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C Ober

Publications and source records attributed to C Ober.

At least 37 records · Page 2Linked to original sources
PubMed2000

HLA-G in reproduction: studies on the maternal-fetal interface.

For more than a decade, investigators have known that membrane-bound and soluble isoforms of the HLA class Ib molecule, HLA-G, are present at the maternal-fetal interface. Although it is clear that extravillous cytotrophoblast cells are major producers, other cells may also contribute. Recent studies in our laboratory raised the question of whether soluble isoforms might reach the maternal and/or fetal blood circulation. A capture enzyme-linked immunoabsorbent assay (ELISA) identified soluble HLA-G (sHLA-G) in maternal blood throughout pregnancy but failed to detect sHLA-G in cord sera. Further studies suggested that the circulating proteins may be either free heavy chain (sHLA-G1 and/or sHLA-G2) or exclusively sHLA-G2. To study the potential function(s) of the soluble isoforms to modulate local or systemic immunity in mothers, we generated recombinant sHLA-G1 and -G2 in both prokaryotic and eukaryotic systems. Preliminary experiments conducted using DNA microarray analysis suggest that sHLA-G is capable of modulating gene expression in blood mononuclear leukocytes. Potential local targets were also identified; decidual and placental macrophages but not trophoblast cells contained mRNA encoding two of the known receptors for HLA-G, ILT2 and ILT4. Collectively, the studies are consistent with the hypothesis that sHLA-G produced at the maternal-fetal interface targets to the cells of the monocyte/macrophage lineage and modulates their functions for the benefit of pregnancy.

Female↗
PubMed2000

Contributing factors to the pathobiology. The genetics of asthma.

Markers in 19 chromosomal regions have shown some evidence of linkage to asthma, atopy, or related phenotypes in multiple independent genome-wide searches. Linkages to five of these regions (5q, 6p, 11q, 12q, and 13q) have also been reported in non-genome-wide screens. In addition, at least two independent studies have reported linkages to markers on 16p. Numerous candidate genes in these regions have shown varying levels of association to asthma or atopic phenotypes, potentially implicating them as disease susceptibility loci. These include the IL4, CD14, and B2ADR genes on 5q, the HLA-DRB1 and TNF genes on 6p, the FCERB1 and CC16 genes on 11q, and the IL4RA gene on 16p. It still remains to be determined whether polymorphisms in these genes account for the reported linkages in these regions. Studies are underway in laboratories around the world to identify the disease-causing variations in these genes that account for the linkages just discussed. Identifying specific genetic polymorphisms that influence asthma and atopic phenotypes will shed light on the molecular pathways involved in these complex disorders and provide a better understanding of the pathophysiology of asthma and atopy.

Asthma↗
PubMed2000

A robust test for assortative mating.

Testing for random mating in human populations is difficult due to confounding factors such as ethnic preference and population stratification. With HLA, the high level of polymorphism is an additional problem since it is rare for couples to share the same haplotype. Focus on an ethnically homogeneous population, where levels of polymorphism at HLA loci are more limited, may provide the best situation in which to detect non-random mating. However, such populations are often genetic isolates where there may be inbreeding to an extent that is difficult to quantify and account for. We have developed a test for random mating at a multiallelic locus that is robust to stratification and inbreeding. This test relies on the availability of genotypic information from the parents of both spouses. The focus of the test is on families where there is allele sharing between the parents of both spouses, so that potential spouses could share an allele. Denoting the shared allele at the locus of interest by A, then under the assumption of random mating, heterozygous parents AX should transmit allele A equally as frequently as allele X to their offspring. When there is positive (negative) assortative mating, A will be transmitted more (less) often than X. The power of the test has been computed in a number of situations. Data on high resolution HLA haplotypes from the Hutterite population were reinvestigated by the proposed test. The test detects significant negative assortative mating when the parental origin of the shared haplotype is taken into account.

Alleles↗
PubMed2000

HLA-DRB1*01 alleles are associated with sensitization to cockroach allergens.

