Henry A. Erlich

Children's Hospital & Research Center Oakland, Oakland, California, United States

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Publications (510)3689.58 Total impact

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    ABSTRACT: Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.
    No preview · Article · Jan 2016 · Proceedings of the National Academy of Sciences
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    Full-text · Dataset · Jul 2015
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    Hanna Kim · Henry A Erlich · Cassandra D Calloway
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    ABSTRACT: To apply massively parallel and clonal sequencing (next generation sequencing or NGS) to the analysis of forensic mixed samples. A duplex polymerase chain reaction (PCR) assay targeting the mitochondrial DNA (mtDNA) hypervariable regions I/II (HVI/HVII) was developed for NGS analysis on the Roche 454 GS Junior instrument. Eight sets of multiplex identifier-tagged 454 fusion primers were used in a combinatorial approach for amplification and deep sequencing of up to 64 samples in parallel. This assay was shown to be highly sensitive for sequencing limited DNA amounts (~100 mtDNA copies) and analyzing contrived and biological mixtures with low level variants (~1%) as well as "complex" mixtures (≥3 contributors). PCR artifact "hybrid" sequences generated by jumping PCR or template switching were observed at a low level (<2%) in the analysis of mixed samples but could be eliminated by reducing the PCR cycle number. This study demonstrates the power of NGS technologies targeting the mtDNA HVI/HVII regions for analysis of challenging forensic samples, such as mixtures and specimens with limited DNA.
    Full-text · Article · Jun 2015 · Croatian Medical Journal
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    ABSTRACT: Compared to Sanger sequencing, next-generation sequencing offers advantages for high resolution HLA genotyping including increased throughput, lower cost, and reduced genotype ambiguity. Here we describe an enhancement of the Roche 454 GS GType HLA genotyping assay to provide very high resolution (VHR) typing, by the addition of 8 primer pairs to the original 14, to genotype 11 HLA loci. These additional amplicons help resolve common and well-documented alleles and exclude commonly found null alleles in genotype ambiguity strings. Simplification of workflow to reduce the initial preparation effort using early pooling of amplicons or the Fluidigm Access Array™ is also described. Performance of the VHR assay was evaluated on 28 well characterized cell lines using Conexio Assign MPS software which uses genomic, rather than cDNA, reference sequence. Concordance was 98.4%; 1.6% had no genotype assignment. Of concordant calls, 53% were unambiguous. To further assess the assay, 59 clinical samples were genotyped and results compared to unambiguous allele assignments obtained by prior sequence-based typing supplemented with SSO and/or SSP. Concordance was 98.7% with 58.2% as unambiguous calls; 1.3% could not be assigned. Our results show that the amplicon-based VHR assay is robust and can replace current Sanger methodology. Together with software enhancements, it has the potential to provide even higher resolution HLA typing. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · May 2015 · Human immunology
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    ABSTRACT: Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.Am J Gastroenterol advance online publication, 26 May 2015; doi:10.1038/ajg.2015.150.
    No preview · Article · May 2015 · The American Journal of Gastroenterology
  • Henry A Erlich

    No preview · Article · Mar 2015 · Human Immunology
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    ABSTRACT: Recently, genome-wide association studies (GWAS) have been particularly successful in identifying vitiligo susceptibility loci in populations of European-derived white, Chinese, and Indian subcontinental ancestry (Spritz, 2013). The strongest genetic associations of vitiligo are in the major histocompatibility complex (MHC) on chromosome 6, both in terms of statistical significance and magnitude of effect (odds ratio; OR). However, the specific associated MHC loci and alleles differ among different world populations. In European-derived whites, vitiligo is associated with both MHC class I (HLA-A) and class II loci. On the Indian subcontinent, vitiligo is associated with MHC class II loci. In Han Chinese, vitiligo is associated with the class III region (Spritz, 2013).This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2015 · Pigment Cell & Melanoma Research
  • Article: P113

