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PubMed1990

High fertility of Old Colony Mennonites in Mexico.

Old Colony Mennonites in Mexico appear to demonstrate natural fertility, using no form of artificial birth control and apparently not attempting to limit family size. The resulting fertility is nearly as high as that of the Hutterites, although the Mennonites lack the communal economic system of the latter. Most Mennonites in Mexico migrated from Canada in the 1920s, and the largest single settlement, called the Manitoba Colony, is one of four in the state of Chihuahua. A 1967 partial census obtained data from 38% of the Mennonite households. Family size in the sample was close to that in a local survey taken in the same year. Available church records matched with census forms permitted verification of and corrections to 560 female reproductive histories. The median number of live births to women over age 45 years was 9.5, compared with 10.4 in the Hutterites. Age-specific marital fertility rates and birth intervals closely resembled those of the Hutterites.

Adolescent↗

PubMed1985

The natural history of familial hypopituitarism.

Familial hypopituitarism in the Hutterite Brethren is an autosomal recessive disorder involving sequential loss of anterior pituitary tropic hormones. Five individuals from two closely related families have been followed for 19 years. Both families are well integrated into the Hutterite community. Three sibs elected not to be treated with growth hormone and sex steroids. These sibs developed growth hormone and gonadotropin deficiency in the first decade of life, with subsequent loss of TSH function and finally ACTH deficiency in the third decade. The pattern of hormone loss differed in the second family, in that deficiency of growth hormone, gonadotropins, and TSH was evident in the first decade. A third family has been reported to have the same disorder and is from a different endogamous subdivision from that of the two families described here. Genealogical analysis of the three families shows that there are four ancestral couples common to the six parents. Thus all affected individuals are likely to be identical by descent for the same ancestral allele. The gene for hypopituitarism is not closely linked to the gene for growth hormone nor to the HLA region.

Chromosomes, Human, 16-18↗

PubMed1984

A statistical test for detection of ancestral genetic contributions to disease occurrence in finite populations.

We have been investigating cancer patterns in the Hutterites, a religious isolate residing on communal farms [Martin et al, 1980a,b,c]. Advantages of this population include extensive and accurate genealogies, essentially complete case ascertainment, and relatively uniform environmental background with regard to geographic location, lifestyle, and diet. However, application of the common epidemiological approach to familial risk assessment based on incidence in relatives of index cases [Haenszel, 1959] posed difficulties because all cases are probands. We also planned to employ matching to control for important confounders and thus had to deal with the problems of the matching of cases and controls as well as the existence of complex inbreeding [Hauck and Martin, 1982]. Our basic approach was to compare coefficients of kinship (Fm, a measure of coancestry) of cases with each other to coefficients between cases and matched controls drawn from the same population. We have developed a paired t-type statistic to assess the significance of observed differences. We present, as examples, application of our methods to the analysis of Hutterite data on neurofibromatosis, known to be inherited in autosomal dominant fashion, and on cancer. Neurofibromatosis showed significant familial aggregation, as expected. Breast, colon-rectal, and stomach cancer did not. We then show how to evaluate power and to determine appropriate sample sizes for detecting specified increases in kinship.

Biometry↗

PubMed2005

Multilocus linkage disequilibrium mapping by the decay of haplotype sharing with samples of related individuals.

We consider the problem of multilocus linkage disequilibrium (LD) mapping of a trait-associated variant from case-control samples in which some individuals may be related. Our method, which we call DHS-R, is an extension of the decay of haplotype sharing (DHS) method of McPeek and Strahs and Strahs and McPeek. The DHS-R method shares the main features of the DHS method: (1) it allows construction of a confidence interval for the location of a trait-associated variant; (2) it allows for missing observations and unphased genotype data, with the uncertainty in the haplotypes taken into account in the analysis; and (3) it allows for heterogeneity, mutation, recombination, and background LD. The main advances of the DHS-R are (1) the ability to include individuals of arbitrary known relationship (including inbreeding) in the case and control samples; (2) an extension to allow partially-phased haplotypes derived from case-parent trio genotype data; and (3) an extension to allow for genotyping error in the model. Our method, which uses a hidden Markov model for likelihood calculation and maximization, has the advantage of being computationally feasible even in a large, complex pedigree. Simulations based on a 13-generation, 1,623-member Hutterite pedigree demonstrate accurate coverage of the confidence intervals for location of the variant. We apply the method to fine-mapping of a susceptibility locus for bronchial hyperresponsiveness (BHR) in the Hutterites. The results confirm the importance of taking into account the relatedness of individuals in LD mapping.

Algorithms↗

PubMed1993

Sex-biased lactational duration in a human population and its reproductive costs.

