Jill Hollenbach | University of California, San Francisco (original) (raw)

Papers by Jill Hollenbach

Research paper thumbnail of 1024-LBP: HLA DPA1∼DPB1 allele-level and motif-level haplotype frequencies of four US populations

Aim Recent data show that DP matching plays an important role in hematopoietic cell transplantati... more Aim Recent data show that DP matching plays an important role in hematopoietic cell transplantation. Our previous work demonstrated that in European Americans haplotypic associations for the DP heterodimer are determined by near complete linkage disequilibrium between amino acid motifs on DPA1 (pos 31) and DPB1 (pos 85–87). We aimed to generate motif and allele-level haplotype frequencies (HF) for four race groups to extend these insights to minorities. Methods We calculated DPA1∼DPB1 HF at allele and motif level from 16,802 Be the Match Registry® members typed by DNA methods, resolving phase, allelic and motif ambiguity using expectation maximization. Motif frequencies were calculated for position 31 on DPA1 and positions 85–87 on DPB1, which play a critical role in the P1 pocket of the peptide binding region. Normalized linkage disequilibrium (LD) was calculated on each haplotype (D′) and globally (Wn) for each population. Results The top three allele-level haplotypes in all popul...

Research paper thumbnail of 177-P: Association of HLA-DR-DQ haplotypes with juvenile idiopathic arthritis (JIA)

Aim: HLA-G plays an important role in the modulation of the maternal immune system during pregnan... more Aim: HLA-G plays an important role in the modulation of the maternal immune system during pregnancy and evidence of balancing selection acting at the promoter and 3'UTR regions has already been reported. Aiming at verifying the existence of selection acting in the HLA-G coding region in the Amazon Rainforest, exons 2, 3 and 4 were evaluated in 142 Amerindians from 5 isolated tribes that inhabit the Central Amazon.

Research paper thumbnail of Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations

The HLA system is the most polymorphic of all human genetic systems. The frequency of HLA class I... more The HLA system is the most polymorphic of all human genetic systems. The frequency of HLA class I alleles and their linkage disequilibrium patterns differ significantly among human populations as shown in studies using serologic methods. Many DNA-defined alleles with identical serotypes may have variable frequencies in different populations. We typed HLA-A, B, and C loci at the allele level by PCR-based methods in 1,296 unrelated subjects from five major outbred groups living in the U.S.A (African, AFAM; Caucasians, CAU; Asian, ORI; Hispanic, HIS, and North American Natives, NAI). We detected 46, 100 and 32 HLA-A, B, and C alleles, respectively. ORI and HIS presented more alleles at each of these loci. There was lack of correlation between the levels of heterozygosity and the number of alleles detected in each population. In AFAM, heterozygosity (Ͼ90%) is maximized at all class I loci. HLA-A had the lowest heterozygosity in all populations but CAU. Tight LD was observed between HLA-B and C alleles. AFAM had weaker or nonexistent associations between alleles of HLA-A and B than other populations. Analysis of the genetic distances between these and other populations showed a close relationship between specific US populations and a population from their original continents. ORI exhibited the largest genetic distance with all the other U.S. groups and were closer to NAI. Evidence of admixture with CAU was observed for AFAM and HIS. HIS also had significant frequencies of AFAM and Mexican Indian alleles. Differences in both LD and heterozygosity levels suggest distinct evolutionary histories of the HLA loci in the geographical regions from where the U.S. populations originated.

Research paper thumbnail of 16-OR: Analysis of the KIR in the CEPH diversity panel reveals evidence of selection on the telomeric portion of the gene cluster

Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) s... more Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their HLA ligands.

Research paper thumbnail of 14-OR: KIR2DL2/S2 in the absence of an HLA-C ligand is protective in Crohn's disease

Aim: The present study investigates the immunosuppressive activity of ILT3-Fc treatment on human ... more Aim: The present study investigates the immunosuppressive activity of ILT3-Fc treatment on human T cells in a humanized mouse model of islet transplantation.

