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C Ober

Publications and source records attributed to C Ober.

At least 19 recordsLinked to original sources
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↗
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↗
PubMed1998

Transmission disequilibrium of maternally-inherited CTLA-4 microsatellite alleles in idiopathic recurrent miscarriage.

To elucidate the mechanisms that facilitate tolerance at the maternal-fetal interface, we are investigating the role of genes that are involved in peripheral self-tolerance in couples with idiopathic recurrent miscarriage. CTLA-4 is a negative regulator of T-cell proliferation and has been associated with human autoimmune disease. An AT(n) polymorphism in the 3'-untranslated region (UTR) of the human gene results in AT stretches that vary in length from 16 to 46 bp. We hypothesized that long stretches of AT repeats would result in mRNA instability, and reduced fetal survival in humans. We examined the transmission of AT(n) alleles in 60 couples with a history of > or = 3 unexplained spontaneous abortions to their 51liveborn children and 10 abortuses. The shorter allele was transmitted from heterozygous mothers to 26 of 35 liveborn children (chi2 = 8.3, P = 0.0040) and to three of nine aborted fetuses (chi2 = 1.0, P = 0.317). The shorter allele was transmitted from heterozygous fathers to 15 of 32 liveborn children (chi2 =0.12, P=0.726) and to five of eight aborted fetuses (chi2 = 0.5, P = 0.480). Furthermore, liveborn fetuses who inherited smaller alleles were more likely to represent the first successful pregnancy than liveborn fetuses who inherited larger maternal alleles (Pexact = 0.044) and fetuses of first pregnancies that inherited the smaller allele were significantly more likely to survive to term (Pexact = 0.0086). The preferential transmission of maternally-inherited shorter alleles to liveborn children, but random transmission of paternally-inherited alleles, suggests that CTLA-4 may be imprinted in humans and that this gene may play a role in inducing or maintaining tolerance at the maternal-fetal interface.

Abatacept↗
PubMed1998

Recurrent miscarriage (REMIS) study: how should data from women who do not become pregnant be handled?

The Recurrent Miscarriage (REMIS) study is a double-blind, multicenter, randomized clinical trial designed to evaluate the efficacy of immunization with paternal leukocytes in the prevention of miscarriages in women who have had three or more unexplained pregnancy losses. Women entering the study are immunized with their husband's leukocytes or with a saline control before they become pregnant. After becoming pregnant, they receive weekly ultrasound examinations and psychological support during the first trimester and are followed until a successful delivery or a miscarriage occurs. The primary analysis for the study will be an intent-to-treat analysis in which we shall compare the proportion of successes in the two groups, defining a "success" as a pregnancy achieved within 12 months of randomization that results in a viable offspring. We shall count both miscarriages and nonpregnancies as failures, owing to the possibility of very early losses prior to the detection of pregnancy. In a secondary analysis, we shall exclude women who do not become pregnant within the alloted 12 month period. We compared the test size and power of these two approaches under various configurations for the true rates of nonpregnancy, miscarriage, and delivery in the two groups. Although the analysis excluding nonpregnant women achieves greater power for alternatives in which pregnancy rates are equal and live birth rates higher in the treated group, the rejection rate is not adequately controlled when pregnancy rates differ but live birth rates are unaffected by treatment. It can also lead to a reduction in power if the treatment prevents early as well as later losses. We conclude that the intent-to-treat analysis should remain the primary analysis for the trial.

Abortion, Habitual↗
PubMed1998

Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma.

Founder populations offer many advantages for mapping genetic traits, particularly complex traits that are likely to be genetically heterogeneous. To identify genes that influence asthma and asthma-associated phenotypes, we conducted a genome-wide screen in the Hutterites, a religious isolate of European ancestry. A primary sample of 361 individuals and a replication sample of 292 individuals were evaluated for asthma phenotypes according to a standardized protocol. A genome-wide screen has been completed using 292 autosomal and three X-Y pseudoautosomal markers. Using the semi-parametric likelihood ratio chi2 test and the transmission-disequilibrium test, we identified 12 markers in 10 regions that showed possible linkage to asthma or an associated phenotype (likelihood ratio P < 0.01). Markers in four regions (5q23-31, 12q15-24.1, 19q13 and 21q21) showed possible linkage in both the primary and replication samples and have also shown linkage to asthma phenotypes in other samples; two adjacent markers in one additional region (3p24.2-22) showing possible linkage is reported for the first time in the Hutterites. The results suggest that even in founder populations with a relatively small number of independent genomes, susceptibility alleles at many loci may influence asthma phenotypes and that these susceptibility alleles are likely to be common polymorphisms in the population.

