Biomedical subjects

Henry Erlich

Publications and source records attributed to Henry Erlich.

8 recordsLinked to original sources

PubMed2006

The Type 1 Diabetes Genetics Consortium.

The Type 1 Diabetes Genetics Consortium (T1DGC) is an international, multicenter program organized to promote research to identify genes and their alleles that determine an individual's risk for type 1 diabetes (T1D). The primary goal of the T1DGC is to establish resources and data that can be used by, and that is fully accessible to, the research community in the study of T1D. All the information on T1DGC can be accessed at the following web address: http://www.t1dgc.org. A resource base of well-characterized families is being assembled that will facilitate the localization and characterization of T1D susceptibility genes. From these families, the T1DGC is establishing banks of DNA, serum, plasma, and cell lines, as well as useful databases. The T1DGC also sponsors training opportunities (bioinformatics) and technology transfer (HLA genotyping).

Alleles↗

PubMed2005

Forensic casework analysis using the HVI/HVII mtDNA linear array assay.

The mitochondrial hypervariable regions I and II have proven to be a useful target for analysis of forensic materials, in which the amount of DNA is limited or highly degraded. Conventional mitochondrial DNA (mtDNA) sequencing can be time-consuming and expensive, limitations that can be minimized using a faster and less expensive typing assay. We have evaluated the exclusion capacity of the linear array mtDNA HVI/HVII region-sequence typing assay (Roche Applied Science) in 16 forensic cases comprising 90 samples. Using the HVI/HVII mtDNA linear array, 56% of the samples were excluded and thus less than half of the samples require further sequencing due to a match or inconclusive results. Of all the samples that were excluded by sequence analysis, 79% could be excluded using the HVI/HVII linear array alone. Using the HVI/HVII mtDNA linear array assay, we demonstrate the potential to decrease sequencing efforts substantially and thereby reduce the cost and the turn-around time in casework analysis.

Crime↗

PubMed2004

Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer.

Cervical cancer is a multifactorial disease and infection by oncogenic human papilloma viruses represents the main environmental risk factor. Only a subset of infections becomes persistent and develops into cancer, implying that genetic susceptibility factors are needed for malignant progression. Here, we use a population-based cohort of affected sib-pairs (ASPs) to examine the role of the human leukocyte antigen (HLA) class I and class II loci in cervical cancer susceptibility. Analysis of 278 ASPs revealed significant excess genetic sharing for all three HLA class II loci studied, DPB1, DQB1 and DRB1, with the strongest evidence for DQB1 and DRB1. No evidence of excess sharing was observed for the HLA class I HLA-B and HLA-A loci. When the material was stratified on the basis of the DQB1*0602/DRB1*1501 susceptibility haplotype, carriers showed significant sharing for all loci, whereas non-carriers showed no evidence of excess genetic sharing at any of the loci. However, for the DPB1 locus there was no difference in allele frequency between carriers and non-carriers indicating that the effect seen in DPB1 is not simply due to linkage disequilibrium. Our results show that the HLA class II represents a major genetic susceptibility locus to cervical cancer in contrary to the class I that do not appear to have a significant impact on predisposition to the disease. The strongest class II effects are coming from the DQB1 and DRB1 loci, but the DPB1 locus also contributes to the susceptibility to cervical cancer.

Cohort Studies↗

PubMed2003

An integrated haplotype map of the human major histocompatibility complex.

Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility. It is likely that a comprehensive analysis of the patterns of LD and variation, by using a high-density map of single-nucleotide polymorphisms (SNPs), would enable a greater understanding of the nature of the observed associations, as well as lead to the identification of causal variation. We present herein an initial analysis of this region, using 201 SNPs, nine classical HLA loci, two TAP genes, and 18 microsatellites. This analysis suggests that LD and variation in the MHC, aside from the classical HLA loci, are essentially no different from those in the rest of the genome. Furthermore, these data show that multi-SNP haplotypes will likely be a valuable means for refining association signals in this region.

