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C Ober

Publications and source records attributed to C Ober.

At least 19 recordsLinked to original sources
PubMed2006

The miscarriage-associated HLA-G -725G allele influences transcription rates in JEG-3 cells.

BACKGROUND: HLA-G is a non-classical HLA with important immunomodulatory roles in pregnancy. A polymorphism in the promoter region, -725G, was previously associated with sporadic miscarriage in women who were unselected with respect to reproductive history. In this study, the transcription levels of different HLA-G promoter haplotypes were examined to determine whether the miscarriage-associated -725G allele influences transcription. METHODS: Five naturally occurring promoter haplotypes and three variant haplotypes created by site-directed mutagenesis were sub-cloned into luciferase expression vectors and transfected into JEG-3 cells. Expression levels of these eight haplotypes were examined in cultured cells before and after treatment with interferon-beta (IFN-beta), cytosine-5-DNA methyltransferase (M. SssI) and 5-aza-2'-deoxycytidine. Differences in expression levels between haplotypes were determined by analysis of variance (ANOVA). RESULT: Promoter haplotypes with the miscarriage-associated -725G allele were expressed at significantly higher levels in all culture conditions compared with otherwise identical haplotypes that had a -725C or -725T allele. CONCLUSION: Variation in the HLA-G promoter region influences transcription rates. Contrary to expectations, increased expression of HLA-G may be disadvantageous in some pregnancies.

Abortion, Spontaneous↗
PubMed2006

Asthma genetics 2006: the long and winding road to gene discovery.

Asthma and atopy are complex phenotypes that are influenced by both genetic and environmental factors. A review of nearly 500 papers on disease association studies identified 25 genes that have been associated with an asthma or atopy phenotype in six or more populations. An additional 54 genes have been associated in 2-5 populations. Here, we discuss the methods that have been used to identify susceptibility genes for common diseases and overview the status of asthma genetic research. Finally, current challenges and future directions are discussed.

Asthma↗
PubMed2006

Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy.

A genome-wide screen for asthma and atopy susceptibility alleles conducted in the Hutterites, a founder population of European descent, reported evidence of linkage with a short tandem repeat polymorphism (STRP) within the type I interferon (IFN) gene cluster on chromosome 9p21. The goal of this study was to identify variation within the IFN gene cluster that influences susceptibility to asthma and atopic phenotypes. We screened approximately 25 kb of sequence, including the flanking sequence of all 15 functional genes and the single coding exon in 12, in Hutterites representing different IFNA-STRP genotypes. We identified 78 polymorphisms, and genotyped 40 of these (in 14 genes) in a large Hutterite pedigree. Modest associations (0.003<P<0.05) with asthma, bronchial hyper-responsiveness (BHR), and atopy were observed with individual variants or genes, spanning the entire 400 kb region. However, pairwise combinations of haplotypes between genes showed highly significant associations with different phenotypes (P<10(-5)) that were localized to specific pairs of genes or regions of this cluster. These results suggest that variation in multiple genes in the type I IFN cluster on 9p22 contribute to asthma and atopy susceptibility, and that not all genes contribute equally to all phenotypes.

Adolescent↗
PubMed2004

Genome scan for loci linked to mite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA).

Mite sensitivity has been reported to be a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome scan using mite reactivity (Dermatophagoides Pteronyssinus (Der p) and Dermatophagoides farinae (Der f)) as the phenotype was conducted. In 287 CSGA families, 122 were informative for linkage. Evidence supporting linkage was observed for regions on chromosome 19 (D19S591, lod=2.43, P=0.0008; D19S1037, lod=1.57, P=0.007) and chromosome 20 (D20S473/D20S604, lod=1.41, P=0.01). All three ethnic groups appeared to contribute to the evidence for linkage on chromosome 20. African-American families gave strongest support for linkage on chromosomes 3 (D3S2409, lod=1.33, P=0.01), 12 (D12S373, lod=1.51, P=0.008) and 18 (ATA82B02, lod=1.32, P=0.01). Caucasian families showed strong evidence for linkage on chromosome 19 (D19S591, lod=3.51, P=0.00006). Hispanic families supported linkage on chromosomes 11 (D11S1984, lod=1.56, P=0.007), 13 (D13S787, lod=1.30, P=0.01) and 20 (D20S470, lod=1.71, P=0.005). These results suggest that multiple genes may be involved in controlling skin reactivity to Dermatophoigoies.

Animals↗
PubMed2003

Immunogenicity of the soluble isoforms of HLA-G.