The authors tested the proposition that among humans (1) differences in lactational duration result in differences in costs of reproduction even under rich nutritional conditions; and (2) elimination of factors postulated to favor male-biased parental care will be reflected in elimination or reversal of sex-biased care. To do so, the authors examined the relationship between lactactational duration and fertility among Hutterites, a communal-living human population in which the levels of nutritional resources and fertility are high, breast feeding is the norm, contraceptive use is limited, and the collective social and economic system results in low resource variance among individuals. The authors demonstrate that even under good nutritional conditions, duration of nursing was a significant predictor of the length of time to next pregnancy and that nursing continued to suppress fertility after the resumption of menses. Moreover, the authors find that daughters were nursed longer than sons, leading to a longer interval to next pregnancy. The authors examine this uncommon, but not unique, finding of female-biased human parental care in the light of Hutterite social structure, and they explore the consistency of this finding with the most applicable models of parental investment.

Amenorrhea↗

PubMed2005

Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample.

A recent genome-scan identified the Leu33Pro polymorphism in the beta3 integrin (ITGB3) gene as a quantitative trait locus for whole blood serotonin level in a large Hutterite pedigree. Because both the Leu33Pro polymorphism and the serotonin system have been implicated in cardiovascular disease (CVD) risk and treatment response, we studied additional variation in ITGB3 and its relationship to intermediate phenotypes associated with CVD in the same population. We examined associations between 15 single nucleotide polymorphisms (SNPs) across ITGB3 and five CVD-related traits in the Hutterites: plasma levels of high density lipoprotein-cholesterol (HDL-c), triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), and lipoprotein(a) [Lp(a)] and blood pressure or hypertension. Seven of these SNPs in ITGB3 were associated with whole blood serotonin. Among the intermediate CVD-related phenotypes, only Lp(a) was associated with multiple ITGB3 SNPs, five of which were also associated with serotonin. A sex-stratified analysis revealed that the association between ITGB3 and Lp(a) is present only in females, whereas the association between ITGB3 and serotonin is concentrated in males. Our results suggest that variation in ITGB3 in addition to Leu33Pro could contribute to susceptibility to CVD and serotonin in a sex-specific manner.

Adolescent↗

PubMed1982

Incisor shape and incisor crowding: a re-evaluation of the Peck and Peck ratio.

Although lower incisor tooth shapes, defined as mesiodistal length divided by labiolingual width, have bee proposed as important factors in lower incisor crowding, the question of whether or not these ratios are more useful than simple measurements of incisor mesiodistal length has not been addressed. In order to test this question, we measured mesiodistal and labiolingual incisor dimensions and lower incisor crowding (defined as the crowding index proposed by Little) on dental casts from two groups: 100 pretreatment orthodontic patients and 100 Hutterites from a religious isolate in Canada. The orthodontic patients are our primary interest. The Hutterites serve mainly to test whether or not results are consistent in another population of different ethnicity, age distribution, and occlusal status. In each population, incisor crowding is correlated with the tooth shape ratios, confirming the general observations of Peck and Peck. However, mesiodistal incisor lengths have slightly higher correlations with crowding than the shape ratios. In multiple regression equations to predict crowding in each population, incisor mesiodistal lengths are the most important variable, and neither the tooth shape ratios nor labiolingual widths significantly improve the equations. Although statistically significant, none of the correlations is higher than 0.30, and they are thus of little clinical value. The use of tooth size measurements or ratios as a guide to clinical procedures is an oversimplification of a complex problem.

Canada↗

PubMed1993

Deficit of HLA homozygotes in a Caucasian isolate.

Deficits of HLA-A, -B homozygotes observed many years ago in two inbred populations suggested negative selection against HLA homozygotes. To determine whether a similar deficiency would be observed in the S-leut Hutterites, a well-characterized Caucasian isolate of European ancestry, and to determine whether selection operated at the allele, locus, or haplotype level, observed and expected numbers of homozygotes were compared in 852 adult Hutterites. Deficits ranging from 11% to 24% were observed for all five loci examined (HLA-A, -B, -C, -DR, and -DQ). However, these deficits were secondary to, and almost completely accounted for by, a 64% loss of individuals homozygous for the haplotype. There was no evidence of deficits affecting only a single allele or locus. The data indicate strong negative selection against HLA homozygotes. This could be due, at least in part, to decreased fecundability among couples sharing HLA-DR. However, these data suggest that additional selective factors acting at the level of the haplotype also operate in this population.

Adult↗

PubMed1988

Review of cancer among 4 religious sects: evidence that life-styles are distinctive sets of risk factors.

