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Results for “Hutterites”

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At least 199 records · Page 11Linked to original sources

PubMed2006

QT intervals in metabolic dilated cardiomyopathy.

OBJECTIVES: The present study determined the prevalence of dilated cardiomyopathy together with prolonged corrected QT (QTc) intervals in children. The study also examined whether an association exists between prolonged QTc intervals and ventricular dysrhythmia in a patient cohort with dilated cardiomyopathy. BACKGROUND: The morbidity and mortality for pediatric patients with dilated cardiomyopathy remains high and is a clinical challenge. The patient population includes a significant number of Hutterite patients with metabolic disease associated with dilated cardiomyopathy. METHODS: Thirty-eight pediatric patients with dilated cardiomyopathy were reviewed for the presence of prolonged QTc and dysrhythmias. Eleven patients had a metabolic etiology for their dilated cardiomyopathy. RESULTS: Thirty-six per cent of the patient cohort had a long QTc interval. After 50 months of follow-up, the probability of survival for a child with a long QTc interval was approximately 50%. The probability of survival for a child with a normal QTc interval was 72%. Seventy per cent of the patients who died had a metabolic etiology for their dilated cardiomyopathy and a long QTc. CONCLUSIONS: Dilated cardiomyopathy may be associated with a prolonged QTc and may increase the patient's risk for sudden death. The presence of a metabolic etiology for dilated cardiomyopathy increases the risk of death.

Adolescent↗

PubMed1998

The varicella-zoster virus and multiple sclerosis.

This article is a review of the evidence suggesting a unique relationship between the varicella-zoster virus (as a possible antigen or antigen mimic) and multiple sclerosis (MS). Both MS and varicella have increased prevalences in temperate zones and both are rare in countries closer to the equator. Migration studies suggest an infectious agent acquired prior to age 14 plays a role in the risk of subsequent MS. Hutterites, who educate their children at home, have less varicella, MS, and herpes zoster than their neighbors and have the appropriate reduced varicella-zoster seropositivity matching these clinical observations. Paradoxically, patients with MS report more herpes zoster, and at an earlier age and more often, than a group of non-MS patients.

Adolescent↗

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↗

PubMed2002

Genetics of population isolates.

Genetic isolates, as shown empirically by the Finnish, Old Order Amish, Hutterites, Sardinian and Jewish communities among others, represent a most important and powerful tool in genetically mapping inherited disorders. The main features associated with that genetic power are the existence of multigenerational pedigrees which are mostly descended from a small number of founders a short number of generations ago, environmental and phenotypic homogeneity, restricted geographical distribution, the presence of exhaustive and detailed records correlating individuals in very well ascertained pedigrees, and inbreeding as a norm. On the other hand, the presence of a multifounder effect or admixture among divergent populations in the founder time (e.g. the Finnish and the Paisa community from Colombia) will theoretically result in increased linkage disequilibrium among adjacent loci. The present review evaluates the historical context and features of some genetic isolates with emphasis on the basic population genetic concepts of inbreeding and genetic drift, and also the state-of-the-art in mapping traits, both Mendelian and complex, on genetic isolates.

Christianity↗

PubMed2006

The sex-specific genetic architecture of quantitative traits in humans.

Mapping genetically complex traits remains one of the greatest challenges in human genetics today. In particular, gene-environment and gene-gene interactions, genetic heterogeneity and incomplete penetrance make thorough genetic dissection of complex traits difficult, if not impossible. Sex could be considered an environmental factor that can modify both penetrance and expressivity of a wide variety of traits. Sex is easily determined and has measurable effects on recognizable morphology; neurobiological circuits; susceptibility to autoimmune disease, diabetes, asthma, cardiovascular and psychiatric disease; and quantitative traits like blood pressure, obesity and lipid levels, among others. In this study, we evaluated sex-specific heritability and genome-wide linkages for 17 quantitative traits in the Hutterites. The results of this study could have important implications for mapping complex trait genes.

Genetic Linkage↗

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↗

PubMed2006

Variation in ITGB3 is associated with whole-blood serotonin level and autism susceptibility.

