other genes and nongenetic factors are expected to contribute to the initiation of islet autoimmunity, the first step in the pathogenesis of T1D.
    No preview · Article · Oct 2015 · Diabetes Care
  • Stephen S Rich · Patrick Concannon
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    ABSTRACT: The Type 1 Diabetes Genetics Consortium (T1DGC) sponsored an Autoantibody Workshop, providing data from a large number of type 1 diabetes-affected sibling pair families with multiple autoantibodies assayed (both islet and nonislet targets) and extensive genetic and clinical information. Multiple groups analyzed the autoantibody data and various forms of genetic data. The groups presented their results at the T1DGC Autoantibody Workshop and compared results across genes and autoantibodies. The reports of the analyses of the autoantibody data with genetic information are contained as individual articles in this supplement. There were several consistent findings that emerged from the T1DGC Autoantibody Workshop. The human MHC (HLA genes) is the major contributor to variation in the presence of islet and nonislet autoantibodies in subjects with established type 1 diabetes. The contribution of non-MHC genes/variants to autoantibody prevalence is dependent on the set of single nucleotide polymorphisms tested, the autoantibody evaluated, and the inclusion criteria for sample selection. On the basis of these results, the HLA alleles DRB1*0101 and DRB1*0404 and the PTPN22 R620W variant are consistently associated with autoimmunity in the T1DGC Autoantibody Workshop data.
    No preview · Article · Sep 2015 · Diabetes care
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    ABSTRACT: Recent evidence has highlighted the role of the innate immune system in type 1 diabetes (T1D) pathogenesis. Specifically, aberrant activation of the interferon response prior to seroconversion of T1D-associated autoantibodies supports a role for the interferon response as a precipitating event toward activation of autoimmunity. Melanoma differentiation-associated protein 5 (MDA5), encoded by IFIH1, mediates the innate immune system's interferon response to certain viral species that form double-stranded RNA (dsRNA), the MDA5 ligand, during their life cycle. Extensive research has associated single nucleotide polymorphisms (SNPs) within the coding region of IFIH1 with T1D. This review discusses the different risk and protective IFIH1 alleles in the context of recent structural and functional analysis that relate to MDA5 regulation of interferon responses. These studies have provided a functional hypothesis for IFIH1 T1D-associated SNPs' effects on MDA5-mediated interferon responses as well as supporting the genome-wide association (GWA) studies that first associated IFIH1 with T1D.
    No preview · Article · Sep 2015 · Current Diabetes Reports
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    ABSTRACT: The MRE11/RAD50/NBS1 (MRN) complex plays a central role as a sensor of DNA double strand breaks (DSB) and is responsible for the efficient activation of ataxia-telangiectasia mutated (ATM) kinase. Once activated ATM in turn phosphorylates RAD50 and NBS1, important for cell cycle control, DNA repair and cell survival. We report here that MRE11 is also phosphorylated by ATM at S676 and S678 in response to agents that induce DNA DSB, is dependent on the presence of NBS1, and does not affect the association of members of the complex or ATM activation. A phosphosite mutant (MRE11S676AS678A) cell line showed decreased cell survival and increased chromosomal aberrations after radiation exposure indicating a defect in DNA repair. Use of GFP-based DNA repair reporter substrates in MRE11S676AS678A cells revealed a defect in homology directed repair (HDR) but single strand annealing was not affected. More detailed investigation revealed that MRE11S676AS678A cells resected DNA ends to a greater extent at sites undergoing HDR. Furthermore, while ATM-dependent phosphorylation of Kap1 and SMC1 was normal in MRE11S676AS678A cells, there was no phosphorylation of Exonuclease 1 consistent with the defect in HDR. These results describe a novel role for ATM-dependent phosphorylation of MRE11 in limiting the extent of resection mediated through Exonuclease 1. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Full-text · Article · Aug 2015 · Nucleic Acids Research
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    ABSTRACT: Islet autoantibodies detected at onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity we carried out dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes affected siblings. The genetic association with positivity for autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated antigen 2 (IA-2A), zinc transporter 8 (ZnT8A), thyroid peroxidase (TPOA), gastric parietal cells (PCA), tissue transglutaminase (TGA) and 21-hydroxylase (OH21A) was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, IA2A with 1q23/FCRL3 and 11q13/RELA, and PCA with 2q24/IFIH1. The 3q28 locus showed association only after 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13 and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    No preview · Article · Mar 2015 · Diabetes
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    ABSTRACT: Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.