Adolescent↗
PubMed1998

Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study.

The role that maternal and fetal human leukocyte antigen (HLA) genes play in pregnancy is unknown, but it has been suggested that fetuses whose HLA alleles do not differ from maternal alleles (i.e. histocompatible fetuses) are more likely to be aborted than fetuses with HLA alleles that differ from maternal alleles (i.e. histoincompatible fetuses). To elucidate the role of HLA compatibility in pregnancy, we tested the hypothesis that couples who match for HLA alleles or haplotypes would have reduced fertility because only these couples could produce histocompatible fetuses. We conducted a 10 year prospective study of HLA matching and pregnancy outcome in 111 Hutterite couples, providing information on 251 pregnancies. A logistic regression analysis was performed to determine the effects of HLA matching at HLA regions and loci on pregnancy outcome (fetal loss versus delivery). Significantly increased fetal loss rates were observed among couples matching for the entire 16-locus haplotype (P = 0.002). Among the individual loci, loss rates were increased among couples matching for HLA-B (P = 0.019), HLA-C (P = 0.033) and the complement component, C4 (P = 0.043). We interpret these results as evidence that matching for the entire 16-locus haplotype and/or alleles at an HLA-B-linked locus confers significant risk for fetal loss.

Abortion, Spontaneous↗
PubMed1998

HLA-H: a pseudogene with increased variation due to balancing selection at neighboring loci.

The HLA complex includes the most polymorphic genes in the human genome. However, the HLA class Ib loci have little, if any, nucleotide variation, presumably due to their specialized functions or perhaps due to a lack of function. This population genetic study of HLA-H, a class I pseudogene, was initiated to determine the pattern of variation at neutral sites within the HLA complex. We found that the pattern of variation for HLA-H is consistent with the neutral model. However, the amount of variation in HLA-H is significantly greater than estimates for other silent sites within the human genome outside of the MHC (theta = 0.0144, P < 0.000001). Our study further indicates that other possible causes of increased variation such as a high mutation rate for HLA-H, interlocus gene conversion, increased diversity in the sample population in general, and selection acting directly on HLA-H are unlikely. Instead, these data suggest that HLA-H has increased variation as a result of balancing selection acting on nearby loci such as HLA-A.

Animals↗
PubMed1998

HLA-G polymorphisms: ethnic differences and implications for potential molecule function.

PROBLEM: Human leukocyte antigen (HLA)-G is uniquely expressed on extravillous cytotrophoblasts of the placenta and is postulated to be a mediator of maternal immune tolerance. Although it was originally considered to be nonpolymorphic, variations of the HLA-G DNA sequence have been reported, and a limited number of HLA-G alleles been defined. METHOD OF STUDY: The HLA-G wild-type sequence was compared with HLA-A2 with regard to the conservation of functionally essential parts of classical HLA-I molecules. HLA-G polymorphisms were analyzed under the aspect of ethnic differences, site, and consequences for postulated molecule functions. RESULTS: HLA-G exhibits a high degree of conservation relative to HLA-A2 in functionally relevant sites of HLA-class I molecules. However, polymorphic sites in HLA-G and classical HLA loci are not congruent. CONCLUSION: The type and localization of HLA-G polymorphisms suggest that different parts of HLA-G molecule underlie different selective constraints.

Ethnicity↗
PubMed1998

Immunogenetic studies in families of children with juvenile dermatomyositis.

OBJECTIVE: We reported an association between juvenile dermatomyositis (JDMS) and the HLA-DQA1*0501 allele. The purpose of this study was to determine whether there is evidence for linkage between JDMS and the DQA1*0501 allele in JDMS families. METHODS: The study population included 18 unrelated patients with JDMS, their parents, and 49 unaffected siblings. Using molecular genetic techniques, we studied the HLA genes, DRB1, DQA1, and tumor necrosis factor-alpha. RESULTS: Using the transmission disequilibrium test, we confirmed our earlier observations that the HLA-DQA1*0501 allele confers primary susceptibility to JDMS. CONCLUSION: DQA1*0501 confers genetic risk for JDMS; we cannot exclude the effects of alleles at other linked loci that were not studied or interactive effects between DQA1 alleles and alleles at other loci.

Alleles↗