    No preview · Article · Oct 2014
  • Article: P106

    No preview · Article · Oct 2014
  • Article: P105

    No preview · Article · Oct 2014
  • Article: P108

    No preview · Article · Oct 2014
  • Article: OR37

    No preview · Article · Oct 2014

  • No preview · Conference Paper · Jul 2014
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    ABSTRACT: NK cells are innate immune cells known for their cytolytic activities toward tumors and infections. They are capable of expressing diverse killer Ig-like receptors (KIRs), and KIRs are implicated in susceptibility to Crohn's disease (CD), a chronic intestinal inflammatory disease. However, the cellular mechanism of this genetic contribution is unknown. In this study, we show that the "licensing" of NK cells, determined by the presence of KIR2DL3 and homozygous HLA-C1 in host genome, results in their cytokine reprogramming, which permits them to promote CD4(+) T cell activation and Th17 differentiation ex vivo. Microfluidic analysis of thousands of NK single cells and bulk secretions established that licensed NK cells are more polarized to proinflammatory cytokine production than unlicensed NK cells, including production of IFN-γ, TNF-α, CCL-5, and MIP-1β. Cytokines produced by licensed NK augmented CD4(+) T cell proliferation and IL-17A/IL-22 production. Ab blocking indicated a primary role for IFN-γ, TNF-α, and IL-6 in the augmented T cell-proliferative response. In conclusion, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel NK cytokine program that activates and induces proinflammatory CD4(+) T cells, thereby providing a potential biologic mechanism for KIR-associated susceptibility to CD and other chronic inflammatory diseases.
    Full-text · Article · Jun 2014 · The Journal of Immunology
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    ABSTRACT: The high-resolution human leukocyte antigen (HLA) genotyping assay that we developed using 454 sequencing and Conexio software uses generic polymerase chain reaction (PCR) primers for DRB exon 2. Occasionally, we observed low abundance DRB amplicon sequences that resulted from in vitro PCR 'crossing over' between DRB1 and DRB3/4/5. These hybrid sequences, revealed by the clonal sequencing property of the 454 system, were generally observed at a read depth of 5%-10% of the true alleles. They usually contained at least one mismatch with the IMGT/HLA database, and consequently, were easily recognizable and did not cause a problem for HLA genotyping. Sometimes, however, these artifactual sequences matched a rare allele and the automatic genotype assignment was incorrect. These observations raised two issues: (1) could PCR conditions be modified to reduce such artifacts? and (2) could some of the rare alleles listed in the IMGT/HLA database be artifacts rather than true alleles? Because PCR crossing over occurs during late cycles of PCR, we compared DRB genotypes resulting from 28 and (our standard) 35 cycles of PCR. For all 21 cell line DNAs amplified for 35 cycles, crossover products were detected. In 33% of the cases, these hybrid sequences corresponded to named alleles. With amplification for only 28 cycles, these artifactual sequences were not detectable. To investigate whether some rare alleles in the IMGT/HLA database might be due to PCR artifacts, we analyzed four samples obtained from the investigators who submitted the sequences. In three cases, the sequences were generated from true alleles. In one case, our 454 sequencing revealed an error in the previously submitted sequence.
    Full-text · Article · Jan 2014 · Tissue Antigens
  • Article: 46-OR