Research paper thumbnail of KIR diversity in Māori and Polynesians: populations in which HLA-B is not a significant KIR ligand

Immunogenetics, 2014

HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system o... more HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system of ligands and receptors that individualize human immune systems in ways that improve the survival of individuals and populations. Human settlement of Oceania by island-hopping East and Southeast Asian migrants started ~3,500 years ago. Subsequently, New Zealand was reached ~750 years ago by ancestral Māori. To examine how this history impacted KIR and HLA diversity, and their functional interaction, we defined at high resolution the allelic and haplotype diversity of the 13 expressed KIR genes in 49 Māori and 34 Polynesians. Eighty KIR variants, including four 'new' alleles, were defined, as were 35 centromeric and 22 telomeric KIR region haplotypes, which combine to give >50 full-length KIR haplotypes. Two new and divergent variant KIR form part of a telomeric KIR haplotype, which appears derived from Papua New Guinea and was probably obtained by the Asian migrants en route t...

Research paper thumbnail of Co-evolution of Human Leukocyte Antigen (HLA) Class I Ligands with Killer-Cell Immunoglobulin-Like Receptors (KIR) in a Genetically Diverse Population of Sub-Saharan Africans

PLoS Genetics, 2013

Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) co... more Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1-14 functional ligandreceptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen.

Research paper thumbnail of HLA class II genotypes are not associated with age related macular degeneration in a case-control, population-based study

Human immunology, 2015

Multiple lines of evidence support an immunologic basis and genetic disposition for the developme... more Multiple lines of evidence support an immunologic basis and genetic disposition for the development of age-related macular degeneration (AMD). Comprehensive human leukocyte antigens (HLA) class II typing at four loci (DRB1, DQA1, DQB1, and DPB1) was assessed using next generation sequencing methods and tested for association with age-related macular degeneration (AMD) in a case-control study of 456 AMD cases and 499 controls from the population-based Study of Osteoporotic Fractures (SOF) cohort. No statistically significant associations were identified for any of the class II loci and a previously identified association between DRB1*13:01 was not replicated in this dataset. These results reported here suggest that common HLA class II genetic variation does not contribute to AMD disease risk.

Research paper thumbnail of SEQUENCE FEATURE VARIANT TYPE (SFVT) ANALYSIS OF THE HLA GENETIC ASSOCIATION IN JUVENILE IDIOPATHIC ARTHRITIS

Biocomputing 2010, 2009

The immune response HLA class II DRB1 gene provides the major genetic contribution to Juvenile Id... more The immune response HLA class II DRB1 gene provides the major genetic contribution to Juvenile Idiopathic Arthritis (JIA), with a hierarchy of predisposing through intermediate to protective effects. With JIA, and the many other HLA associated diseases, it is difficult to identify the combinations of biologically relevant amino acid (AA) residues directly involved in disease due to the high level of HLA polymorphism, the pattern of AA variability, including varying degrees of linkage disequilibrium (LD), and the fact that most HLA variation occurs at functionally important sites. In a subset of JIA patients with the clinical phenotype oligoarticularpersistent (OP), we have applied a recently developed novel approach to genetic association analyses with genes/proteins sub-divided into biologically relevant smaller sequence features (SFs), and their "alleles" which are called variant types (VTs). With SFVT analysis, association tests are performed on variation at biologically relevant SFs based on structural (e.g., beta-strand 1) and functional (e.g., peptide binding site) features of the protein. We have extended the SFVT analysis pipeline to additionally include pairwise comparisons of DRB1 alleles within serogroup classes, our extension of the Salamon Unique Combinations algorithm, and LD patterns of AA variability to evaluate the SFVT results; all of which contributed additional complementary information. With JIA-OP, we identified a set of single AA SFs, and SFs in which they occur, particularly pockets of the peptide binding site, that account for the major disease risk attributable to HLA DRB1. These are (in numeric order): AAs 13 (pockets 4 and 6), 37 and 57 (both pocket 9), 67 (pocket 7), 74 (pocket 4), and 86 (pocket 1), and to a lesser extent 30 (pockets 6 and 7) and 71 (pockets 4, 5, and 7).

Research paper thumbnail of Allele-Level Haplotype Frequencies and Pairwise Linkage Disequilibrium for 14 KIR Loci in 506 European-American Individuals

PLoS ONE, 2012

The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobuli... more The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5,KIR2DS3S5 and KIR2DS3S5,KIR2DL1, and telomeric KIR3DL1,KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.