BACKGROUND: Sensitization to cockroach allergens is an important epidemiologic risk factor for asthma, particularly among African Americans living in urban environments. A recent genome screen in the Hutterites, a white founder population, identified a linkage between an HLA-linked marker and sensitization to cockroach allergens. OBJECTIVE: Our purpose was to determine whether alleles at one or more HLA loci are associated with sensitization to cockroach allergens in ethnically diverse populations. METHODS: Alleles at 14 HLA region loci were studied in the Hutterites. On the basis of these results, selected loci were examined in 54 African Americans with cockroach sensitization (cases) and 65 African Americans without cockroach sensitization (controls). Sensitivity to cockroach allergens was assessed in both samples by skin prick test to purified cockroach allergens (Periplaneta americana and Blatella germanica). RESULTS: Significant associations between cockroach allergies and DRB1*0101 (P(corrected) =.0066), DQA1*0101 (P(corrected) =.0012), and DQB1*0501 (P(corrected) =.00096) were detected in the Hutterites. In the African American sample, the most significant association was with the DRB1*0102 allele (P(corrected) =.0088, odds ratio 16.4, 95% confidence interval 2.0, 131). The DRB1*0101 allele was infrequent in the African American sample (frequency 0.06) and the DRB1*0102 allele was absent in the Hutterites. DRB1*0101 and DRB1*0102 are closely related alleles that differ from nearly all other DRB1 alleles at 3 amino acids in the 1 peptide binding domain of the HLA-DR molecule. CONCLUSIONS: The DRB1*0101 allele in the Hutterites and the DRB1*0102 allele in African Americans confer risk for cockroach sensitization. Elucidating this interaction at the molecular level may allow for more targeted treatment and prevention of atopic asthma in inner-city populations.

Adolescent↗
PubMed2000

Soluble HLA-G circulates in maternal blood during pregnancy.

OBJECTIVE: Soluble isoforms of the HLA class Ib gene HLA-G have been identified at the maternal-fetal interface. Because soluble forms of other HLA class I antigens modulate T-cell reactivity and induce cellactivated apoptosis, our goal was to determine whether soluble HLA-G circulates in maternal or fetal blood and to identify the specific isoform. STUDY DESIGN: Capture enzyme-linked immunosorbent assays with mouse monoclonal antibodies directed toward an epitope present on all isoforms of soluble HLA-G were constructed to identify soluble HLA-G in 44 serum samples from nonpregnant control subjects, 129 serum samples from pregnant women, and 10 samples of term cord blood. Distinguishing between soluble HLA-G1, which is composed of heavy chains complexed with light chains (beta(2)-microglobulin), and soluble HLA-G2, which consists only of heavy chains, was achieved by substituting a monoclonal antibody that requires beta(2)-microglobulin for binding (W6/32) in the capture phase of the enzyme-linked immunosorbent assay. RESULTS: Capture enzyme-linked immunosorbent assays with mouse anti-soluble HLA-G showed that soluble HLA-G was present at all stages of gestation and that levels of soluble HLA-G were statistically significantly higher in serum samples from pregnant women than in serum samples from nonpregnant women. In contrast, W6/32 failed to detect soluble HLA-G in serum samples from pregnant women. Cord serum samples did not contain detectable soluble HLA-G. CONCLUSION: Collectively, the data indicate that pregnancy is characterized by the presence of soluble HLA-G circulating in maternal blood and strongly suggest that the major isoform is soluble HLA-G2.

Animals↗
PubMed2000

Estimation of variance components of quantitative traits in inbred populations.

Use of variance-component estimation for mapping of quantitative-trait loci in humans is a subject of great current interest. When only trait values, not genotypic information, are considered, variance-component estimation can also be used to estimate heritability of a quantitative trait. Inbred pedigrees present special challenges for variance-component estimation. First, there are more variance components to be estimated in the inbred case, even for a relatively simple model including additive, dominance, and environmental effects. Second, more identity coefficients need to be calculated from an inbred pedigree in order to perform the estimation, and these are computationally more difficult to obtain in the inbred than in the outbred case. As a result, inbreeding effects have generally been ignored in practice. We describe here the calculation of identity coefficients and estimation of variance components of quantitative traits in large inbred pedigrees, using the example of HDL in the Hutterites. We use a multivariate normal model for the genetic effects, extending the central-limit theorem of Lange to allow for both inbreeding and dominance under the assumptions of our variance-component model. We use simulated examples to give an indication of under what conditions one has the power to detect the additional variance components and to examine their impact on variance-component estimation. We discuss the implications for mapping and heritability estimation by use of variance components in inbred populations.

Algorithms↗
PubMed2000

Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations.

