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H A Erlich

Publications and source records attributed to H A Erlich.

At least 109 records · Page 6Linked to original sources
PubMed1994

Analysis of HLA class II haplotypes in the Cayapa Indians of Ecuador: a novel DRB1 allele reveals evidence for convergent evolution and balancing selection at position 86.

PCR amplification, oligonucleotide probe typing, and sequencing were used to analyze the HLA class II loci (DRB1, DQA1, DQB1, and DPB1) of an isolated South Amerindian tribe. Here we report HLA class II variation, including the identification of a new DRB1 allele, several novel DR/DQ haplotypes, and an unusual distribution of DPB1 alleles, among the Cayapa Indians (N = 100) of Ecuador. A general reduction of HLA class II allelic variation in the Cayapa is consistent with a population bottle-neck during the colonization of the Americas. The new Cayapa DRB1 allele, DRB1*08042, which arose by a G-->T point mutation in the parental DRB1*0802, contains a novel Val codon (GTT) at position 86. The generation of DRB1*08042 (Val-86) from DRB1*0802 (Gly-86) in the Cayapa, by a different mechanism than the (GT-->TG) change in the creation of DRB1*08041 (Val-86) from DRB1*0802 in Africa, implicates selection in the convergent evolution of position 86 DR beta variants. The DRB1*08042 allele has not been found in > 1,800 Amerindian haplotypes and thus presumably arose after the Cayapa separated from other South American Amerindians. Selection pressure for increased haplotype diversity can be inferred in the generation and maintenance of three new DRB1*08042 haplotypes and several novel DR/DQ haplotypes in this population. The DPB1 allelic distribution in the Cayapa is also extraordinary, with two alleles, DPB1*1401, a very rare allele in North American Amerindian populations, and DPB1*0402, the most common Amerindian DPB1 allele, constituting 89% of the Cayapa DPB1.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1994

PCR/oligonucleotide probe typing of HLA class II alleles in a Filipino population reveals an unusual distribution of HLA haplotypes.

We have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population by PCR amplification of the DRB1, DQB1, and DPB1 second-exon sequences from buccal swabs obtained from 124 family members and 53 unrelated individuals. The amplified DNA was typed by using nonradioactive sequence-specific oligonucleotide probes. Twenty-two different DRB1 alleles, including the novel Filipino *1105, and 46 different DRB1/DQB1 haplotypes, including the unusual DRB1*0405-DQB1*0503, were identified. An unusually high frequency (f = .383) of DPB1*0101, a rare allele in other Asian populations, was also observed. In addition, an unusual distribution of DRB1 alleles and haplotypes was seen in this population, with DR2 (f = .415) and DRB1*1502-DQB1*0502 (f = .233) present at high frequencies. This distribution of DRB1 alleles differs from the typical HLA population distribution, in which the allele frequencies are more evenly balanced. The distribution of HLA class II alleles and haplotypes in this Filipino population is different from that of other Asian and Pacific groups: of those populations studied to date; the Indonesian population is the most similar. DRB1*1502-DQB1*0502 was in strong linkage disequilibrium (D' = .41) with DPB1*0101 (f = .126, for the extended haplotype), which is consistent with selection for this DR, DQ, DP haplotype being responsible for the high frequency of these three class II alleles in this population.

Alleles↗
PubMed1993

Genetic factors in multiple sclerosis.

OBJECTIVE: To evaluate the role of candidate genes in the susceptibility to multiple sclerosis (MS) and describe the role of T-cell receptor (TCR) gene rearrangements in the MS brain lesion in identifying a major target of the immune response in this disease. DATA SOURCES: MEDLINE, bibliography review of published data, and unpublished studies. STUDY SELECTION: Published studies using novel molecular approaches to analyze the role of the major histocompatibility complex (MHC) and TCR gene complexes, as well as other candidate genes, in susceptibility to MS. We analyze epigenetic events involving TCR genes in individuals with MS and describe recent clinical trials in which immunotherapy has been attempted. DATA SYNTHESIS: Consistent with a polygenic model for disease predisposition, MHC and TCR gene associations with MS are relatively weak. Despite intensive research, no other putative "MS genes" have been firmly established. The analysis of TCR rearrangements in the brain lesion has helped to identify a major target of the immune response in MS. CONCLUSION: Understanding the genetic basis for autoimmune demyelination will offer new possibilities for the treatment of this illness.