Research paper thumbnail of 16 th IHIW: Immunogenomic Data-Management Methods. Report from the Immunogenomic Data Analysis Working Group (IDAWG)

International Journal of Immunogenetics, 2012

The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent... more The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent analysis of HLA and KIR data, and the sharing of those data among the immunogenomic and larger genomic communities. However, the data management approaches currently applied by immunogenomic researchers are not widely discussed or reported in the literature, and the effect of different approaches on data analyses is not known. With ASHI's support, the IDAWG developed a 45 question survey on HLA and KIR data generation, data management and data analysis practices. Survey questions detailed the loci genotyped, typing systems used, nomenclature versions reported, computer operating systems and software used to manage and transmit data, the approaches applied to resolve HLA ambiguity and the methods used for basic population-level analyses. Respondents were invited to demonstrate their HLA ambiguity resolution approaches in simulated data sets. By May 2012, 156 respondents from 35 nations had completed the survey. These survey respondents represent a broad sampling of the Immunogenomic community; 52% were European, 30% North American, 10% Asian, 4% South American and 4% from the Pacific. The project will continue in conjunction with the 17th Workshop, with the aim of developing community data sharing standards, ambiguity resolution documentation formats, single-task data Management tools and novel data analysis methods and applications. While additional project details and plans for the 17th IHIW will be forthcoming, we welcome the input and participation in these projects from the histocompatibility and immunogenetics community.

Research paper thumbnail of Susceptibility to Crohn’s disease is mediated by KIR2DL2/KIR2DL3 heterozygosity and the HLA-C ligand

Immunogenetics, 2009

In the present study, we investigated the relationship between the KIR loci and the genes encodin... more In the present study, we investigated the relationship between the KIR loci and the genes encoding their HLA ligands and genetic susceptibility to Crohn's disease (CD). Analyses of the interactions between KIR3DL1, KIR2DL1, KIR2DL2 and KIR2DL3 with their respective HLA ligands indicate that there is a protective effect for KIR2DL2 in the absence of its HLA ligand C1. Given that KIR2DL2 and KIR2DL3 segregate as alleles, we compared their genotypic distributions to expectations under Hardy-Weinberg Equilibrium (HWE) with regard to the HLA ligand C1 status. While all the genotypic distributions conform to expectations under HWE in controls, in C2 ligand homozygous cases there is significant deviation from HWE, with a reduction of KIR2DL2, KIR2DL3 heterozygotes. KIR2DL2, KIR2DL3 heterozygosity is the only genotypic combination that confers protection from CD. In addition to the protective effect (OR = 0.44, CI = 0.22-0.87; p = 0.018) observed in C2 ligand homozygotes, the KIR2DL2, KIR2DL3 genotype is predisposing (OR = 1.34, CI = 1.03-4.53; p = 0.031) in the presence of C1 ligand. A test for trend of HLA class I C ligand group genotypes with KIR2DL2, KIR2DL3 heterozygosity in cases and controls indicates that C1, C2 ligand group heterozygotes have an intermediate effect on predisposition. These results show for the first time that disease susceptibility may be related to heterozygosity at a specific KIR locus, and that HLA ligand genotype influences the relative effect of the KIR genotype.

Research paper thumbnail of A combined DPA1∼DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer

Research paper thumbnail of 220-P: Examination of HLA class II amino acid variation in juvenile idiopathic arthritis (JIA) implicates P4 with position 86

Human Immunology, 2009

Aim: To identify amino acid residues which are important in predisposition to JIA. Methods: High-... more Aim: To identify amino acid residues which are important in predisposition to JIA. Methods: High-resolution HLA class II typing was performed in a large cohort (n ϭ 820) of JIA patients and controls (n ϭ 273); the data are examined at the allele, genotype and haplotype level, and amino acid sequences between associated alleles and haplotypes are compared.

Research paper thumbnail of 15-OR: Report from the KIR anthropology component of the 15th international histocompatibility workshop

Human Immunology, 2009

Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) s... more Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their HLA ligands.

