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Biomedical subjects

H A Erlich

Publications and source records attributed to H A Erlich.

At least 73 records · Page 4Linked to original sources
PubMed1996

Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY)

OBJECTIVE: To examine whether infant dietary exposure to cow's milk is associated with beta-cell autoimmunity (BCA), an early predictor of insulin-dependent diabetes mellitus (IDDM). SETTING: Denver, Colo. DESIGN: Cross-sectional with retrospective analysis. PARTICIPANTS: Between January 1994 and December 1995, 253 children from 171 families of persons with IDDM were screened for BCA. All children were between the ages of 9 months and 7 years. MAIN OUTCOME MEASURES: BCA was defined as elevated levels of insulin autoantibody, glutamic acid decarboxylase autoantibody, or insulinoma-associated islet tyrosine phosphatases autoantibody (IA-2) above the 99th percentile of 198 normal subjects. RESULTS: Eighteen cases of BCA were detected; 153 unrelated autoantibody-negative children were selected from the cohort as controls. There were no differences in the proportion of cases and controls who were exposed to cow's milk or foods containing cow's milk or to cereal, fruit and vegetable, or meat protein by 3 months or by 6 months of age. Children with BCA were breast-fed for a slightly longer duration than controls (median duration 10 vs 8 months, P=.07). CONCLUSIONS: These data suggest that early exposure to cow's milk or other dietary protein is not associated with BCA. This calls into question the importance of cow's milk avoidance as a preventive measure for IDDM.

Animals↗
PubMed1996

Beta-cell autoantibodies in infants and toddlers without IDDM relatives: diabetes autoimmunity study in the young (DAISY).

Little is known concerning the natural history of beta-cell autoimmunity in infants and toddlers, especially in those without a first degree IDDM relative. A population-based cohort of Colorado infants at increased IDDM risk due to their HLA genotype has been identified through a PCR-based HLA screening of cord blood and is being prospectively studied. We report the distribution of insulin (IAA), GAD65 (GAA), and ICA512 autoantibody levels in 312 children aged 9 months and in 131 children aged 15 months from this cohort, without family history of IDDM. The levels of IAA, GAA and ICA512 did not differ by the HLA genotype (DR3/4,DQB1*0302 vs. DR3/3, vs. DR2/DR4,DQB1*0302 vs. DRx/4,DQB1*0302, where x is not DR3 or DR2), by ethnicity (non-Hispanic whites vs. other ethnic groups), or by age (9 vs. 15 months). The 95th and 99th percentiles of the IAA distribution were respectively 40 and 61 nU/ml at the age of 9 months and 38 and 59 nU/ml at the age of 15 months. The 95th and 99th percentiles of the GAA distribution were respectively 0.020 and 0.046 at the age of 9 months and 0.022 and 0.098 at the age of 15 months. We propose to use IAA levels greater than 60 nU/ml and GAA index greater than 0.05 to define the presence of beta-cell autoimmunity in children younger than 2 years.

Alleles↗
PubMed1996

Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY).

Autoimmunity causing insulin-dependent diabetes mellitus (IDDM) begins in early childhood due to interactions between genes and unknown environmental factors that may be identified through follow-up of a large cohort of genetically susceptible children. Such a cohort has been established using a simple and rapid cord blood screening for HLA alleles. The DRB1 and DQB1 second exon sequences were co-amplified using the polymerase chain reaction and hybridized with single and pooled sequence-specific oligonucleotide probes. Four individual probes were used to detect the susceptibility alleles DRB1*03, DRB1*04, and DQB1*0302 as well as the usually protective DRB1*15/16 (DR2) alleles. In addition, pooled probes allow the distinction of DR3/3 from the DR3/x genotype (where x is neither DR2, 3, nor 4) and DR4/4 from DR4/x. Among 5000 newborns from the general Denver population, we have found the high-risk genotype (DRB1*03/ DRB1*04, DQB1*0302) to be present in 2.4% of non-Hispanic whites, 2.8% of Hispanics, and 1.6% of African Americans. The moderate-risk genotypes (DRB1*04, DQB1*0302/DRB1*04, DQB1*0302, DRB1*04, DQB1*0302/x, or DRB1*03/DRB1*03) are present in 17% of American non-Hispanic whites, 24% of Hispanics and in 10% of African Americans. These results demonstrate the feasibility of a large-scale newborn screening for genes associated with IDDM. The ultimate role for such a screening in future routine prediction and prevention of IDDM will depend on the availability of an effective and acceptable form of clinical intervention.

Asian People↗
PubMed1996

DNA-based HLA typing for cord blood stem cell transplantation.