    No preview · Article · Mar 2015 · Nature Genetics
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
    Full-text · Article · Jan 2015 · Nature Genetics
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    ABSTRACT: Pathway analysis can complement point-wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease-associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene-based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene-based pathway analysis of a type 1 diabetes (T1D) meta-analysis GWAS (of 7,514 cases and 9,045 controls). An important feature of the conducted analysis is the removal of the major histocompatibility complex gene region, the major genetic risk factor for T1D. Thirty-one of the 1,583 (2%) tested pathways were identified to be enriched for association with T1D at a 5% false discovery rate. We analyzed these 31 pathways and their genes to identify SNPs in or near these pathway genes that showed potentially novel association with T1D and attempted to replicate the association of 22 SNPs in additional samples. Replication P-values were skewed () with 12 of the 22 SNPs showing . Support, including replication evidence, was obtained for nine T1D associated variants in genes ITGB7 (rs11170466, ), NRP1 (rs722988, ), BAD (rs694739, ), CTSB (rs1296023, ), FYN (rs11964650, ), UBE2G1 (rs9906760, ), MAP3K14 (rs17759555, ), ITGB1 (rs1557150, ), and IL7R (rs1445898, ). The proposed methodology can be applied to other GWAS datasets for which only summary level data are available.
    Full-text · Article · Dec 2014 · Genetic Epidemiology
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    ABSTRACT: Most vaccine assessments have occurred in well-nourished populations of higher socioeconomic status. However, vaccines are often used in populations with high incidences of malnutrition and infections, in whom the effectiveness of some vaccines is inferior for unknown reasons. The degree and extent of vaccine underperformance have not been systematically studied for most vaccines across differing epidemiologic settings. This paper outlines the methods used and challenges associated with measuring immunological responses to oral vaccines against poliovirus and rotavirus, and parenteral vaccines against pertussis, tetanus, and measles in an observational study that monitored daily illness, monthly growth, intestinal inflammation and permeability, pathogen burden, dietary intake, and micronutrient status in children in 8 countries. This evaluation of vaccine response in the context of low- and middle-income countries is intended to address the gaps in knowledge of the heterogeneity in vaccine response in diverse epidemiological settings and the interplay between infections, nutrition, and immune response.
    Full-text · Article · Nov 2014 · Clinical Infectious Diseases
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    ABSTRACT: Background: Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. Methods: We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. Results: The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. Conclusions: Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).
    Full-text · Article · Aug 2014 · New England Journal of Medicine
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13, have been previously associated with risk for several autoimmune diseases including type 1 diabetes. In order to identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we re-sequenced a 455 kb region in type 1 diabetes patients and unaffected controls, identifying 93 novel variants. A panel of 939 SNPs, that included 46 of these novel variants, was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided statistically significant association (P < 5.32 x 10(-5)) with disease, with rs34306440 (P = 5.74 x 10(-6)) being most significantly associated. The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease, and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to risk for type 1 diabetes is through reduced expression of DEXI.
    Preview · Article · Jul 2014 · Diabetes
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    ABSTRACT: Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat β-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh(-/-) mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower β-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of β-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic β-cells, the target cells of the autoimmune assault.
    Full-text · Article · Jun 2014 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n = 541) and the Children's Oncology Group (n= 1,329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 x 10(-5), OR = 1.64; P = 1.4 x 10(-5), OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 x 10(-4), OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. Studies were registered at ClinicalTrials.gov, identifiers: NCT00137111, NCT00549848, NCT00005603, and NCT00075725.
    Full-text · Article · Jun 2014 · Blood
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    ABSTRACT: Killer Immunoglobulin-like Receptors (KIRs) are surface receptors of natural killer cells that bind to their corresponding Human Leukocyte Antigen (HLA) class I ligands, making them interesting candidate genes for HLA-associated autoimmune diseases, including type 1 diabetes (T1D). However, allelic and copy number variation in the KIR region effectively mask it from standard genome-wide association studies: single nucleotide polymorphism (SNP) probes targeting the region are often discarded by standard genotype callers since they exhibit variable cluster numbers. Quantitative Polymerase Chain Reaction (qPCR) assays address this issue. However, their cost is prohibitive at the sample sizes required for detecting effects typically observed in complex genetic diseases. We propose a more powerful and cost-effective alternative, which combines signals from SNPs with more than three clusters found in existing datasets, with qPCR on a subset of samples. First, we showed that noise and batch effects in multiplexed qPCR assays are addressed through normalisation and simultaneous copy number calling of multiple genes. Then, we used supervised classification to impute copy numbers of specific KIR genes from SNP signals. We applied this method to assess copy number variation in two KIR genes, \textit{KIR3DL1} and KIR3DS1, which are suitable candidates for T1D susceptibility since they encode the only KIR molecules known to bind with HLA-Bw4 epitopes. We find no association between KIR3DL1/3DS1 copy number and T1D in 6744 cases and 5362 controls; a sample size twenty-fold larger than in any previous KIR association study. Due to our sample size, we can exclude odds ratios larger than 1.1 for the common KIR3DL1/3DS1 copy number groups at the 5% significance level. We found no evidence of association of KIR3DL1/3DS1 copy number with T1D, either overall or dependent on HLA-Bw4 epitope. Five other KIR genes, KIR2DS4, KIR2DL3, KIR2DL5, KIR2DS5 and KIR2DS1, in high linkage disequilibrium with KIR3DL1 and KIR3DS1, are also unlikely to be significantly associated. Our approach could potentially be applied to other KIR genes to allow cost effective assaying of gene copy number in large samples.