Research paper thumbnail of 8-OR

Human Immunology, 2012

ABSTRACT Aim A ‘Silver Standard’ for HLA data collection and reporting has been described at ImmP... more ABSTRACT Aim A ‘Silver Standard’ for HLA data collection and reporting has been described at ImmPort (immport.niaid.nih.gov, “Proposal for HLA Data Validation”) to address ambiguity resolution in the recording and reporting of HLA typing results. While standards are critical for HLA data interoperability, they are not meaningful until useful tools are developed and made available for community use. We are developing distributable tools that implement this silver standard. Here we describe the development a web service to create, update, and retrieve HLA typing data in standardized formats without the need for NMDP allele codes and the corresponding inherent introduction of new ambiguities. Methods ReST web services with HTTP negotiation are being developed employing a Java library that manages HLA typing data using standardized formats. These formats include the XML based Histoimmunogenetics Markup Language (HML) and a simple character-delimited string format (GL String) able to encode ambiguity within HLA typing. Resources are identified with a simple Uniform Resource Identifier (URI). Results The services build on a foundation of an open access database schema for IMGT/HLA reference sequence data (updated quarterly), and objects such as alleles, lists of alleles, haplotypes, genotypes, lists of genotypes and multi-locus unphased genotypes. Public services include creating, updating, and retrieving these objects. Content negotiation allows data retrieval in a variety of formats including GL String, HML, HTML, JSON, and QR Code. Conclusions The tools being developed here provide the HLA researcher, clinician and lab technician a common resource for managing HLA data in a standardized way. We envision these tools to augment workflows through creating new instances of HLA typing objects when needed, and retrieval of those objects and their associated metadata when called upon.

Research paper thumbnail of Juvenile idiopathic arthritis and HLA Class I and Class II interactions and age-at-onset effects

Arthritis & Rheumatism, 2010

Objective-To quantitate risk and study heterogeneity at high resolution for HLA in the most commo... more Objective-To quantitate risk and study heterogeneity at high resolution for HLA in the most common JIA subtypes, IgM RF negative polyarticular and oligoarticular. Four digit comprehensive HLA typing enabled great precision and a large cohort allowed for consideration of both age of onset and subtype.

Research paper thumbnail of Hardy-Weinberg Proportions Methods Manual Version 0.1. 2-(September 9, 2009)

immport.net

A. History B. Estimating allele frequencies: the method of gene (allele) counting C. The variance... more A. History B. Estimating allele frequencies: the method of gene (allele) counting C. The variance of the allele frequency estimates D. Derivation of Hardy-Weinberg proportions (HWP) E. Evolutionary implications of HW F. Two extreme examples showing fit and lack of fit to HWP G. Hardy-Weinberg equilibrium for an X-linked trait H. Estimation of allele frequency and carrier frequency for a recessive trait

Research paper thumbnail of Haplotype Estimation and Linkage Disequilibrium Methods Manual: Version 0.1. 8 (June 3, 2011)

immport.org, 2011

LD—linkage disequilibrium; LE—linkage equilibrium; n—# of individuals in a sample; NK—Natural Kil... more LD—linkage disequilibrium; LE—linkage equilibrium; n—# of individuals in a sample; NK—Natural Killer PyPop—www. pypop. org, www. ImmPort. org (Python for Population Genomics–PyPop, current release version 0.7. 0)(Lancaster et al. 2003, 2007a, 2007b, 2008; Lancaster 2006); r—the correlation coefficient between the allele frequency distributions at two bi-allelic loci denoted A and B, with r 2= D 2/[pA1pA2pB1pB2]; SIRE—self identified race/ethnicity Wn—also denoted WAB, the multi-allelic extension of the bi- ...

Research paper thumbnail of Validation of statistical imputation of allele-level multilocus phased genotypes from ambiguous HLA assignments

Tissue antigens, 2014

Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patie... more Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patient in hematopoietic stem cell transplantation (HSCT) is critical to outcome; however, methods for HLA genotyping of donors in unrelated stem cell registries often yield results with allelic and phase ambiguity and/or do not query all clinically relevant loci. We present and evaluate a statistical method for in silico imputation of HLA alleles and haplotypes in large ambiguous population data from the Be The Match(®) Registry. Our method builds on haplotype frequencies estimated from registry populations and exploits patterns of linkage disequilibrium (LD) across HLA haplotypes to infer high resolution HLA assignments. We performed validation on simulated and real population data from the Registry with non-trivial ambiguity content. While real population datasets caused some predictions to deviate from expectation, validations still showed high percent recall for imputed results with aver...

