Fifty years of HLA-associated type 1 diabetes risk: history, current knowledge, and future directions.

More than 50 years have elapsed since the association of human leukocyte antigens (HLA) with type 1 diabetes (T1D) was first reported. Since then, methods for identification of HLA have progressed from cell based to DNA based, and the number of recognized HLA variants has grown from a few to tens of thousands. Current genotyping methodology allows for exact identification of all HLA-encoding genes in an individual's genome, with statistical analysis methods evolving to digest the enormous amount of data that can be produced at an astonishing rate.

NKp44/HLA-DP-dependent regulation of CD8 effector T cells by NK cells.

Although natural killer (NK) cells are recognized for their modulation of immune responses, the mechanisms by which human NK cells mediate immune regulation are unclear. Here, we report that expression of human leukocyte antigen (HLA)-DP, a ligand for the activating NK cell receptor NKp44, is significantly upregulated on CD8 effector T cells, in particular in human cytomegalovirus (HCMV) individuals. HLA-DP CD8 T cells expressing NKp44-binding HLA-DP antigens activate NKp44 NK cells, while HLA-DP CD8 T cells not expressing NKp44-binding HLA-DP antigens do not.

Targeting hepatitis B vaccine escape using immunogenetics in Bangladeshi infants.

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens.

Clinical features, biochemistry, and HLA-DRB1 status in youth-onset type 1 diabetes in Mali.

Objective: Limited information is available regarding youth-onset diabetes in Mali. We investigated demographic, clinical, biochemical, and genetic features in new diabetes cases in children and adolescents.

Research Design And Methods: The study was conducted at Hôpital du Mali in Bamako.

HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes.

Aims/hypothesis: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes.

Methods: A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing.

Results: The susceptible DR3 (β = -0.

HLA class I and II associations with common enteric pathogens in the first year of life.

Background: genetic susceptibility to infection is mediated by numerous host factors, including the highly diverse, classical human leukocyte antigen (HLA) genes, which are critical genetic determinants of immunity. We systematically evaluated the effect of HLA alleles and haplotypes on susceptibility to 12 common enteric infections in children during the first year of life in an urban slum of Dhaka, Bangladesh.

Methods: a birth cohort of 601 Bangladeshi infants was prospectively monitored for diarrhoeal disease.

Clinical features, biochemistry, and HLA-DRB1 status in youth-onset type 1 diabetes in Sudan.

Objective: To further understand clinical and biochemical features, and HLA-DRB1 genotypes, in new cases of diabetes in Sudanese children and adolescents.

Research Design And Methods: Demographic characteristics, clinical information, and biochemical parameters (blood glucose, HbA1c, C-peptide, autoantibodies against glutamic acid decarboxylase 65 [GADA] and insulinoma-associated protein-2 [IA-2A], and HLA-DRB1) were assessed in 99 individuals <18 years, recently (<18 months) clinically diagnosed with T1D. HLA-DRB1 genotypes for 56 of these Arab individuals with T1D were compared to a mixed control group of 198 healthy Arab (75%) and African (25%) individuals without T1D.

Adult-onset type 1 diabetic patients with less severe clinical manifestation have less risk DR-DQ genotypes than childhood-onset patients.

Background: The aim of this study was to investigate differences in clinical features and HLA genotypes between adult-onset and childhood-onset patients with type 1 diabetes in a Chinese population.

Materials And Methods: This study enrolled 716 Han Chinese patients with type 1 diabetes from Guangdong (258 childhood-onset and 458 adult-onset) to compare their clinical features. Of them 214 patients with classical type 1 diabetes (100 childhood-onset and 114 adult-onset) were selected for HLA DR and DQ genotyping by next-generation sequencing.

Clinical features, biochemistry and HLA-DRB1 status in children and adolescents with diabetes in Dhaka, Bangladesh.

Aims: Little information is published on diabetes in young people in Bangladesh. We aimed to investigate the demographic, clinical, and biochemical features, and HLA-DRB1 alleles in new cases of diabetes affecting Bangladeshi children and adolescents <22 years of age.

Methods: The study was conducted at Bangladesh Institute of Research and Rehabilitation of Diabetes, Endocrine and Metabolic Disorders (BIRDEM) in Dhaka.

Genetic Variation Within the Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes.

Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci.

Clinical features, biochemistry and HLA-DRB1 status in youth-onset type 1 diabetes in Pakistan.

Published information on diabetes in Pakistani youth is limited. We aimed to investigate the demographic, clinical, and biochemical features, and HLA-DRB1 alleles in new cases of diabetes affecting children and adolescents <22 years of age. The study was conducted at Baqai Institute of Diabetology and Endocrinology in Karachi from June 2013-December 2015.

Mother-child histocompatibility and risk of rheumatoid arthritis and systemic lupus erythematosus among mothers.

The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags).

Epidemiology of childhood-onset type 1 diabetes in Azerbaijan: Incidence, clinical features, biochemistry, and HLA-DRB1 status.

Aims: Determine the incidence and typology of diabetes in children in Azerbaijan.