Molecular analysis of the HLA loci has revealed a pattern of extensive sequence polymorphism. For the class II loci, the polymorphism is localized to the second exon, whereas for the class I loci, both the second and third exons are polymorphic. These polymorphic regions encode the peptide binding groove and appear to be functionally significant in terms of disease susceptibility and transplantation. However, much of this polymorphism cannot be detected by serologic HLA typing methods. DNA typing methods based on PCR amplification and hybridization with sequence-specific oligonucleotide (SSO) probes can distinguish the many allelic sequence variants identified at these loci. The use of arrays of immobilized SSO probes allows genetic typing at many polymorphic sequence motifs in a single PCR and single hybridization reaction, making possible the development of simple, robust, and automated tests. PCR-SSO probe typing of the HLA loci requires very little sample material, is capable of either general or fine discrimination of alleles, and can be used to detect maternal contamination of cord blood. The application of this approach to typing HLA class I and II loci is discussed with regard to hematopoietic transplantation therapy.

Female↗
PubMed1996

Rapid allelic diversification and intensified selection at antigen recognition sites of the Mhc class II DPB1 locus during hominoid evolution.

The evolution of polymorphism at the Mhc class II DPB1 locus was studied by comparison of chimpanzee (Pan troglodytes), pygmy chimpanzee (Pan paniscus), gorilla (Gorilla gorilla) and human DPB1 alleles. Extensive polymorphism was found in all hominoids. The clustering of sequences in the phylogenetic tree is consistent with rapid generation of the DPB1 polymorphism. Analysis of the substitution pattern for human alleles shows an excess of non-synonymous changes to synonymous changes at antigen recognition sites, indicating that the amino acid polymorphism at these sites is being maintained by selection. By contrast, no excess of nonsynonymous changes was found at the antigen recognition sites of nonhuman hominoid species. Thus, it appears that diversifying selection on the DPB1 polymorphism has intensified in the lineage leading to humans. No evidence was found for the existence of ancient allelic lineages predating the divergence of the hominoid species. The number of synonymous differences among DPB1 alleles is lower than among DQB1 and DRB1 alleles, indicative of a more recent origin for the DPB1 polymorphism and consistent with the more rapid evolution suggested by the phylogenetic tree.

Alleles↗
PubMed1996

Results of Expedicion Humana. I. Analysis of HLA class II (DRB1-DQA1-DPB1) alleles and DR-DQ haplotypes in nine Amerindian populations from Colombia.

HLA class II variation was analyzed in nine Native American populations of Colombia using PCR/SSOP typing methods. Under the auspices of the Expedition Humana, approximately 30 unrelated native Colombia Indian samples each from the Tule (NW Pacific Coast), Kogui (Sierra Nevada). Ijka (Sierra Nevada), Ingano (Amazonas), Coreguaje (Amazonas), Nukak (Amazonas), Waunana (Pacific), Embera (Pacific) and Sikuani (Northeastern Plains) were collected and analyzed at the DRBI, DQA1, DQB1 and DPB1 loci. The number of different DRB1, DQA1, DQB1 and DPB1 alleles in the Colombian Indians is markedly reduced in comparison with neighboring African Colombian populations, which exhibit a very high degree of class II variability, as discussed in an accompanying paper. In the Colombian Amerindian groups, DR2 (DRB1*1602), DR4 (DRB1*0407, *0404, *0403 AND *0411), DR6 (DRB1*1402) and DR8 (DRB1*0802) comprise > 95% of all DRB1 alleles. We also found an absence of DR3 in all populations, and DR1, DR7 and DR9 allelic groups were either very rare or absent. Each Colombian Amerindian population has a predominant DRB1 allele (f = approximately 0.22-0.65) and DRB1-DQA1-DQB1 haplotype. Several novel DR-DQ haplotypes were also found. At the DPB1 locus, DPB1*0402 (f = 0.28-0.82), *1401 (f = 0.03-0.45), and *3501 (f = 0.03-0.27), were the three most prevalent alleles, each population maintaining one of these three alleles as the predominant (f > 0.26) DPB1 allele. The reduction of diversity for the HLA class II alleles in the Colombian Indians is suggestive of a population bottleneck during the colonization of the Americans, with little to no subsequent admixture with neighboring African Colombian populations in the last approximately 300 years.

Colombia↗
PubMed1996

Results of Expedicion Humana. II. Analysis of HLA class II alleles in three African American populations from Colombia using the PCR/SSOP: identification of a novel DQB1*02 (*0203) allele.