Chromosome Mapping↗

PubMed2003

Advantage of rare HLA supertype in HIV disease progression.

The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.

Amino Acid Motifs↗

PubMed2003

A prospective study of the incidence of childhood celiac disease.

OBJECTIVES: To estimate the frequency of celiac disease (CD) in children in the general population of Denver, Colorado. STUDY DESIGN: From 22,346 newborns characterized as expressing 0, 1, or 2 HLA-DR3(DQB1*0201) alleles, 987 were selected for a prospective stratified cohort study. Participants were followed for as long as 7 years with serial testing for serum IgA anti-transglutaminase antibodies and for evidence of CD (intestinal mucosal changes or persistent seropositivity). RESULTS: Of 40 children with at least one positive serologic test, 19 had evidence of CD (10 by biopsy, 9 by persistent seropositivity). Those expressing 0, 1, or 2 HLA-DR3 alleles had, respectively, 0.3% (95% CI, 0.0-2.7), 3.4% (3.0-11.7), and 3.2% (1.0-11.0) risk for evidence of CD by age 5 years. The adjusted risk estimate for evidence of CD by age 5 years for the Denver general population was 0.9% (0.4-2.0), or 1 in 104 (1:49-221). After adjusting for number of HLA-DR3 alleles expressed, risk was higher in females: RR=3.34 (1.00-10.9, P=.048). Evidence of CD was not observed before age 2.6 years. CONCLUSIONS: Celiac disease may affect 0.9% of Denver children by 5 years of age. Children positive for the HLA-DR3 allele and females appear to be at increased risk.

Celiac Disease↗

PubMed2002

Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.

Alleles↗

PubMed2002

HLA-DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias.

OBJECTIVE: The HLA-DRB1 "shared epitope" (SE) genotypes are associated with rheumatoid arthritis (RA), but it remains controversial whether the association is with incidence, severity, or both, whether there are associations in seronegative patients, and whether different DRB1 alleles that contain the SE have similar effects on RA susceptibility and/or severity. The present study was undertaken to study these issues in a large cohort of patients with RA. METHODS: White patients with RA of <6 months' duration (n = 793) were enrolled in an inception cohort. HLA-DRB1 typing was performed, and patients were categorized into 21 DRB1 genotype groups. The disability index of the Health Assessment Questionnaire was the primary outcome measure. RESULTS: DRB1 associations in seronegative RA patients closely resembled those in controls. Of seropositive patients, 21% had 2 copies of the epitope, 52% had 1 copy, and 27% had none. However, not all genotypes with 1 copy were associated with increased susceptibility; for example, frequencies of DRB1*0404/X and *01/X did not differ from those in controls. Absolute differences between seropositive RA patients and controls were greatest for DRB1*0401 homozygosity (3.8% versus 0.8%, respectively) and *0401/0404 heterozygosity (4.7% versus 1.0%). DRB1*0404 was increased in frequency in seropositive RA but, unlike *0401, an increased frequency was seen only with 2 epitope copies. The relatively rare DRB1*10 had an unexpected association with seropositive RA, being present in 1.7% of seropositive RA patients and 0.7% of controls, and also showed a trend toward association with greater disease severity. The presence of 2 epitope copies was associated with increased frequency of seropositivity and younger age at disease onset, not with disease severity. Treatment indication bias was substantial and may have accounted for some of these effects. HLA-DRB1*0401/0404 was found much more frequently in men and in patients with a lower age at disease onset, and there was a trend toward a higher frequency of *0404/0401 in women. CONCLUSION: This large inception cohort study confirms previously identified major associations and provides additional insights. Only one dominant association was found: *0401, which differs from other SE alleles in a single Lys-for-Arg substitution. The association of the rare DRB1*10 allele has not previously been postulated. Sex associations were confirmed. Associations with seronegative RA were not seen. Not all genotypes containing an SE copy showed increased susceptibility to RA. The association of SE genotypes found in this study related to disease susceptibility rather than severity.

Alleles↗