Research paper thumbnail of 1024-LBP: HLA DPA1∼DPB1 allele-level and motif-level haplotype frequencies of four US populations

Aim Recent data show that DP matching plays an important role in hematopoietic cell transplantati... more Aim Recent data show that DP matching plays an important role in hematopoietic cell transplantation. Our previous work demonstrated that in European Americans haplotypic associations for the DP heterodimer are determined by near complete linkage disequilibrium between amino acid motifs on DPA1 (pos 31) and DPB1 (pos 85–87). We aimed to generate motif and allele-level haplotype frequencies (HF) for four race groups to extend these insights to minorities. Methods We calculated DPA1∼DPB1 HF at allele and motif level from 16,802 Be the Match Registry® members typed by DNA methods, resolving phase, allelic and motif ambiguity using expectation maximization. Motif frequencies were calculated for position 31 on DPA1 and positions 85–87 on DPB1, which play a critical role in the P1 pocket of the peptide binding region. Normalized linkage disequilibrium (LD) was calculated on each haplotype (D′) and globally (Wn) for each population. Results The top three allele-level haplotypes in all popul...

Research paper thumbnail of 177-P: Association of HLA-DR-DQ haplotypes with juvenile idiopathic arthritis (JIA)

Aim: HLA-G plays an important role in the modulation of the maternal immune system during pregnan... more Aim: HLA-G plays an important role in the modulation of the maternal immune system during pregnancy and evidence of balancing selection acting at the promoter and 3'UTR regions has already been reported. Aiming at verifying the existence of selection acting in the HLA-G coding region in the Amazon Rainforest, exons 2, 3 and 4 were evaluated in 142 Amerindians from 5 isolated tribes that inhabit the Central Amazon.

Research paper thumbnail of Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations

The HLA system is the most polymorphic of all human genetic systems. The frequency of HLA class I... more The HLA system is the most polymorphic of all human genetic systems. The frequency of HLA class I alleles and their linkage disequilibrium patterns differ significantly among human populations as shown in studies using serologic methods. Many DNA-defined alleles with identical serotypes may have variable frequencies in different populations. We typed HLA-A, B, and C loci at the allele level by PCR-based methods in 1,296 unrelated subjects from five major outbred groups living in the U.S.A (African, AFAM; Caucasians, CAU; Asian, ORI; Hispanic, HIS, and North American Natives, NAI). We detected 46, 100 and 32 HLA-A, B, and C alleles, respectively. ORI and HIS presented more alleles at each of these loci. There was lack of correlation between the levels of heterozygosity and the number of alleles detected in each population. In AFAM, heterozygosity (Ͼ90%) is maximized at all class I loci. HLA-A had the lowest heterozygosity in all populations but CAU. Tight LD was observed between HLA-B and C alleles. AFAM had weaker or nonexistent associations between alleles of HLA-A and B than other populations. Analysis of the genetic distances between these and other populations showed a close relationship between specific US populations and a population from their original continents. ORI exhibited the largest genetic distance with all the other U.S. groups and were closer to NAI. Evidence of admixture with CAU was observed for AFAM and HIS. HIS also had significant frequencies of AFAM and Mexican Indian alleles. Differences in both LD and heterozygosity levels suggest distinct evolutionary histories of the HLA loci in the geographical regions from where the U.S. populations originated.

Research paper thumbnail of 16-OR: Analysis of the KIR in the CEPH diversity panel reveals evidence of selection on the telomeric portion of the gene cluster

Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) s... more Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their HLA ligands.

Research paper thumbnail of 14-OR: KIR2DL2/S2 in the absence of an HLA-C ligand is protective in Crohn's disease

Aim: The present study investigates the immunosuppressive activity of ILT3-Fc treatment on human ... more Aim: The present study investigates the immunosuppressive activity of ILT3-Fc treatment on human T cells in a humanized mouse model of islet transplantation.