Soluble class Ib HLA-G glycoproteins synthesized in the placenta are abundant in the pregnant uterus and circulate in maternal blood throughout pregnancy. To establish immunogenicity of these proteins, we tested sera from 64 women with at least one successful pregnancy (multigravid), 21 women who had never been pregnant, and 54 males for antibodies to epitopes present on recombinant sHLA-G isoforms (sHLA-G1, sHLA-G2) derived from HLA 6.0 cDNA (HLA-G*0101 allele). By indirect enzyme-linked immunosorbent assay, antibodies to sHLA-G isoforms were identified in six sera, all from multigravid women; all other sera were negative (P = 0.0083). Immunoblots showed that two of the positive sera reacted exclusively with sHLA-G1 and -G2 whereas four reacted to both sHLA-G and pooled HLA class I antigens. To establish potential relationships between anti-sHLA-G and exposure to foreign paternal alleles (*0101, *0103, *0104, *0106), all multigravid women and their partners were genotyped. No relationship between allelic disparity and antibody production was identified. Taken together, these results indicate that (i) tolerance to HLA-G is the usual condition as antibodies to HLA-G were not detected in 91% (58/64) multigravid women, and (ii) pregnancy stimulates loss of tolerance in 9% (6/64) of multigravid women. All six women delivered healthy babies, demonstrating that maternal antibodies to epitopes on sHLA-G do not abrogate pregnancy.

Adult↗
PubMed2002

Missing data in haplotype analysis: a study on the MILC method.

Given the enormous progress in the knowledge of the human genome, genetic markers are now available throughout the genome. Haplotype analysis, allowing the simultaneous use of information from several markers, has thus become increasingly popular. However, we often face the problem of missing data and of haplotype identification. We have proposed a haplotype based method for the genetic study of multifactorial diseases in founder populations, the MILC method (Bourgain et al. 2000). MILC is based on the contrast of identity length between haplotypes transmitted to affected offspring and haplotype non-transmitted. In this study, the impact of different strategies, regarding missing data, on the MLIC method are evaluated. A real situation is considered where data are derived from a genome screen for asthma susceptibility alleles in the Hutterites. Results are illustrated on this asthma data set.

Asthma↗
PubMed2001

The genetic dissection of complex traits in a founder population.

We estimated broad heritabilities (H(2)) and narrow heritabilities (h(2)) and conducted genomewide screens, using a novel association-based mapping approach for 20 quantitative trait loci (QTLs) among the Hutterites, a founder population that practices a communal lifestyle. Heritability estimates ranged from.21 for diastolic blood pressure (DBP) to.99 for whole-blood serotonin levels. Using a multipoint method to detect association under a recessive model we found evidence of major QTLs for six traits: low-density lipoprotein (LDL), triglycerides, lipoprotein (a) (Lp[a]), systolic blood pressure (SBP), serum cortisol, and whole-blood serotonin. Second major QTLs for Lp(a) and for cortisol were identified using a single-point method to detect association under a general two-allele model. The heritabilities for these six traits ranged from.37 for triglycerides to.99 for serotonin, and three traits (LDL, SBP, and serotonin) had significant dominance variances (i.e., H(2) > h(2)). Surprisingly, there was little correlation between measures of heritability and the strength of association on a genomewide screen (P>.50), suggesting that heritability estimates per se do not identify phenotypes that are influenced by genes with major effects. The present study demonstrates the feasibility of genomewide association studies for QTL mapping. However, even in this young founder population that has extensive linkage disequilibrium, map densities <<5 cM may be required to detect all major QTLs.

Adolescent↗
PubMed2001

Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma.

The genomewide screen to search for asthma-susceptibility loci, in the Collaborative Study on the Genetics of Asthma (CSGA), has been conducted in two stages and includes 266 families (199 nuclear and 67 extended pedigrees) from three U.S. populations: African American, European American, and Hispanic. Evidence for linkage with the asthma phenotype was observed for multiple chromosomal regions, through use of several analytical approaches that facilitated the identification of multiple disease loci. Ethnicity-specific analyses, which allowed for different frequencies of asthma-susceptibility genes in each ethnic population, provided the strongest evidence for linkage at 6p21 in the European American population, at 11q21 in the African American population, and at 1p32 in the Hispanic population. Both the conditional analysis and the affected-sib-pair two-locus analysis provided further evidence for linkage, at 5q31, 8p23, 12q22, and 15q13. Several of these regions have been observed in other genomewide screens and linkage or association studies, for asthma and related phenotypes. These results were used to develop a conceptual model to delineate asthma-susceptibility loci and their genetic interactions, which provides a promising basis for initiation of fine-mapping studies and, ultimately, for gene identification.

Adolescent↗
PubMed2001

Broad and narrow heritabilities of quantitative traits in a founder population.