    Full-text · Article · Apr 2014 · BMC Genomics
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    ABSTRACT: Highly prevalent conditions with multiple and complex underlying etiologies are a challenge to public health. Undernutrition, for example, affects 20% of children in the developing world. The cause and consequence of poor nutrition are multifaceted. Undernutrition has been associated with half of all deaths worldwide in children aged <5 years; in addition, its pernicious long-term effects in early childhood have been associated with cognitive and physical growth deficits across multiple generations and have been thought to suppress immunity to further infections and to reduce the efficacy of childhood vaccines. The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) Study, led by the Fogarty International Center of the National Institutes of Health and the Foundation for the National Institutes of Health, has been established at sites in 8 countries with historically high incidence of diarrheal disease and undernutrition. Central to the study is the hypothesis that enteropathogen infection contributes to undernutrition by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. It is further postulated that this leads to growth faltering and deficits in cognitive development. The effects of repeated enteric infection and undernutrition on the immune response to childhood vaccines is also being examined in the study. MAL-ED uses a prospective longitudinal design that offers a unique opportunity to directly address a complex system of exposures and health outcomes in the community G Çörather than the relatively rarer circumstances that lead to hospitalization G Çöduring the critical period of development of the first 2 years of life. Among the factors being evaluated are enteric infections (with or without diarrhea) and other illness indicators, micronutrient levels, diet, socioeconomic status, gut function, and the environment. MAL-ED aims to describe these factors, their interrelationships, and their overall impact on health outcomes in unprecedented detail, and to make individual, site-specific, and generalized recommendations regarding the nature and timing of possible interventions aimed at improving child health and development in these resource-poor settings
    Full-text · Article · Jan 2014
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    ABSTRACT: The role of leptin in the mucosal immune response to Clostridium difficile colitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due to Entamoeba histolytica as well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same LEPR Q223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of C. difficile infection (odds ratio, 3.03; P = 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance of C. difficile from the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin in C. difficile colitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the LEPR Q223R mutation. Identification of the role of leptin in protection from C. difficile offers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.
    Preview · Article · Oct 2013 · Infection and immunity
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    ABSTRACT: Purpose Women who receive chemotherapy for a first primary breast cancer have been observed to have a reduced risk of contralateral breast cancer (CBC), however, whether the genetic profile of a patient modifies this protective effect is currently not understood. The purpose of this study is to investigate the impact of germline genetic variation in genes coding for drug metabolizing enzymes, transporters, and targets on the association between chemotherapy and risk of CBC. Methods From the population-based Women’s Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 636 Caucasian women with CBC (cases) and 1,224 women with unilateral breast cancer (controls). The association between common chemotherapeutic regimens, CMF and FAC/FEC, and risk of CBC stratified by genotype of 180 single nucleotide polymorphisms in 14 genes selected for their known involvement in metabolism, action, and transport of breast cancer chemotherapeutic agents, were determined using conditional logistic regression. Results CMF (RR = 0.5, 95 % CI 0.4, 0.7) and FAC/FEC (RR = 0.7, 95 % CI 0.4, 1.0) are associated with lower CBC risk relative to no chemotherapy in multivariable-adjusted models. Here we show that genotype of selected genes involved in the metabolism and uptake of these therapeutic agents does not significantly alter the protective effect of either CMF or FAC/FEC on risk of CBC. Conclusion The results of this study show that germline genetic variation in selected gene does not significantly alter the protective effect of CMF, FAC, and FEC on risk of CBC.
    Full-text · Article · Jun 2013 · Cancer Causes and Control

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11k Citations
1,346.54 Total Impact Points

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Institutions

  • 2015
    • Genetics and IVF Institute
      N. Bethesda, Maryland, United States
  • 2013-2015
    • University of Florida
      • Department of Pathology, Immunology, and Laboratory Medicine
      Gainesville, Florida, United States
  • 2008-2015
    • University of Virginia
      • • Department of Biochemistry, Molecular Biology and Genetics
      • • Center for Public Health Genomics (CPHG)
      Charlottesville, Virginia, United States
  • 2010
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2004-2006
    • Benaroya Research Institute
      • Diabetes Research Program
      Seattle, Washington, United States
  • 1991-2006
    • University of Washington Seattle
      • Department of Immunology
      Seattle, Washington, United States
  • 2003
    • Wake Forest University
      Winston-Salem, North Carolina, United States
  • 1988-2003
    • Virginia Mason Medical Center
      Seattle, Washington, United States
  • 1990
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States