Research paper thumbnail of KIR diversity in Māori and Polynesians: populations in which HLA-B is not a significant KIR ligand

Immunogenetics, 2014

HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system o... more HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system of ligands and receptors that individualize human immune systems in ways that improve the survival of individuals and populations. Human settlement of Oceania by island-hopping East and Southeast Asian migrants started ~3,500 years ago. Subsequently, New Zealand was reached ~750 years ago by ancestral Māori. To examine how this history impacted KIR and HLA diversity, and their functional interaction, we defined at high resolution the allelic and haplotype diversity of the 13 expressed KIR genes in 49 Māori and 34 Polynesians. Eighty KIR variants, including four 'new' alleles, were defined, as were 35 centromeric and 22 telomeric KIR region haplotypes, which combine to give >50 full-length KIR haplotypes. Two new and divergent variant KIR form part of a telomeric KIR haplotype, which appears derived from Papua New Guinea and was probably obtained by the Asian migrants en route t...

Research paper thumbnail of Co-evolution of Human Leukocyte Antigen (HLA) Class I Ligands with Killer-Cell Immunoglobulin-Like Receptors (KIR) in a Genetically Diverse Population of Sub-Saharan Africans

PLoS Genetics, 2013

Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) co... more Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1-14 functional ligandreceptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen.

Research paper thumbnail of HLA class II genotypes are not associated with age related macular degeneration in a case-control, population-based study

Human immunology, 2015

Multiple lines of evidence support an immunologic basis and genetic disposition for the developme... more Multiple lines of evidence support an immunologic basis and genetic disposition for the development of age-related macular degeneration (AMD). Comprehensive human leukocyte antigens (HLA) class II typing at four loci (DRB1, DQA1, DQB1, and DPB1) was assessed using next generation sequencing methods and tested for association with age-related macular degeneration (AMD) in a case-control study of 456 AMD cases and 499 controls from the population-based Study of Osteoporotic Fractures (SOF) cohort. No statistically significant associations were identified for any of the class II loci and a previously identified association between DRB1*13:01 was not replicated in this dataset. These results reported here suggest that common HLA class II genetic variation does not contribute to AMD disease risk.

Research paper thumbnail of SEQUENCE FEATURE VARIANT TYPE (SFVT) ANALYSIS OF THE HLA GENETIC ASSOCIATION IN JUVENILE IDIOPATHIC ARTHRITIS

Biocomputing 2010, 2009

The immune response HLA class II DRB1 gene provides the major genetic contribution to Juvenile Id... more The immune response HLA class II DRB1 gene provides the major genetic contribution to Juvenile Idiopathic Arthritis (JIA), with a hierarchy of predisposing through intermediate to protective effects. With JIA, and the many other HLA associated diseases, it is difficult to identify the combinations of biologically relevant amino acid (AA) residues directly involved in disease due to the high level of HLA polymorphism, the pattern of AA variability, including varying degrees of linkage disequilibrium (LD), and the fact that most HLA variation occurs at functionally important sites. In a subset of JIA patients with the clinical phenotype oligoarticularpersistent (OP), we have applied a recently developed novel approach to genetic association analyses with genes/proteins sub-divided into biologically relevant smaller sequence features (SFs), and their "alleles" which are called variant types (VTs). With SFVT analysis, association tests are performed on variation at biologically relevant SFs based on structural (e.g., beta-strand 1) and functional (e.g., peptide binding site) features of the protein. We have extended the SFVT analysis pipeline to additionally include pairwise comparisons of DRB1 alleles within serogroup classes, our extension of the Salamon Unique Combinations algorithm, and LD patterns of AA variability to evaluate the SFVT results; all of which contributed additional complementary information. With JIA-OP, we identified a set of single AA SFs, and SFs in which they occur, particularly pockets of the peptide binding site, that account for the major disease risk attributable to HLA DRB1. These are (in numeric order): AAs 13 (pockets 4 and 6), 37 and 57 (both pocket 9), 67 (pocket 7), 74 (pocket 4), and 86 (pocket 1), and to a lesser extent 30 (pockets 6 and 7) and 71 (pockets 4, 5, and 7).

Research paper thumbnail of Allele-Level Haplotype Frequencies and Pairwise Linkage Disequilibrium for 14 KIR Loci in 506 European-American Individuals

PLoS ONE, 2012

The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobuli... more The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5,KIR2DS3S5 and KIR2DS3S5,KIR2DL1, and telomeric KIR3DL1,KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.