PCR/SSOP typing methods were used to analyze the HLA Class II DRB1, DQA1, DQB1 and DPB1 loci of samples from three African American populations of Colombia. Forty samples from the Cauca (Pacific), and twenty samples each from the Choco (North Pacific Coast) and the Providencia (Caribbean island) populations, were collected and the Class II loci analyzed under the auspices of the Expedicion Humana. Despite the limited number of samples analyzed, the African Colombian populations exhibit a very high degree of class II polymorphism. A great diversity of DRB1 alleles was found, with representatives from all serological classes, including 19 DRB1 alleles in the Providencia, 16 in the Cauca and 14 in the Choco groups. In addition, a novel DQB1*02 allele (*0203) was found in two individuals from the Cauca population of the Pacific Coast. The sequence of the DQB1*0203 allele, associated with DR3, differs from DQB1*0201 by only one nucleotide substitution (C-->A) in the second position of codon 57, resulting in an Ala to Asp change. The addition of DQB1*0203 brings the total number of DQB1 alleles identified to date to 26. HLA class II diversity is much greater in these African Colombian populations than that seen in nearby Amerindian populations. Analysis of regional Colombian African American HLA population genetics is discussed with respect to the Colombian Amerindian HLA genetics described in an accompanying paper.

Alleles↗
PubMed1996

Association of HLA-DPB1*0301 with IDDM in Mexican-Americans.

Susceptibility to IDDM has been associated with specific alleles at the HLA class II loci in a variety of human populations. Previous studies among Mexican-Americans, a group ancestrally derived from Native Americans and Hispanic whites, showed that the DR4 haplotypes (DRB1*0405-DQB1*0302 and DRB1*0402-DQB1*0302) and the DR3 haplotype (DRB1*0301-DQB1*0201) were increased among patients and suggested a role for both DR and DQ alleles in susceptibility and resistance. Based on the analysis of 42 Mexican-American IDDM families and ethnically matched control subjects by polymerase chain reaction/sequence-specific oligonucleotide probe typing, we report an association of IDDM with the DPB1 allele, *0301 (relative risk = 6.6; P = 0.0012) in this population. The analysis of linkage disequilibrium patterns in this population indicates that the observed increased frequency in DPB1*0301 among patients cannot be attributed simply to linkage disequilibrium with high-risk DR-DQ haplotypes. These data suggest that in addition to alleles at the DRB1 and DQB1 loci, polymorphism at the DPB1 locus may also influence IDDM risk.

Cell Line, Transformed↗
PubMed1996

The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families.

We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB1*0302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB1*0302 and DQB1*0301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB1*1501-DQB1*0602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB1*1601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB1*0301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB1*0101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB1*0301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.

Adolescent↗
PubMed1995

Quantitative determination of bone marrow transplant engraftment using fluorescent polymerase chain reaction primers for human identity markers.

We have developed a quantitative, nonisotopic method using variable number tandem repeat (VNTR) and short tandem repeat (STR) markers for monitoring donor cell engraftment in marrow transplant recipients. Posttransplant DNA from the recipient is amplified with fluorescent polymerase chain reaction (PCR) primers for polymorphic markers that distinguish donor alleles from recipient alleles. The fluorescent PCR products are then separated on agarose or acrylamide gels on the Applied Biosystems 373A Sequencer (Foster City, CA). Using GeneScan 672 software (Applied Biosystems) to analyze the separated alleles, we can correlate allele peak areas to the percentage of donor or recipient DNA. We quantitate engraftment in a mixed chimeric sample by mixing pretransplant recipient and donor DNAs in a range of percentages and amplifying the mixtures to produce a standard curve. By amplifying and analyzing the posttransplant sample DNA(s), we can determine the extent of engraftment by interpolating the percent peak area of the informative allele(s) from this standard curve. This approach provides a precision of measurement ranging, depending on the marker, from 3.5% to 8.0% (percent coefficient of variation) and an accuracy of engraftment determination ranging from 97% to 99%, with a sensitivity of detection of 1% donor or recipient DNA. We retrospectively analyzed a panel of 32 patients and found seven to be informative for some degree of mixed chimerism, indicative of either residual normal host cells or leukemic relapse. An analysis of different cell lineages obtained posttransplant showed different degrees of engraftment in myeloid and T-cell populations. In summary, this method can provide an accurate, quantitative assessment of mixed chimerism in patients posttransplant. Such information may be useful in the future in guiding early implementation of additional treatment designed to circumvent graft failure or suppress relapse.

Base Sequence↗
PubMed1995

Comparison of human leukocyte antigen DR-DQ disease associations found with cervical dysplasia and invasive cervical carcinoma.