Autism is a pervasive developmental disorder affecting more males than females. Heritability estimates for autism can rise above 90%, and genes influencing the serotonin system are strong candidates for autism susceptibility genes, as drugs selectively acting on the serotonin system are some of the most effective treatments for maladaptive behaviors seen in autism. ITGB3 was recently identified as a male quantitative trait locus (QTL) for whole-blood serotonin levels in the Hutterites (P = 0.0003). Here, we demonstrate associations between variation in ITGB3 and serotonin levels in two outbred samples (P = 0.010 and 0.015). Lastly, we show that a coding variant of ITGB3 is associated with autism susceptibility in a large multiplex sample (P = 0.00082), and that this variation has different effects in males and females (P = 0.0018).

Alleles↗

PubMed1996

The low-incidence blood group antigen, Wda, is associated with the substitution Val557-->Met in human erythrocyte band 3 (AE1).

The Waldner blood group antigen (Wda) was first identified in members of a Hutterite kindred. Evidence that the gene governing the Waldner polymorphism is located on chromosome 17, and the observation that the antigen is inactivated by chymotrypsin prompted the investigation of a possible association between Wda and band 3. Single Stranded Conformational Polymorphism (SSCP) analysis and DNA sequence analysis of the AE1 gene, from subjects of known Waldner phenotypes, showed a heterozygous mutation leading to the substitution Val557-->Met in the presumptive Wd(a+) heterozygotes. Therefore the Wda blood group antigen is associated with the presence of Met557 on band 3. the Waldner antigen has been assigned to the Diego blood group system with the International Society of Blood Transfusion number D15.

Blood Group Antigens↗

PubMed2003

Sequence variation in the promoter region of the cholinergic receptor muscarinic 3 gene and asthma and atopy.

BACKGROUND: Muscarinic acetylcholine receptors are members of the superfamily of G protein-coupled, 7 transmembrane- spanning proteins. They are important in the development of airway hyperresponsiveness. In the lung the M3 receptor, encoded by the cholinergic receptor muscarinic 3 gene, is present in airway smooth muscle and mediates smooth muscle contraction. OBJECTIVE: We considered the cholinergic receptor muscarinic 3 gene as a possible candidate gene for bronchial asthma and initiated studies to identify polymorphisms in the promoter region. METHOD: We identified 4 single-nucleotide polymorphisms (-708A/G, -627G/C, -513C/A, and -492C/T) and 2 short tandem repeat polymorphisms, a tetranucleotide (CTTT)12-20 and a dinucleotide (GT)6-19 repeat. RESULTS: None of the identified single nucleotide polymorphisms were significantly more frequent in asthmatic patients (n = 76) compared with in healthy control subjects (n = 81). Furthermore, there was no evidence for nonrandom transmission of short tandem repeat polymorphism haplotypes to individuals with asthma or bronchial hyperresponsiveness (P >.50) in a large Hutterite pedigree. However, there was significant nonrandom transmission of haplotypes to individuals with skin test reactivity to cockroach allergens (global transmission disequilibrium test: chi2 = 38.55, P =.013). CONCLUSIONS: These results suggest a possible role for this gene in atopic disorders.

Allergens↗

PubMed1996

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Two isoforms of the human growth hormone receptor (hGHR), which differ in the presence (hGHRwt) or absence (hGHRd3) of exon 3, are expressed in the placenta. Specifically, three expression patterns are observed: only hGHRwt, only hGHRd3, or an approximately 1:1 combination of both isoforms. We investigated several potential regulatory mechanisms which might account for the expression of the hGHR isoforms. The frequency of hGHRd3 expression did not change when placentas from differing stages of gestation were examined, suggesting splicing was not developmentally regulated. However, when hGHR isoform expression patterns were examined in each component of a given placenta, it was evident that alternative splicing of exon 3 is individual-specific. Surprisingly, the individual-specific regulation of hGHR isoforms appears to be the result of a polymorphism in the hGHR gene. We analyzed hGHRwt and hGHRd3 expression in Hutterite pedigrees, and our results are consistent with a simple Mendelian inheritance of two differing alleles in which exon 3 is spliced in an "all-or-none" fashion. We conclude the alternative splicing of exon 3 in hGHR transcripts is the result of an unusual polymorphism which significantly alters splicing of the hGHR transcript and that the relatively high frequency (approximately 10%) of homozygous hGHRd3 expression suggests the possibility it may play a role in polygenic determined events.

Alleles↗

PubMed1990

Estimating fecundability from data on waiting times to first conception.