    No preview · Article · Nov 2013
  • Article: 21-OR

    No preview · Article · Nov 2013
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    ABSTRACT: Historically, association of disease with the major histocompatibility complex (HLA) genes has been tested with HLA alleles that encode antigen-binding affinity. The association with Parkinson disease (PD), however, was discovered with noncoding SNPs in a genome-wide association study (GWAS). We show here that several HLA-region SNPs that have since been associated with PD form two blocks tagged by rs3129882 (p = 9 × 10(-11)) and by rs9268515 and/or rs2395163 (p = 3 × 10(-11)). We investigated whether these SNP-associations were driven by HLA-alleles at adjacent loci. We imputed class I and class II HLA-alleles for 2000 PD cases and 1986 controls from the NeuroGenetics Research Consortium GWAS and sequenced a subset of 194 cases and 204 controls. We were therefore able to assess accuracy of two imputation algorithms against next-generation-sequencing while taking advantage of the larger imputed data sets for disease study. Additionally, we imputed HLA alleles for 843 cases and 856 controls from another GWAS for replication. PD risk was positively associated with the B(∗)07:02_C(∗)07:02_DRB5(∗)01_DRB1(∗)15:01_DQA1(∗)01:02_DQB1(∗)06:02 haplotype and negatively associated with the C(∗)03:04, DRB1(∗)04:04 and DQA1(∗)03:01 alleles. The risk haplotype and DQA1(∗)03:01 lost significance when conditioned on the SNPs, but C(∗)03:04 (OR = 0.72, p = 8 × 10(-6)) and DRB1(∗)04:04 (OR = 0.65, p = 4 × 10(-5)) remained significant. Similarly, rs3129882 and the closely linked rs9268515 and rs2395163 remained significant irrespective of HLA alleles. rs3129882 and rs2395163 are expression quantitative trait loci (eQTLs) for HLA-DR and HLA-DQ (9 × 10(-5) ≥ PeQTL ≥ 2 × 10(-79)), suggesting that HLA gene expression might influence PD. Our data suggest that PD is associated with both structural and regulatory elements in HLA. Furthermore, our study demonstrates that noncoding SNPs in the HLA region can be associated with disease irrespective of HLA alleles, and that observed associations with HLA alleles can sometimes be secondary to a noncoding variant.
    Full-text · Article · Oct 2013 · The American Journal of Human Genetics
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    ABSTRACT: Aim Next generation sequencing of HLA exonic amplicons with the 454 Life Sciences GS FLX System and Conexio AssignTM-ATF software provides high resolution, high throughput HLA genotyping for 8 class I and class II loci (Bentley et al., 20091, Holcomb et al., 20112). HLA typing of potential donors for Unrelated Bone Marrow Donor Registries requires using a subset of these loci at high sample throughput and low cost per sample. To maximize the throughput, we have incorporated the Fluidigm® Access ArrayTM system to simplify amplicon library preparation and allow the efficient introduction of MIDs (Multiplex Identifiers) or barcodes. Methods For this application, a streamlined amplicon sequencing workflow employing many different Multiplex Identifiers (MIDs) enables multiplexed sequencing of a large number of samples, allowing researchers to meet these cost targets. The Fluidigm® 48 x 48 Access ArrayTM system and the “4 primer” approach provides an efficient way to achieve parallel semi-automated genomic PCRs with simultaneous incorporation of 48 different MIDs corresponding to 48 genomic DNA samples, and up to 48 different primer pairs, making possible 2,304 reactions in one amplification run. Minimal volumes (calculated to be about 45% less cost per run) of reagents are used in this micro- fluidics-based system. During genomic PCR, the outer set of primers containing the MIDs and the 454 adaptor sequences are incorporated into the amplicons generated by the inner set of HLA specific primers containing a complementary “universal” Fluidigm tag. Pools of the resulting amplicons are used for emulsion PCR and clonal sequencing on the 454 GS FLX System, as well as genotyping with Conexio AssignTM-ATF software. Results Using the Access Array system, we have successfully (100% concordance with known genotypes) genotyped 192 samples with 8 primer pairs (covering exons 2 and 3 in HLA-A, B, C and Exon 2 in DRB1, DRB3/4/5 and DQB1) using 96 MIDs per region in a single GS FLX run on a 2 region PicoTiterPlate™ (PTP) and 96 samples using 48 MIDs per region in a 4 region PTP. An average of 166 and 137 sequence reads per amplicon were recovered respectively. We have also genotyped, in a single run, 96 samples at high resolution (14 primer pairs covering exons 2, 3, and 4 of the class I loci and exons 2 of DRB1,3/4/5, DQA1, DQB1, DPB1, and exon 3 of DQB1) recovering an average of 175 sequence reads per amplicon at 100% concordance. The system reduces the overall time for the entire process (192 samples) from 8 days for manual processing to about 4 days with 1 FTE.
    No preview · Article · May 2013
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    ABSTRACT: OBJECTIVE This study assessed the ability to distinguish between type 1 diabetes-affected individuals and their unaffected relatives using HLA and single nucleotide polymorphism (SNP) genotypes.RESEARCH DESIGN AND METHODS Eight models, ranging from only the high-risk DR3/DR4 genotype to all significantly associated HLA genotypes and two SNPs mapping to the cytotoxic T-cell-associated antigen-4 gene (CTLA4) and insulin (INS) genes, were fitted to high-resolution class I and class II HLA genotyping data for patients from the Type 1 Diabetes Genetics Consortium collection. Pairs of affected individuals and their unaffected siblings were divided into a "discovery" (n = 1,015 pairs) and a "validation" set (n = 318 pairs). The discriminating performance of various combinations of genetic information was estimated using receiver operating characteristic (ROC) curve analysis.RESULTSThe use of only the presence or absence of the high-risk DR3/DR4 genotype achieved very modest discriminating ability, yielding an area under the curve (AUC) of 0.62 in the discovery set and 0.59 in the validation set. The full model, which included HLA information from the class II loci DPB1, DRB1, DQB1, selected alleles from HLA class I loci A and B, and SNPs from the CTLA4 and INS genes, increased the AUC to 0.74 in the discovery set and to 0.71 in the validation set. A cost-effective alternative is proposed, using genotype information equivalent to typing four SNPs (DR3, DR4-DQB1*03:02, CTLA-4, and INS), which achieved an AUC of 0.72 in the discovery set and 0.69 in the validation set.CONCLUSIONS Genotyping data sufficient to tag DR3, DR4-DQB1*03:02, CTLA4, and INS was shown to distinguish between subjects with type 1 diabetes and their unaffected siblings adequately to achieve clinically utility to identify children in multiplex families to be considered for early intervention.
    Full-text · Article · Apr 2013 · Diabetes care