The occurrence of various types of cancer have been reviewed and evaluated in 4 religious groups. These patterns have been critically assessed in light of the distinctive life-style features of these groups. All 4 religious groups considered in this paper have reduced overall rates of cancer, suggesting that the life-styles of all 4 groups have merit in terms of reducing the overall risk of cancer. The rate of smoking among these groups is nearly nil, and the lung cancer rate in all 4 of these religious groups is strikingly low. Cancer of the oral structures, pharynx, larynx, and esophagus is also generally quite low. Amish and Hutterites have unusually high rates of breast cancer and juvenile leukemia. Reproductive factors frequently mentioned as risk factors for breast cancer cannot explain the excess breast cancer in the Amish and Hutterite women because they should have had the effect of reducing the rate. None of the numerous risk factors, normally suggested for leukemia, are consistent with this observation. The observations on ovarian cancer tend to confirm low parity and late age at first birth as risk factors, although the evidence is not entirely consistent. Also, contrary to common observations, the pattern of ovarian cancer contrasts greatly with the breast cancer pattern, suggesting dissimilar risk factors. Their low rate of cervical cancer is consistent with promiscuity being a strong risk factor, but other frequently suggested risk factors were generally inconsistent with the observations. Cancers of the stomach, colon, rectum, urinary bladder and prostate, in these 4 religious groups, are not readily explained by the risk factors commonly implicated in cancer of these sites. The patterns of a few types of cancers were consistent with the prevailing opinions of risk factors, but some cancers were poorly explained and, in some cases, the cancer patterns contradicted commonly held opinions concerning risk factors. Religions that provide strong directives for the personal lives of adherents result in distinctive life-style, reflecting multiple disease related factors (risk factors and protective factors). Disease related factors are related to each other in simple or more complex ways (e.g. additive, multiplicative or even more complex). Therefore, when dealing with distinctive life-styles, it may be unwarranted to attempt to isolate individual risk factors.

Adult↗

PubMed2001

Variable association between genetic variation in the CYP7 gene promoter and plasma lipoproteins in three Canadian populations.

The promoter sequence variant -278A in the CYP7 gene, which encodes cholesterol 7-alpha hydroxylase, was previously reported to be associated with reduced plasma low density lipoprotein (LDL) cholesterol concentration. We tested for association of CYP7-278A with plasma lipoprotein traits in samples taken from three distinct Canadian populations: 594 Alberta Hutterites, 325 Ontario Oji-Cree and 190 Keewatin Inuit. The CYP7-278A allele frequencies in these three groups were 0.708, 0.466 and 0.490, respectively. The frequencies of CYP7-278A/A homozygotes were 0.481, 0.215 and 0.247, respectively. In the Hutterites, CYP7-278A was associated with reduced plasma HDL-cholesterol and apolipoprotein AI concentration. In the Oji-Cree, CYP7-278A was not significantly associated with any plasma lipoprotein trait. In the Inuit CYP7-278A was associated with elevated plasma total and LDL-cholesterol. There was no consistent relationship between the population mean plasma LDL-cholesterol concentration and the population CYP7-278A frequency. Our findings suggest that the common -278A promoter variant of CYP7 was inconsistently associated with variation in plasma LDL- and HDL-cholesterol in samples from three independent populations. The inconsistencies could be due to differences in genetic background or to unspecified environmental or genetic factors.

Adult↗

PubMed2000

Polymorphisms in olfactory receptor genes: a cautionary note.

The hundreds of human olfactory receptor (OR) genes are organized into clusters occurring on nearly every chromosome. Although their sequences are not always closely related, they share stretches of considerable similarity, both at the amino acid and nucleotide levels. We demonstrate here that an HLA complex-linked OR sequence, FAT11, for which recently a number of alleles have been claimed within the Hutterites, contains sequences derived from two closely related, linked OR genes, hs6M1-12 and hs6M1-16. Instead of indicating a difference between alleles of a given locus, two of the polymorphisms described for FAT11 (at amino acids 48 and 220 of the deduced protein sequence, respectively) may in fact reflect distinct sequences of hs6M1-12 and a further, closely related HLA-linked OR locus, hs6M1-13P. As a consequence, recombination rates in Hutterites in the region telomeric of HLA-G may have to be reconsidered.

Amino Acid Substitution↗

PubMed2005

Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification.

An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population. An identity-by-descent mapping approach using eight patients from three interrelated Hutterite families localized the gene for this syndrome to chromosome region 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. A 199-kb homozygous deletion encompassing the entire very low density lipoprotein receptor (VLDLR) gene was present in all affected individuals. VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. To our knowledge, this syndrome represents the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect.

Base Sequence↗

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↗

PubMed2004

Best linear unbiased allele-frequency estimation in complex pedigrees.