"This article tests assumptions invoked in the demographic literature to estimate the population distribution of fecundability from data on waiting times to first conception. In continuous time, the key assumption is that waiting times are realizations from a mixture of exponentials distribution. In discrete time, the key assumption is that waiting times are realizations from a mixture of geometrics distribution. The [U.S.] Hutterite data analyzed by Sheps (1965) are consistent with this assumption. Various models, however, have one representation in mixture of exponentials form. A fundamental identification problem plagues the conventional estimation procedure. Our analysis calls into question the conventional practice of checking model specification by using goodness-of-fit tests. The practical importance of the identification problem in duration models is demonstrated."

Americas↗

PubMedDate not supplied

Pitcairn Island: fertility and population growth, 1790-1856.

The hybrid English-Tahitian community which lived on Pitcairn Island between 1790 and 1856 exhibited a high population growth (3% overall). Unlike some other isolated groups, they did not live long lives (expectation of life at birth was 50.4 years overall for both sexes combined), but infant mortality, at 5.5% of births is lower than might have been expected. The level of marital fertility on Pitcairn was extremely high, higher even than for the Hutterites. Although births outside marriage were uncommon, brides were frequently pregnant at marriage. Age at first marriage changed markedly in response to changes in the community. There is some evidence that premarital sex became more frequent, possibly as an adjustment to Tahitian behavioural norms within the community's English religious ethic.

Adolescent↗

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↗

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↗

PubMed2002

Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene.

Limb-girdle muscular dystrophy type 2H (LGMD2H) is a mild autosomal recessive myopathy that was first described in the Manitoba Hutterite population. Previous studies in our laboratory mapped the causative gene for this disease to a 6.5-Mb region in chromosomal region 9q31-33, flanked by D9S302 and D9S1850. We have now used additional families and a panel of 26 microsatellite markers to construct haplotypes. Twelve recombination events that reduced the size of the candidate region to 560 kb were identified or inferred. This region is flanked by D9S1126 and D9S737 and contains at least four genes. Exons of these genes were sequenced in one affected individual, and four sequence variations were identified. The families included in our study and 100 control individuals were tested for these variations. On the basis of our results, the mutation in the tripartite-motif-containing gene (TRIM32) that replaces aspartate with asparagine at position 487 appears to be the causative mutation of LGMD2H. All affected individuals were found to be homozygous for D487N, and this mutation was not found in any of the controls. This mutation occurs in an NHL (named after the proteins NCL1, HT2A, and LIN-41) domain at a position that is highly conserved. NHL domains are known to be involved in protein-protein interactions. Although the function of TRIM32 is unknown, current knowledge of the domain structure of this protein suggests that it may be an E3-ubiquitin ligase. If proven, this represents a new pathogenic mechanism leading to muscular dystrophy.

Amino Acid Sequence↗

PubMed2003

Novel case-control test in a founder population identifies P-selectin as an atopy-susceptibility locus.

To avoid problems related to unknown population substructure, association studies may be conducted in founder populations. In such populations, however, the relatedness among individuals may be considerable. Neglecting such correlations among individuals can lead to seriously spurious associations. Here, we propose a method for case-control association studies of binary traits that is suitable for any set of related individuals, provided that their genealogy is known. Although we focus here on large inbred pedigrees, this method may also be used in outbred populations for case-control studies in which some individuals are relatives. We base inference on a quasi-likelihood score (QLS) function and construct a QLS test for allelic association. This approach can be used even when the pedigree structure is far too complex to use an exact-likelihood calculation. We also present an alternative approach to this test, in which we use the known genealogy to derive a correction factor for the case-control association chi2 test. We perform analytical power calculations for each of the two tests by deriving their respective noncentrality parameters. The QLS test is more powerful than the corrected chi2 test in every situation considered. Indeed, under certain regularity conditions, the QLS test is asymptotically the locally most powerful test in a general class of linear tests that includes the corrected chi2 test. The two methods are used to test for associations between three asthma-associated phenotypes and 48 SNPs in 35 candidate genes in the Hutterites. We report a highly significant novel association (P=2.10-6) between atopy and an amino acid polymorphism in the P-selectin gene, detected with the QLS test and also, but less significantly (P=.0014), with the transmission/disequilibrium test.

Alleles↗

PubMed2004

A genomewide search using an original pairwise sampling approach for large genealogies identifies a new locus for total and low-density lipoprotein cholesterol in two genetically differentiated isolates of Sardinia.

A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.

Cholesterol↗

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↗