Estimation of the components of variance for a quantitative trait allows one to evaluate both the degree to which genetics influences the trait and the trait's underlying genetic architecture. For particular traits, the estimates also may have implications for discriminating between potential models of selection and for choosing an appropriate model for linkage analysis. Using a recently developed method, we estimate the additive and dominance components of variance--or, equivalently, the narrow and broad sense heritabilities--of several traits in the Hutterites, a founder population with extensive genealogical records. As a result of inbreeding and because Hutterite individuals are typically related through multiple lines of descent, we expect that power to detect dominance variance will be increased relative to that in outbred studies. Furthermore, the communal lifestyle of the Hutterites allows us to evaluate the genetic influences in a relatively homogeneous environment. Four phenotypes had a significant dominance variance, resulting in a relatively high broad heritability. We estimated the narrow and broad heritabilities as being, respectively,.36 and.96 for LDL,.51 and 1.0 for serotonin levels, and.45 and.76 for fat free mass (FFM). There was no significant additive component for systolic blood pressure (SBP), resulting in a narrow heritability of 0 and a broad heritability of.45. There were several traits for which we found no significant dominance component, resulting in equal broad and narrow heritability estimates. These traits and their heritabilities are as follows: HDL,.63; triglycerides,.37; diastolic blood pressure,.21; immunoglobulin E,.63; lipoprotein(a),.77; and body-mass index,.54. The large difference between broad and narrow heritabilities for LDL, serotonin, FFM, and SBP are indicative of strong dominance effects in these phenotypes. To our knowledge, this is the first study to report an estimate of heritability for serotonin and to detect a dominance variance for LDL, FFM, and SBP.

Blood Pressure↗
PubMed2001

Description of three data sets: Collaborative Study on the Genetics of Asthma (CSGA), the German Affected-Sib-Pair Study, and the Hutterites of South Dakota.

Three different data sets with clinical data and markers from genome-wide screens were submitted for analysis at Genetic Analysis Workshop 12. In each study, participants were carefully characterized for asthma and related phenotypes. Testing for bronchial hyper-responsiveness using methacholine and standardized protocols was performed. Total serum IgE levels were measured using standardized techniques. In addition, similar questionnaire data on symptoms and relevant environmental exposures were obtained. Relevant clinical data and genotypes for the polymorphic markers used for each genome-wide screen were submitted. The data set from the United States Collaborative Study on the Genetics of Asthma represents a heterogeneous population consisting of both Caucasian and African American families ascertained through two siblings with clinical asthma from multiple centers. Likewise, the families from the German Asthma Genetics Group were also ascertained through two siblings with asthma at multiple centers. In a contrast to these data sets, Dr. Carole Ober and her collaborators submitted data from the inbred Hutterite population in South Dakota.

Adolescent↗
PubMed2001

Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families.

Variance components models were used to analyze total IgE levels in families ascertained though the Collaborative Study of the Genetics of Asthma (CSGA) using a genome-wide array of polymorphic markers. While IgE levels are known to be associated with clinical asthma and recognized to be under strong genetic control (here the heritability was estimated at 44-60% in the three racial groups), specific genes influencing this trait are still largely unknown. Multipoint analysis of 323 markers yielded little indication of specific regions containing a trait locus controlling total serum IgE levels (adjusted for age and gender). Although a number of regions showed LOD statistics above 1.5 in Caucasian families (chromosome 4) and in African-American families (chromosomes 2 and 4), none yielded consistent evidence in all three racial groups. Analysis of total IgE adjusted for gender, age and Allergy Index (a quantitative score of skin test sensitivity to 14 common aeroallergens) was conducted on these data. In this analysis, a much stronger signal for a trait locus controlling adjusted log[total IgE] was seen on the telomeric end of chromosome 18, but only in Caucasian families. This region accounted for most of the genetic variation in log[total IgE], and may represent a quantitative trait locus for IgE levels independent of atopic response. Oligogenic analysis accounting simultaneously for the contribution of this locus on chromosome 18 and other chromosomal regions showing some evidence of linkage in these Caucasian families (on chromosomes 2, 4 and 20) failed to yield significant evidence for interaction.

Asthma↗
PubMed2001

Susceptibility genes in asthma and allergy.

Genome-wide screens for asthma and atopy susceptibility loci have been completed in six population samples. Despite the extensive clinical heterogeneity associated with these phenotypes, 20 chromosomal regions show evidence of linkage (P < 0.01) in three or more population samples. Thus, this survey suggests that at least 20 independent loci influence susceptibility to asthma, atopy, or associated phenotypes and indicates that the genetics of these phenotypes are truly complex. Ongoing studies are aimed at identifying the specific gene or genes in these regions that confer susceptibility to asthma or atopy.

Asthma↗
PubMed2001

A population genetics study of single nucleotide polymorphisms in the interleukin 4 receptor alpha (IL4RA) gene.