Animals↗
PubMed1993

Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome.

To better define the genetic factors that predispose to primary Sjögren's syndrome (SS), we have used polymerase chain reaction in combination with oligonucleotide probe hybridization and DNA sequencing to analyze HLA-DRB1, -DQA1, -DQB1, and -DPB1 alleles in Caucasoid (California), Japanese (Tokyo), and Chinese (Shanghai and Beijing) SS patients. In comparison to local controls in each region, we found: 1) increased frequency of the predicted haplotype HLA-DRB1*0301-DRB3*0101-DQA1*0501-DQB1*0201 in Caucasoid patients (p < 0.001); 2) increased frequency of the predicted haplotype HLA-DRB1*0405-DRB4*0101-DQA1*0301-DQB1*0401 in Japanese patients (p < 0.05); 3) increased frequency of the predicted haplotype DRB1*0803-DQA1*0103-DQB1*0601 in Chinese patients (p < 0.05); and 4) no statistically significant association with DPB1 alleles in any group, although an increased number of Caucasoid and Japanese SS patients possessed DPB1*0301. Comparison of DNA sequences for the three disease-associated haplotypes in these ethnic groups revealed a shared region of predicted amino acids from positions 58 to 69 in the first domain of HLA-DQB1. These results extend previous studies by demonstrating that no single class II allele was associated with 1 degree SS in the different ethnic groups. However, a shared amino acid motif in the DQB1 first domain was present in each disease-associated haplotype.

Alleles↗
PubMed1993

Selection for T-cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system in which a restricted cellular immune response has been observed. In order to establish whether such T cell responses are likely to be antigen-specific particularly with regard to myelin basic protein (MBP), we analysed T-cell receptor (TCR) gene rearrangements directly from MS brain plaques, using the polymerase chain reaction on reverse transcribed messenger RNA, and compared these with TCR of previously described MBP-specific T cell clones from MS and the rat model experimental allergic encephalomyelitis. Rearranged V beta 5.2 genes were detected in the brains of all patients who were HLA DRB1*1501, DQA1*0102, DQB1*0602, DPB1*0401. The V beta 5.2-D beta-J beta sequences in these MS brain plaques revealed five motifs. One of the common motifs was identical to that described for the VDJ region of a V beta 5.2 T-cell clone. This clone was from an MS patient who was HLA DRB1*1501, DQB1*0602, DPB1*0401, and it was cytotoxic towards targets containing the MBP peptide 89-106 (ref. 1). The deduced amino-acid sequence of this VDJ rearrangement, Leu-Arg-Gly, has also been described in rat T cells cloned from experimental allergic encephalomyelitis lesions, which are specific for MBP peptide 87-99 (ref. 2). VDJ sequences with specificity for this MBP epitope constitute a large fraction (40%) of the TCR V beta 5.2 N(D)N rearrangements in MS lesions. The capacity of rat T cells with these VDJ sequences to cause experimental allergic encephalomyelitis and the prevalence of such sequences in demyelinated human lesions indicate that T cells with this rearranged TCR may be critical in MS.

Amino Acid Sequence↗
PubMed1993

MHC class II haplotypes and linkage disequilibrium in primates.

The loci encoding the major histocompatibility class II cell surface antigens DR, DQ, and DP exhibit a remarkable degree of allelic polymorphism. Strong linkage disequilibrium is also found between these loci in the human population. To study the evolutionary conservation of this disequilibrium the DQA1, DQB1, and DRB1-6 loci were analyzed in chimpanzee and gorilla by sequencing or/and oligonucleotide hybridization of PCR-amplified DNA. This analysis revealed several new DRB sequences. The distribution of DRB loci differs between human and nonhuman primate haplotypes, and the strong disequilibrium found on human haplotypes between alleles at DQA1 and DQB1 as well as between the DQ loci and the DRB1 locus was not detected in the nonhuman hominoids. Extensive recombination within and between the DR and DQ region appears to have occurred during the 3-7 million years since the divergence of the three species, resulting in little similarity of haplotypes between species. The strong disequilibrium found in the human species between these loci may either reflect haplotype-specific barriers to recombination, recent founder effects in the evolution of humans, or selection for specific haplotypes.