Publication Stats

61k Citations
3,689.58 Total Impact Points

Institutions

  • 2004-2015
    • Children's Hospital & Research Center Oakland
      Oakland, California, United States
    • Pontificia Universidad Catolica de Puerto Rico
      Ponce, Ponce, Puerto Rico
  • 1996-2015
    • Children's Hospital Oakland Research Institute
      Oakland, California, United States
  • 2001-2010
    • Anthony Nolan Research Institute
      Londinium, England, United Kingdom
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1992-2009
    • University of Geneva
      Genève, Geneva, Switzerland
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • University of California, Los Angeles
      • Department of Human Genetics
      Los Ángeles, California, United States
  • 2007
    • Medical University of Bialystok
      • Department of Endocrinology, Diabetology and Internal Medicine
      Belostok, Podlasie, Poland
  • 2006
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2000-2006
    • Roche
      • Department of Human Genetics
      Bâle, Basel-City, Switzerland
    • University of Florida
      • Department of Pathology, Immunology, and Laboratory Medicine
      Gainesville, Florida, United States
  • 1996-2005
    • University of Colorado
      • Barbara Davis Center for Childhood Diabetes
      Denver, Colorado, United States
  • 2003
    • Catholic University of Korea
      • Department of Internal Medicine
      Sŏul, Seoul, South Korea
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2001-2003
    • National Cancer Institute (USA)
      • • Division of Cancer Epidemiology and Genetics
      • • Occupational and Environmental Epidemiology
      Bethesda, MD, United States
  • 1980-2002
    • Stanford University
      • • Department of Health Research and Policy
      • • Department of Neurobiology
      Palo Alto, California, United States
    • Princeton University
      Princeton, New Jersey, United States
  • 1992-2001
    • University of California, Berkeley
      • Department of Integrative Biology
      Berkeley, California, United States
  • 1999
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 1990-1998
    • Uppsala University
      • Department of Immunology, Genetics and Pathology
      Uppsala, Uppsala, Sweden
  • 1995
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
    • NCI-Frederick
      Фредерик, Maryland, United States
    • Tel Aviv Sourasky Medical Center
      • Dermatology
      Tell Afif, Tel Aviv, Israel
  • 1994
    • College of Alameda
      Аламеда, California, United States
  • 1992-1994
    • Bernhard Nocht Institute for Tropical Medicine
      • Department of Molecular Medicine
      Hamburg, Hamburg, Germany
  • 1993
    • University of Vic
      Vic, Catalonia, Spain
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, California, United States
  • 1989
    • National Heart, Lung, and Blood Institute
      • Hematology Branch
      베서스다, Maryland, United States
  • 1988
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 1985-1988
    • University of Washington Seattle
      • Department of Pediatrics
      Seattle, WA, United States
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 1987
    • Virginia Mason Medical Center
      Seattle, Washington, United States
  • 1986
    • University of Wisconsin–Madison
      • Department of Human Oncology
      Madison, Wisconsin, United States
  • 1983-1985
    • Stanford Medicine
      Stanford, California, United States