Research paper thumbnail of 16 th IHIW: Immunogenomic Data-Management Methods. Report from the Immunogenomic Data Analysis Working Group (IDAWG)

International Journal of Immunogenetics, 2012

The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent... more The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent analysis of HLA and KIR data, and the sharing of those data among the immunogenomic and larger genomic communities. However, the data management approaches currently applied by immunogenomic researchers are not widely discussed or reported in the literature, and the effect of different approaches on data analyses is not known. With ASHI's support, the IDAWG developed a 45 question survey on HLA and KIR data generation, data management and data analysis practices. Survey questions detailed the loci genotyped, typing systems used, nomenclature versions reported, computer operating systems and software used to manage and transmit data, the approaches applied to resolve HLA ambiguity and the methods used for basic population-level analyses. Respondents were invited to demonstrate their HLA ambiguity resolution approaches in simulated data sets. By May 2012, 156 respondents from 35 nations had completed the survey. These survey respondents represent a broad sampling of the Immunogenomic community; 52% were European, 30% North American, 10% Asian, 4% South American and 4% from the Pacific. The project will continue in conjunction with the 17th Workshop, with the aim of developing community data sharing standards, ambiguity resolution documentation formats, single-task data Management tools and novel data analysis methods and applications. While additional project details and plans for the 17th IHIW will be forthcoming, we welcome the input and participation in these projects from the histocompatibility and immunogenetics community.

Research paper thumbnail of Susceptibility to Crohn’s disease is mediated by KIR2DL2/KIR2DL3 heterozygosity and the HLA-C ligand

Immunogenetics, 2009

In the present study, we investigated the relationship between the KIR loci and the genes encodin... more In the present study, we investigated the relationship between the KIR loci and the genes encoding their HLA ligands and genetic susceptibility to Crohn's disease (CD). Analyses of the interactions between KIR3DL1, KIR2DL1, KIR2DL2 and KIR2DL3 with their respective HLA ligands indicate that there is a protective effect for KIR2DL2 in the absence of its HLA ligand C1. Given that KIR2DL2 and KIR2DL3 segregate as alleles, we compared their genotypic distributions to expectations under Hardy-Weinberg Equilibrium (HWE) with regard to the HLA ligand C1 status. While all the genotypic distributions conform to expectations under HWE in controls, in C2 ligand homozygous cases there is significant deviation from HWE, with a reduction of KIR2DL2, KIR2DL3 heterozygotes. KIR2DL2, KIR2DL3 heterozygosity is the only genotypic combination that confers protection from CD. In addition to the protective effect (OR = 0.44, CI = 0.22-0.87; p = 0.018) observed in C2 ligand homozygotes, the KIR2DL2, KIR2DL3 genotype is predisposing (OR = 1.34, CI = 1.03-4.53; p = 0.031) in the presence of C1 ligand. A test for trend of HLA class I C ligand group genotypes with KIR2DL2, KIR2DL3 heterozygosity in cases and controls indicates that C1, C2 ligand group heterozygotes have an intermediate effect on predisposition. These results show for the first time that disease susceptibility may be related to heterozygosity at a specific KIR locus, and that HLA ligand genotype influences the relative effect of the KIR genotype.

Research paper thumbnail of A combined DPA1∼DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer

Research paper thumbnail of 220-P: Examination of HLA class II amino acid variation in juvenile idiopathic arthritis (JIA) implicates P4 with position 86

Human Immunology, 2009

Aim: To identify amino acid residues which are important in predisposition to JIA. Methods: High-... more Aim: To identify amino acid residues which are important in predisposition to JIA. Methods: High-resolution HLA class II typing was performed in a large cohort (n ϭ 820) of JIA patients and controls (n ϭ 273); the data are examined at the allele, genotype and haplotype level, and amino acid sequences between associated alleles and haplotypes are compared.

Research paper thumbnail of 15-OR: Report from the KIR anthropology component of the 15th international histocompatibility workshop

Human Immunology, 2009

Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) s... more Aim: The KIR Anthropology component of the 15th International Histocompatibility workshop (IHW) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their HLA ligands.