Methods: Clinical features, C-peptide, autoantibodies (glutamic acid decarboxylase 65 (GAD65) and islet antigen 2 (IA-2)), and HLA-DRB1 status were studied in 106 subjects <18 years of age who were recently diagnosed. 104 cases were consecutive.

Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans.

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population.

Identifying genetic risk loci for diabetic complications and showing evidence for heterogeneity of type 1 diabetes based on complications risk.

There is a growing body of evidence suggesting that type 1 diabetes (T1D) is a genetically heterogeneous disease. However, the extent of this heterogeneity, and what observations may distinguish different forms, is unclear. One indicator may be T1D-related microvascular complications (MVCs), which are familial, but occur in some families, and not others.

Increased risk of rheumatoid arthritis among mothers with children who carry risk-associated alleles.

Objective: To investigate whether a child's genotype affects a mother's risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles.

Methods: A case-control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acids (AAs) associated with RA including the 'shared epitope' (SE) and DERAA AA sequences at positions 70-74; AA valine, lysine and alanine at positions 11, 71 and 74 of HLA-DRB1; aspartic acid at position 9 of HLA-B and phenylalanine at position 9 of DPB1.

A Child's HLA-DRB1 genotype increases maternal risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) disproportionately affects women of reproductive age. During pregnancy, women are exposed to various sources of fetal material possibly constituting a significant immunologic exposure relevant to the development of SLE. The objective of this study was to investigate whether having any children who carry DRB1 alleles associated with SLE increase the risk of maternal SLE.

Predominance of DR3 in Somali children with type 1 diabetes in the twin cities, Minnesota.

Background: Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seeing increasing numbers of Somali children with diabetes.

Objective: To assess the immune basis of diabetes in Somali children in the Twin Cities, Minnesota.

Methods: A total of 31 Somali children ≤19 yr were treated for type 1 diabetes (T1D) at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota underwent analysis of human leukocyte antigen (HLA) alleles (n = 30) and diabetes autoantibodies [glutamic acid decarboxylase (GAD65), islet antigen 2 (IA-2), zinc transporter 8 (ZnT8); n = 31].

HAPCAD: An open-source tool to detect PCR crossovers in next-generation sequencing generated HLA data.

Next-generation sequencing (NGS) based HLA genotyping can generate PCR artifacts corresponding to IMGT/HLA Database alleles, for which multiple examples have been observed, including sequence corresponding to the HLA-DRB1(∗)03:42 allele. Repeat genotyping of 131 samples, previously genotyped as DRB1(∗)03:01 homozygotes using probe-based methods, resulted in the heterozygous call DRB1(∗)03:01+DRB1(∗)03:42. The apparent rare DRB1(∗)03:42 allele is hypothesized to be a "hybrid amplicon" generated by PCR crossover, a process in which a partial PCR product denatures from its template, anneals to a different allele template, and extends to completion.

Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins.

Genetic susceptibility to type 1 diabetes (T1D) is well supported by epidemiologic evidence; however, disease risk cannot be entirely explained by established genetic variants identified so far. This study addresses the question of whether epigenetic modification of the inherited DNA sequence may contribute to T1D susceptibility. Using the Infinium HumanMethylation450 BeadChip array (450k), a total of seven long-term disease-discordant monozygotic (MZ) twin pairs and five pairs of HLA-identical, disease-discordant non-twin siblings (NTS) were examined for associations between DNA methylation (DNAm) and T1D.

Linkage Analysis of Genomic Regions Contributing to the Expression of Type 1 Diabetes Microvascular Complications and Interaction with HLA.

We conducted linkage analysis to follow up earlier work on microvascular complications of type 1 diabetes (T1D). We analyzed 415 families (2,008 individuals) previously genotyped for 402 SNP markers spanning chromosome 6. We did linkage analysis for the phenotypes of retinopathy and nephropathy.

Immunogenetics of type 1 diabetes: A comprehensive review.

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta cells in the pancreas. Prevention of T1D will require the ability to detect and modulate the autoimmune process before the clinical onset of disease. Genetic screening is a logical first step in identification of future patients to test prevention strategies.

Concordance of next generation sequence-based and sequence specific oligonucleotide probe-based HLA-DRB1 genotyping.

Next generation sequencing (NGS) of clonally amplified DNA, using Roche 454 technology, was used to genotype HLA-DRB1, DRB3, DRB4, and DRB5 loci (exon 2 only) from a set of 993 samples from newborns with maternally-reported African American ancestry. DRB1 exon 2 was genotyped previously on the same sample set using sequence-specific oligonucleotide probe (SSOP) technology. Comparison of the genotype calls from both methods indicated concordance of 92.

DNA storage under high temperature conditions does not affect performance in human leukocyte antigen genotyping via next-generation sequencing (DNA integrity maintained in extreme conditions).

Background: Stable dry-state storage of DNA is desirable to minimize required storage space and to reduce electrical and shipping costs. DNA purified from various commercially available dry-state stabilization matrices has been used successfully in downstream molecular applications (e.g.