After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.

Alleles↗
PubMed2000

beta(2)-adrenergic receptor Arg16/Arg16 genotype is associated with reduced lung function, but not with asthma, in the Hutterites.

In a genome-wide screen for asthma loci in the Hutterites, a marker locus on chromosome 5q23-31 showed evidence of linkage to asthma (C. Ober and colleagues, Hum. Molec. Genet. 1998;7:1393). To determine whether the beta(2)-adrenergic receptor (beta(2)AR) gene is the 5q-linked asthma locus in the Hutterites, we genotyped this sample for polymorphisms in the beta(2)AR gene. Neither the Arg16Gly nor Gln27Glu polymorphisms showed evidence of linkage to qualitative measures of asthma and bronchial hyperresponsiveness (BHR) (p > 0.10) or to quantitative measures of serum IgE and airway reactivity (p > 0.10). In contrast, FEV(1) percentage of predicted and FVC percentage of predicted were significantly lower among individuals homozygous for the Arg16 allele (FEV(1) %: 98.3 +/- 13.2% versus 103. 8 +/- 14.9%, p = 0.003; FVC %: 104.2 +/- 12.3% versus 108.3 +/- 13. 2%, p = 0.02 by t test). These findings held true for adolescents and adults, but not for children </= 12 yr of age. This study demonstrates that the observed linkage to asthma in the 5q23-31 region is unrelated to variation in the beta(2)AR gene. However, it is the first study to suggest that the beta(2)AR Arg16Gly polymorphism influences either lung growth or the rate of decline of lung function with age.

Adult↗
PubMed1999

Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial.

BACKGROUND: Couples with unexplained recurrent miscarriage may have an alloimmune abnormality that prevents the mother from developing immune responses essential for the survival of the genetically foreign conceptus. Immunisation with paternal mononuclear cells is used as a treatment for such alloimmune-mediated pregnancy losses. However, the published results on this treatment are conflicting. In this study (the Recurrent Miscarriage [REMIS] Study), we investigated whether paternal mononuclear cell immunisation improves the rate of successful pregnancies. METHODS: Women who had had three or more spontaneous abortions of unknown cause were enrolled in a double-blind, multicentre, randomised clinical trial. 91 were assigned immunisation with paternal mononuclear cells (treatment) and 92 immunisation with sterile saline (control). The primary outcomes were the inability to achieve pregnancy within 12 months of randomisation, or a pregnancy which terminated before 28 weeks of gestation (failure); and pregnancy of 28 or more weeks of gestation (success). Two analyses were done: one included all women (intention to treat), and the other included only those who became pregnant. FINDINGS: Two women in each group received no treatment, and eight (three treatment, five control) were censored after an interim analysis. In the analysis of all randomised women who completed the trial, the success rate was 31/86 (36%) in the treatment group and 41/85 (48%) in the control group (odds ratio 0.60 [95% CI 0.33-1.12], p=0.108). In the analysis of pregnant women only, the corresponding success rates were 31/68 (46%) and 41/63 (65%; odds ratio 0.45 [0.22-0.91], p=0.026). The results were unchanged after adjustment for maternal age, number of previous miscarriages, and whether or not the couple had had a previous viable pregnancy. Similar results were obtained in a subgroup analysis of 133 couples with no previous livebirth. INTERPRETATION: Immunisation with paternal mononuclear cells does not improve pregnancy outcome in women with unexplained recurrent miscarriage. This therapy should not be offered as a treatment for pregnancy loss.

Abortion, Habitual↗
PubMed1999

Effect of inbreeding avoidance on Hardy-Weinberg expectations: examples of neutral and selected loci.