BACKGROUND: Human leukocyte antigen (HLA) molecules, whose biological role is in the regulation of immune responses to foreign antigens and in discrimination of self from non-self antigens, are encoded by a series of closely linked genetic loci found on chromosome 6. Although the evidence for a link between HLA and cervical cancer has been controversial, it has been recently reported that certain HLA class II haplotypes (linked class II alleles) are positively associated with invasive cervical cancer, while other class II haplotypes are negatively associated or protective. Since HLA associations between human papillomavirus type 16 (HPV16)-mediated cancer cases and non-HPV16-mediated cancer cases have been found to be different, this suggests that specific HLA class II haplotypes may influence the immune response to HPV infection and may affect the risk of acquiring invasive cervical carcinoma. PURPOSE: This study was conducted to determine if the same HLA class II haplotypes that are associated with invasive cervical carcinoma are also associated with cervical dysplasia (presumed precursors of invasive cervical cancer). METHODS: We have examined HLA DR-DQ haplotypes among 128 Hispanic women from New Mexico with biopsy-confirmed cervical dysplasia in a case-control study using sensitive DNA-based polymerase chain reaction amplification and sequence-specific oligonucleotide probe hybridization methods to detect the presence and type of HPV and to detect allelic polymorphism in the HLA DRB1 and DQB1 loci. RESULTS: Dysplasia cases were divided into two groups for comparison to controls: severe dysplasia/carcinoma in situ (CIS), and slight/moderate dysplasia. The frequency distribution of HLA class II haplotypes among the HPV16-positive severe dysplasia/CIS cases had a statistically significant (two-tailed P < .005) difference compared with controls, whereas haplotypes among the severe dysplasia/CIS cases containing HPV types other than HPV16 did not show statistically significant frequency differences. DR-DQ haplotypes previously found to be associated with HPV16-invasive cervical carcinomas were also associated with HPV16-positive severe dysplasia/CIS. However, no statistically significant haplotype frequency difference was observed between slight/moderate dysplasia cases and controls. In addition, we noted a DQA1-DQB1 haplotype negatively associated with severe dysplasia/CIS but not with invasive cervical cancers. CONCLUSIONS: Our results strongly suggest that certain HLA haplotypes confer an increased risk for severe cervical dysplasia and invasive cervical carcinoma following HPV16 infection. IMPLICATIONS: Further molecular studies are needed to identify HLA alleles or haplotypes that may provide increased susceptibility to HPV-associated cervical disease.

Adult↗
PubMed1995

Analysis of mutational changes at the HLA locus in single human sperm.

Using a simple and efficient single sperm PCR and direct sequencing method, we screened for HLA-DPB1 gene mutations that may give rise to new alleles at this highly polymorphic locus. More than 800 single sperm were studied from a heterozygous individual whose two alleles carried 16 nucleotide sequence differences clustered in six polymorphic regions. A potential microgene conversion event was detected. Unrepaired heteroduplex DNA similar to that which gives rise to postmeiotic segregation events in yeast was observed in three cases. Control experiments also revealed unusual sperm from DPB1 homozygous individuals. The data may help explain allelic diversity in the MHC and suggest that a possible source of human mosaicism may be incomplete DNA mismatch repair during gametogenesis.

Alleles↗
PubMed1995

HLA-B alleles of the Cayapa of Ecuador: new B39 and B15 alleles.

Recent data suggest that HLA-B locus alleles can evolve quickly in native South American populations. To investigate further this phenomenon of new HLA-B variants among Amerindians, we studied samples from another South American tribe, the Cayapa from Ecuador. We selected individuals for HLA-B molecular typing based upon their HLA class II typing results. Three new variants of HLA-B39 and one new variant of HLA-B15 were found in the Cayapa: HLA-B*3905, HLA-B*3906, HLA-B*3907, and HLA-B*1522. A total of thirteen new HLA-B alleles have now been found in the four South American tribes studied. Each of these four tribes studied, including the Cayapa, had novel alleles that were not found in any of the other tribes, suggesting that many of these new HLA-B alleles may have evolved since the Paleo-Indians originally populated South America. Each of these 13 new alleles contained predicted amino acid replacements that were located in the peptide binding site. These amino acid replacements may affect the sequence motif of the bound peptides, suggesting that these new alleles have been maintained by selection. New allelic variants have been found for all common HLA-B locus antigenic groups present in South American tribes with the exception of B48. In spite of its high frequency in South American tribes, no evidence for variants of B48 has been found in all the Amerindians studied, suggesting that B48 may have unique characteristics among the B locus alleles.

Alleles↗