Amino Acid Sequence↗
PubMed1993

HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families.

The role of HLA class II alleles in genetic predisposition to insulin dependent diabetes mellitus (IDDM) was examined by PCR/oligonucleotide probe typing of 42 Mexican-American IDDM families derived from Hispanic Caucasians and Native Americans. All high risk haplotypes (HLA-DR3 and DR4) were of European origin while the most strongly protective haplotype (DRB1*1402) was Native American. Of the 16 DR-DQ DR4 haplotypes identified, only those bearing DQB1*0302 conferred risk; the DRB1 allele, however, also markedly influenced IDDM risk. The general pattern of neutral and protective haplotypes indicates that the presence of Asp-57 in the HLA-DQ beta chain does not confer IDDM protection per se and indicates that both DRB1 and DQB1 influence IDDM susceptibility as well as protection.

Alleles↗
PubMed1993

Association of HLA-DQB1*0201 with stiff-man syndrome.

Stiff-man syndrome (SMS) is a rare disorder of the central nervous system of probable autoimmune origin. Patients with SMS often have other autoimmune diseases, in particular type I (insulin-dependent) diabetes mellitus (IDDM). Approximately 60% of patients with SMS have high titers of autoantibodies against the enzyme glutamic acid decarboxylase. Similar to SMS, the majority of patients with IDDM have autoantibodies against glutamic acid decarboxylase at or before diabetes onset, although usually at a lower titer and with a different reaction pattern than patients with SMS. To investigate the immunogenetic basis of SMS, we HLA-typed 18 patients with the disease. Seventy-two percent carried the DQB1*0201 allele (13 of 18, P = 0.02 vs. 18 of 48 controls), indicating that SMS is associated with this allele. DQB1*0201 is also a susceptibility allele for IDDM and other autoimmune diseases. Patients with SMS carried the IDDM-protective DQB1*0602 allele and other sequence-related DQB1*06 alleles with the same frequency observed in controls. In contrast, these alleles are rarely found in IDDM. Five of 8 (62.5%) SMS patients lacking a DQB1*06 allele were diabetic in contrast to only 2 of 10 (20%) with a DQB1*06 allele (P = 0.08), suggesting that the presence of DQB1*0602 or other DQB1*06 alleles may be associated with a reduced prevalence of diabetes among patients with SMS.

Adult↗
PubMed1992

Polymorphism, recombination, and linkage disequilibrium within the HLA class II region.

Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individuals, have been typed for the HLA class II genes DRB1, DQA1, DQB1, and DPB1 using nonradioactive sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA. This population, which consists of 266 independent chromosomes, contains 27 DRB1, 7 DQA1, 12 DQB1, and 17 DPB1 alleles. Analysis of the distribution of allele frequencies using the homozygosity statistic, which gives an indication of past selection pressures, suggests that balancing selection has acted on the DRB1, DQA1, and DQB1 loci. The distribution of DPB1 alleles, however, suggests a different evolutionary past. Family data permits the estimation of recombination rates and the unambiguous assignment of haplotypes. No recombinants were found between DRB1, DQA1, and DQB1; however, recombinants were detected between DQB1 and DPB1, resulting in an estimated recombination fraction of greater than or equal to 0.008 +/- 0.004. Only 33 distinct DRB1-DQA1-DQB1 haplotypes were found in this population which illustrates the extreme nonrandom haplotypic association of alleles at these loci. A few of these haplotypes are unusual (previously unreported) for a Caucasian population and most likely result from past recombination events between the DR and DQ subregions. Examination of disequilibrium across the HLA region using these data and the available serologic HLA-A and HLA-B types of these samples shows that global disequilibrium between these loci declines with the recombination fraction, approaching statistic nonsignificance at the most distant interval, HLA-A to HLA-DP.DR-DQ haplotypes in linkage disequilibrium with DPB1 and B are noted and, finally, the evolutionary origin of certain class II haplotypes is addressed.