Although all human populations avoid close inbreeding, the effect of inbreeding avoidance on genotype proportions has not been formally considered. This paper examines the expected proportions of genotype frequencies after adjusting the Hardy-Weinberg model for close inbreeding avoidance in an inbred population. This corrected model was used to evaluate genotype distributions for HLA haplotypes and haplotypes created from three microsatellite loci on human chromosome 13 in a sample of 315 married Hutterites. In this sample, there were five individuals who were homozygous for an HLA haplotype and 15 individuals who were homozygous for a chromosome 13 haplotype. The expected numbers of homozygotes were 21 for HLA and 26 for chromosome 13 haplotypes using a model adjusted for overall inbreeding (P = 0.00031 for HLA and P = 0.019 for chromosome 13) and 18 for HLA and 22 chromosome 13 haplotypes using a model adjusted for both overall inbreeding and close inbreeding avoidance (P = 0. 0016 for HLA and P = 0.099 for chromosome 13). The model that takes into account both overall inbreeding and inbreeding avoidance provided a better fit to the observed genotype distributions for chromosome 13 haplotypes (P = 0.099), suggesting that nonrandom aspects of Hutterite mating structure, other than inbreeding and inbreeding avoidance, have small effects on genotype distributions in the population. The fact that significant deficiencies of HLA homozygotes persist after taking into account inbreeding avoidance further suggests that factors related to the HLA haplotype per se influence the genotype proportions at HLA loci in the Hutterites.

Adult↗
PubMed1999

Ancestral and recombinant 16-locus HLA haplotypes in the Hutterites.

Prior studies in the Schmiedeleut Hutterites of South Dakota have demonstrated associations between human leukocyte antigen (HLA) haplotype matching and fetal loss (Ober et al. 1992) and mate preferences (Ober et al. 1997), as well as deficiencies of homozygotes for HLA haplotypes (Kostyu et al. 1993). These studies were based on the serologically-defined five-locus HLA-A, -C, -B, -DR, -DQ haplotype. To further elucidate the effects of specific major histocompatibility (MHC) loci or regions on fetal loss and mate choice, we genotyped a sample of Hutterites for 14 MHC loci by DNA or biochemical methods. Typing for additional loci in the HLA-A to HLA-DPB1 region increased the number of recognized Hutterite MHC haplotypes to 67, and further localized the site of crossover in 9 of 15 recombinant haplotypes. Hutterite MHC haplotype sequences are similar to those observed in outbred Caucasians, suggesting that the influence of HLA haplotypes on fetal loss and mating structure may be general.

Alleles↗
PubMed1999

Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides.

The expression of the Duffy Antigen/Receptor for Chemokines (DARC) on red blood cells (RBC) has been commonly determined using hemagglutination tests. Because the vast majority of African individuals are Duffy-negative, screening for DARC expression on RBC is a valuable tool to assess Caucasian admixture in populations of African descent. Furthermore, blood group antigens have been frequently tested as potential risk factors for complex diseases. We established a dot-blotting protocol using sequence-specific oligonucleotides (SSOs) for the DARC-46T ("Duffy-positive") and -46C ("Duffy-negative") alleles. With this method, but not with serological methods, Duffy-positive individuals can be further characterized as homozygous or heterozygous for the dominant Duffy-positive allele, allowing more precise estimation of allele frequencies and admixture in heterogeneous populations. In unrelated African American (n = 235), Afro-Caribbean (n = 90) and Colombian (n = 93) subjects, the frequency of the -46T allele was 21.7%, 12.2% and 74.7%, respectively. The percentage of Duffy-positive individuals (homozygous or heterozygous for the -46T allele) in each population was in accordance with published frequencies. As expected, the -46C allele was not detected in 20 Caucasian subjects. This sensitive and specific method allows for the rapid and inexpensive screening of large samples for Duffy genotypes using small quantities of genomic DNA.

Alleles↗
PubMed1999

Inbreeding effects on fertility in humans: evidence for reproductive compensation.

The effects of inbreeding on prereproductive mortality have been demonstrated in many natural populations, including humans. However, little is known about the effects in inbred individuals who survive to adulthood. We have investigated the effects of inbreeding on fertility among inbred adult Hutterites and demonstrate significantly reduced fecundity among the most inbred Hutterite women, as evidenced by longer interbirth intervals (P=.024) and longer intervals to a recognized pregnancy (P=.010) but not by increased rates of fetal loss (P>.50). These data suggest the presence of recessive alleles that adversely affect fecundity among the population. In contrast, completed family sizes do not differ among the more and the less-inbred Hutterite women who were born after 1920, suggesting that reproductive compensation is occurring among the more-inbred and less-fecund women. This recent reproductive strategy would facilitate the maintenance of recessive alleles and contribute to an overall decline in fertility in the population.

Adult↗
PubMed1999

The CTLA-4 gene is expressed in placental fibroblasts.