Interleukin 4 (IL4) plays a critical role in T helper 2 (Th2) immune responses. Here we report a population genetics study of variation in the gene encoding the alpha-chain of the IL4 receptor (IL4RA) in three ethnic groups: African Americans, European Americans and East Asians. A 2941-bp region spanning exon 12 of IL4RA gene was sequenced in 12 individuals from each group. A total of 24 single nucleotide polymorphisms (SNPs) were identified in the combined sample. The genetic variation of the coding region of exon 12 is two to three times higher than in other reported genes. A significant departure from the expectation of evolutionary neutrality was observed, suggesting that natural selection may have influenced the evolution of this gene. We propose a model in which past selection by pathogens contributed to the increasing prevalence of atopic disorders in Western societies.

Black or African American↗
PubMed2001

Three polymorphisms in the 3' UTR of the TRAIL (TNF-related apoptosis-inducing ligand) gene.

Screening of the TRAIL (TNF-related apoptosis inducing ligand/Apo-2L) gene revealed three single nucleotide polymorphisms (SNPs) in the 3' UTR at nucleotides 1525G/A, 1588G/A, and 1591C/T. Over 50 individuals from each of two populations, Caucasian and African Americans, were genotyped for these three polymorphisms and allele frequencies were determined.

3' Untranslated Regions↗
PubMed2001

Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma.

BACKGROUND: In the Collaborative Study on the Genetics of Asthma, 314 families with 2584 subjects were characterized for asthma and allergy. OBJECTIVE: The purpose of this investigation was to examine clinical heterogeneity observed in asthma and allergic characteristics among 3 ethnic groups (African American, white, and Hispanic family members). METHODS: Pulmonary function parameters and asthma associated phenotypes were compared among the ethnic groups. RESULTS: In comparison with the other groups, African American sibling pairs had a significantly lower baseline FEV(1) percent of predicted (P =.0001) and a higher rate of skin test reactivity to cockroach allergen (P =.0001); Hispanic sibling pairs had significantly more skin reactivity overall (P =.001); and white sibling pairs had significantly lower total serum IgE (P <.05). In addition, there were significantly more relatives with asthma among the African American families than among the white and the Hispanic families (P =.001). CONCLUSION: Although different environmental backgrounds should be considered, these clinical differences could be due to differences in genetic susceptibility among the ethnic groups, such as those suggested by our previous genome screen.

Adolescent↗
PubMed2001

HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage.

HLA-G is a non-classical human leukocyte antigen expressed primarily in fetal tissues at the maternal-fetal interface. This expression pattern is unique among HLA genes and suggests that HLA-G may be involved in interactions that are critical in establishing and/or maintaining pregnancy. To evaluate the role of polymorphisms at this locus in maternal-fetal interactions, 113 couples with unexplained recurrent miscarriage were genotyped for seven polymorphisms that define 12 HLA-G alleles. Logistic regression analysis was used to assess whether HLA-G genotypes were associated with an increased risk for a subsequent miscarriage. The presence of an HLA-G*0104 or HLA-G*0105N allele in either partner was significantly associated with an increased risk for miscarriage, after adjustment for maternal age, number of previous miscarriages, history of a previous liveborn, and treatment with paternal mononuclear cells. The *0104 and *0105N alleles are defined by polymorphisms in the alpha-2 domain and encode protein variants that are present only in the full-length HLA-G1 protein. The significant genotype-specific risk in this population suggests that allelic variation in the alpha-2 domain of the HLA-G1 isoforms contributes to recurrent miscarriage.

Abortion, Habitual↗
PubMed2000

A second-generation genomewide screen for asthma-susceptibility alleles in a founder population.

A genomewide screen for asthma- and atopy-susceptibility loci was conducted, using 563 markers, in 693 Hutterites who are members of a single 15-generation pedigree, nearly doubling the sample size from the authors' earlier studies. The resulting increase in power led to the identification of 23 loci in 18 chromosomal regions showing evidence for linkage that is, in general, 10-fold more significant (P<.001 vs. P<.01) than the linkages reported previously in this population. Moreover, linkages to loci in 11 chromosomal regions were identified for the first time in the Hutterites in this report, including five regions (5p, 5q, 8p, 14q, and 16q) showing evidence both of linkage, by the likelihood ratio (LR) chi(2), and of disequilibrium, by the transmission/disequilibrium test. A region on chromosome 19 continues to show evidence for linkage, by both tests, in this study. Studies of 17 candidate genes provide evidence for association with variation in the IL4RA gene (16p12), the HLA class II genes (6p21), and the interferon-alpha gene cluster (9p22), but the lack of evidence for linkage in these regions by the LR chi(2) test suggests that these are minor susceptibility loci. A polymorphism in the CD14 gene is in linkage disequilibrium with an as yet unidentified susceptibility allele in the 5q cytokine cluster, a region showing evidence for linkage among the Hutterites. Finally, 10 of the regions showing evidence for linkage in the Hutterites have shown evidence of linkage to related phenotypes in other genome screens, suggesting that these regions may contain common alleles that have relatively large effects on asthma and atopy phenotypes in diverse populations.

Adult↗