Base Sequence↗
PubMed1992

Genetic control of nonresponsiveness to hepatitis B virus vaccine by an extended HLA haplotype.

We previously reported evidence for a statistical association between the serologically determined HLA-Bw54, DR4 and DRw53 alleles and the non-immune responsiveness to hepatitis B virus surface antigen (HBsAg) in the Japanese population. To identify the locus and allele within the HLA region associated with the nonresponsiveness to HBsAg, serological HLA typing, DNA typing of HLA-DQ and DP alleles using amplified HLA genes and sequence-specific oligonucleotide probes, and restriction fragment length polymorphism (RFLP) analysis of the fourth component of complement (C4) genes were performed in healthy unrelated Japanese vaccinees who were immunized subcutaneously three times with plasma-derived HBsAg vaccine. In nonresponders to HBsAg, the frequencies of HLA-Bw54 cross-reactive epitope group (CREG); (Bw54, Bw55, Bw56 and other Bw22), C4 RFLP (6.5 kb + 12.0 kb), DR4, DRw53 and DQw4 (DQA1*0301-DQB1*0401) were increased and the frequencies of HLA-DR1, DRw6 and DQw1 were decreased as compared with those in healthy unrelated controls. Further analysis revealed that the coexistence of HLA-Bw54CREG and DR4-DRw53-DQw4 (DQA1*0301-DQB1*0401) was associated with the nonresponder group, whereas, donors positive for exclusively either Bw54 CREG or DR4-DRw53-DQw4 (DQA1*0301-DQB1*0401) were not associated with the nonresponder group. Because there is a strong linkage disequilibrium between HLA-Bw54CREG, C4 RFLP (6.5 kb + 12.0 kb) and HLA-DR4-DRw53-DQw4 (DQA1*0301-DQB1*0401) in the Japanese population, the extended HLA-Bw54CREG-C4 RFLP (6.5 kb + 12.0 kb)-DR4-DR-w53-DQw4 (DQA1*0301-DQB1*0401) haplotype may well control nonimmune responsiveness to HBsAg. This extended HLA haplotype controls nonresponsiveness as a dominant genetic trait because all ten heterozygotes and two of three probable homozygotes of this extended HLA haplotype were nonresponders.

Adult↗
PubMed1992

Preferential PCR amplification of alleles: mechanisms and solutions.

The preferential PCR amplification of one allele relative to another in a heterozygous sample could result in an incorrect or ambiguous genetic typing of that sample. There are several mechanisms that could potentially lead to such preferential PCR amplification. First, preferential amplification can result from significant GC% differences between alleles if the conditions of the reaction (denaturation temperature (Tden), duration at the Tden' salt and co-solvent concentrations, etc.) allow the denaturation of one allele but not the other (differential denaturation). For example, the DQa1.1, -1.2, and -1.3 alleles of the HLA-DQa locus do not amplify at a Tden < 89 degrees C; these same conditions still allow amplification of the DQa2, -3, and -4 alleles. However, no differences in amplification efficiency were found between the different HLA-DQa alleles when the Tden was set at the recommended Tden of 94 degrees C, even after as many as 102 cycles of amplification. Second, for PCR-based genetic typing systems in which the PCR products from different alleles differ in length, preferential amplification of the shorter allelic product can occur. Experiments in which the variable number tandem repeat (VNTR) marker D17S5 (YNZ22) was amplified under various conditions suggest that the smaller allelic products are amplified preferentially when Taq polymerase is limiting. Preferential amplification of VNTR alleles can also occur if the target DNA is sufficiently degraded. Third, when the initial number of genomes sampled is very small, stochastic fluctuation in the number of copies of each allele can result in what appears to be preferential amplification. Finally, less efficient priming of DNA synthesis of one allele versus another can occur because of mismatches between the primer and the specific allelic template, resulting in preferential amplification of the other allele. General strategies to avoid preferential amplification are discussed.

Alleles↗