Research paper thumbnail of 8-OR

Human Immunology, 2012

ABSTRACT Aim A ‘Silver Standard’ for HLA data collection and reporting has been described at ImmP... more ABSTRACT Aim A ‘Silver Standard’ for HLA data collection and reporting has been described at ImmPort (immport.niaid.nih.gov, “Proposal for HLA Data Validation”) to address ambiguity resolution in the recording and reporting of HLA typing results. While standards are critical for HLA data interoperability, they are not meaningful until useful tools are developed and made available for community use. We are developing distributable tools that implement this silver standard. Here we describe the development a web service to create, update, and retrieve HLA typing data in standardized formats without the need for NMDP allele codes and the corresponding inherent introduction of new ambiguities. Methods ReST web services with HTTP negotiation are being developed employing a Java library that manages HLA typing data using standardized formats. These formats include the XML based Histoimmunogenetics Markup Language (HML) and a simple character-delimited string format (GL String) able to encode ambiguity within HLA typing. Resources are identified with a simple Uniform Resource Identifier (URI). Results The services build on a foundation of an open access database schema for IMGT/HLA reference sequence data (updated quarterly), and objects such as alleles, lists of alleles, haplotypes, genotypes, lists of genotypes and multi-locus unphased genotypes. Public services include creating, updating, and retrieving these objects. Content negotiation allows data retrieval in a variety of formats including GL String, HML, HTML, JSON, and QR Code. Conclusions The tools being developed here provide the HLA researcher, clinician and lab technician a common resource for managing HLA data in a standardized way. We envision these tools to augment workflows through creating new instances of HLA typing objects when needed, and retrieval of those objects and their associated metadata when called upon.

Research paper thumbnail of Juvenile idiopathic arthritis and HLA Class I and Class II interactions and age-at-onset effects

Arthritis & Rheumatism, 2010

Objective-To quantitate risk and study heterogeneity at high resolution for HLA in the most commo... more Objective-To quantitate risk and study heterogeneity at high resolution for HLA in the most common JIA subtypes, IgM RF negative polyarticular and oligoarticular. Four digit comprehensive HLA typing enabled great precision and a large cohort allowed for consideration of both age of onset and subtype.

Research paper thumbnail of Hardy-Weinberg Proportions Methods Manual Version 0.1. 2-(September 9, 2009)

immport.net

A. History B. Estimating allele frequencies: the method of gene (allele) counting C. The variance... more A. History B. Estimating allele frequencies: the method of gene (allele) counting C. The variance of the allele frequency estimates D. Derivation of Hardy-Weinberg proportions (HWP) E. Evolutionary implications of HW F. Two extreme examples showing fit and lack of fit to HWP G. Hardy-Weinberg equilibrium for an X-linked trait H. Estimation of allele frequency and carrier frequency for a recessive trait

Research paper thumbnail of Haplotype Estimation and Linkage Disequilibrium Methods Manual: Version 0.1. 8 (June 3, 2011)

immport.org, 2011

LD—linkage disequilibrium; LE—linkage equilibrium; n—# of individuals in a sample; NK—Natural Kil... more LD—linkage disequilibrium; LE—linkage equilibrium; n—# of individuals in a sample; NK—Natural Killer PyPop—www. pypop. org, www. ImmPort. org (Python for Population Genomics–PyPop, current release version 0.7. 0)(Lancaster et al. 2003, 2007a, 2007b, 2008; Lancaster 2006); r—the correlation coefficient between the allele frequency distributions at two bi-allelic loci denoted A and B, with r 2= D 2/[pA1pA2pB1pB2]; SIRE—self identified race/ethnicity Wn—also denoted WAB, the multi-allelic extension of the bi- ...

Research paper thumbnail of Validation of statistical imputation of allele-level multilocus phased genotypes from ambiguous HLA assignments

Tissue antigens, 2014

Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patie... more Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patient in hematopoietic stem cell transplantation (HSCT) is critical to outcome; however, methods for HLA genotyping of donors in unrelated stem cell registries often yield results with allelic and phase ambiguity and/or do not query all clinically relevant loci. We present and evaluate a statistical method for in silico imputation of HLA alleles and haplotypes in large ambiguous population data from the Be The Match(®) Registry. Our method builds on haplotype frequencies estimated from registry populations and exploits patterns of linkage disequilibrium (LD) across HLA haplotypes to infer high resolution HLA assignments. We performed validation on simulated and real population data from the Registry with non-trivial ambiguity content. While real population datasets caused some predictions to deviate from expectation, validations still showed high percent recall for imputed results with aver...