In order to elucidate the mechanisms that ensure survival of the allogeneic fetus, we are investigating the expression pattern of genes that are involved in peripheral self-tolerance in tissues at the maternal-fetal interface. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a negative regulator of T cell activation and may modulate peripheral self-tolerance. Previously, we reported the preferential transmission of maternally-inherited shorter alleles at a 3'-UTR microsatellite locus to liveborn children, but random transmission of paternally-inherited alleles, suggesting that CTLA-4 may be involved in the maintenance of tolerance at the maternal-fetal interface. In this report, we demonstrate that CTLA-4 mRNA and protein are indeed expressed in fetal tissues at the maternal-fetal interface throughout gestation.

Abatacept↗
PubMed1999

Genome-wide screen for atopy susceptibility alleles in the Hutterites.

A genome-wide screen for loci influencing positive skin prick tests (SPT) to airborne allergens was conducted in the Hutterites, a founder population of European ancestry. Positive SPT to 14 standardized allergens was measured in 370 subjects in our primary sample and 324 subjects in a replication sample. Evidence for linkage to positive SPT was assessed using the transmission disequilibrium test (TDT) with 337 autosomal markers (average spacing 9.13 cM, SD = 7.8 cM). Three loci showed the strongest overall evidence of linkage to atopy, with at least one allele-specific and a locus-specific p< 1 x 10(-4). This study provides evidence for at least three atopy-susceptibility loci in the Hutterites on chromosomes 1, 6 and 16.

Adult↗
PubMed1998

Expression and cytogenetic localization of the human SM22 gene (TAGLN).

SM22 is a 22-kDa protein identified variously as SM22, transgelin, WS3-10, or mouse p27. Though its precise function is unknown, it is abundant in smooth muscle and so may contribute to the physiology of this widespread tissue. We found that cosmid 16b6 contains the entire 5.4-kb, five-exon human SM22 gene (HGMW-approved symbol, TAGLN), and we cytogenetically localized the gene to chromosome 11q23.2. Northern analysis of human adult tissues showed that SM22 mRNA is most prevalent in smooth muscle-containing tissues, but is also found at lower levels in heart. The human SM22 promoter contains nuclear factor-binding motifs known to regulate transcription in smooth muscle, and human SM22 promoter-luciferase reporter constructs exhibited high transcriptional activity in A7r5 or primary canine aortic smooth muscle cells, but show little activity in nonmuscle COS7 cells. In addition, human SM22 promoter activity increased by two- to threefold upon serum stimulation of nonmuscle cells.

Adult↗
PubMed1998

Microchimerism and HLA-compatible relationships of pregnancy in scleroderma.

BACKGROUND: Fetal cells can be found in the maternal circulation in most pregnancies. Fetal progenitor cells have been found to persist in the circulation of women many years after childbirth. We tested the hypothesis that microchimerism is involved in the pathogenesis of scleroderma. Scleroderma is of interest because of a strong female predilection, an increased incidence in the years after childbearing, and clinical similarities between scleroderma and chronic graft-versus-host disease after allogeneic bone-marrow transplantation. We also investigated whether HLA-compatibility of a child was associated with later development of scleroderma in the mother. METHODS: We enrolled 40 women who had previously given birth to at least one son--16 healthy controls, 17 scleroderma patients, and seven healthy sisters of patients. We used quantitative PCR to amplify a Y-chromosome-specific sequence in whole peripheral blood from these women. Also 32 controls with 58 children, and 21 scleroderma patients with 47 children were HLA genotyped. FINDINGS: The mean number of male cell DNA equivalents among controls was 0.38 cells per 16 mL whole blood (median 0 [range 0-2]) and 11.1 (6.0 [0-61]) among scleroderma patients (p = 0.0007). Controls' youngest sons were born a mean of 15.4 years previously, and scleroderma patients' sons 18.5 years previously. Some scleroderma patients had concentrations of male DNA higher than those found in most pregnant women. HLA-class II compatibility of a child from the mother's perspective was more common among scleroderma patients than among controls, but was not essential for persistence of male DNA in maternal peripheral blood. INTERPRETATION: Low concentrations of male DNA can be detected in healthy women decades after the birth of a son. Microchimerism in scleroderma patients could be secondary to the underlying disease. However, the finding that HLA class II compatibility of a child was more common for scleroderma patients than for controls, supports the possibility that microchimerism may be involved in the pathogenesis of scleroderma.

Adolescent↗