Many types of genetic analyses depend on estimates of allele frequencies. We consider the problem of allele-frequency estimation based on data from related individuals. The motivation for this work is data collected on the Hutterites, an isolated founder population, so we focus particularly on the case in which the relationships among the sampled individuals are specified by a large, complex pedigree for which maximum likelihood estimation is impractical. For this case, we propose to use the best linear unbiased estimator (BLUE) of allele frequency. We derive this estimator, which is equivalent to the quasi-likelihood estimator for this problem, and we describe an efficient algorithm for computing the estimate and its variance. We show that our estimator has certain desirable small-sample properties in common with the maximum likelihood estimator (MLE) for this problem. We treat both the case when parental origin of each allele is known and when it is unknown. The results are extended to prediction of allele frequency in some set of individuals S based on genotype data collected on a set of individuals R. We compare the mean-squared error of the BLUE, the commonly used naive estimator (sample frequency) and the MLE when the latter is feasible to calculate. The results indicate that although the MLE performs the best of the three, the BLUE is close in performance to the MLE and is substantially easier to calculate, making it particularly useful for large complex pedigrees in which MLE calculation is impractical or infeasible. We apply our method to allele-frequency estimation in a Hutterite data set.

Algorithms↗

PubMed2005

Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition.

BACKGROUND: A novel autosomal recessive condition, dilated cardiomyopathy with ataxia (DCMA) syndrome, has been identified in the Canadian Dariusleut Hutterite population, characterised by early onset dilated cardiomyopathy with conduction defects, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria. OBJECTIVE: To map DCMA syndrome and identify the mutation underlying this condition. METHODS: A genome wide scan was undertaken on consanguineous Hutterite families using a homozygosity mapping approach in order to identify the DCMA associated chromosomal region. Mutation analysis was carried out on positional candidate genes in this region by sequencing. Reverse transcriptase polymerase chain reaction and bioinformatics analyses were then used to characterise the mutation and determine its effect on the protein product. RESULTS: The association of DCMA syndrome with a 2.2 Mb region of chromosome 3q26.33 was found. A disease associated mutation was identified: IVS3-1 G-->C in the DNAJC19 gene, encoding a DNAJ domain containing protein of previously unknown function (Entrez Gene ID 131118). CONCLUSIONS: The DNAJC19 protein was previously localised to the mitochondria in cardiac myocytes, and shares sequence and organisational similarity with proteins from several species including two yeast mitochondrial inner membrane proteins, Mdj2p and Tim14. Tim14 is a component of the yeast inner mitochondrial membrane presequence translocase, suggesting that the unique phenotype of DCMA may be the result of defective mitochondrial protein import. It is only the second human disorder caused by defects in this pathway that has been identified.

Abnormalities, Multiple↗

PubMed1994

A gene-gender interaction affecting plasma lipoproteins in a genetic isolate.

The Hutterite Brethren are a genetic isolate characterized by high indices of relatedness and a communal agrarian lifestyle. We hypothesized that variation in their apolipoprotein (apo) E and lipoprotein lipase (LPL) genes would be associated with variation in fasting plasma lipoproteins. We measured plasma lipids, lipoproteins, and apolipoproteins and analyzed DNA for genotypes of apoE and LPL in 803 Hutterites. We observed that apoE and LPL genotypes were significantly associated with variations in plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, and apoB. When the data were subdivided by sex, apoE genotype was associated with plasma apoB-related traits in men, but LPL genotype was not. In contrast, LPL genotype was associated with plasma apoB-related traits in women, including triglycerides and LDL cholesterol. After accounting for age, body mass index, and colony of origin, the variation in these variables was much more significantly associated with LDL genotype than with apoE genotype in women but not in men. The association of LPL variation with plasma lipoproteins in women suggests that the functional effects of important structural elements within, flanking, or proximal to the LPL gene on chromosome 8p22 may be sex related.

Adult↗

PubMed1994

A polymorphism of the angiotensinogen gene associated with variation in blood pressure in a genetic isolate.

BACKGROUND: The Hutterite Brethren are a genetic isolate characterized by high indices of relatedness and a communal agrarian lifestyle. We hypothesized that variation of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes would be associated with variation in resting blood pressure in this group. We also hypothesized that the association would depend on the sex of the subjects. METHODS AND RESULTS: In 741 Hutterites, we measured blood pressure in quadruplicate and analyzed DNA for genotypes of an insertion/deletion (I/D) polymorphism of ACE and of two protein polymorphisms of AGT, namely, M235T and T174M. We tested for association between variation in systolic and diastolic blood pressures and genotypic class. We observed that genotypes of AGT codon 174 were significantly associated with variation in systolic blood pressure. We also tested for an interaction between the AGT genotype and sex. We observed that genotypes of AGT codon 174 were significantly associated with variation in systolic blood pressure only in men. The AGT codon 174 polymorphism accounted for 3.1% of the total variation in systolic blood pressure in men. CONCLUSIONS: The association of AGT variation with resting blood pressure in men is consistent with the existence of important structural elements within, flanking, or proximal to the AGT gene, whose functional impact might be related to differences in sex.

Adult↗

PubMedDate not supplied

Refusals and delay of immunization within southwest Alberta. Understanding alternative beliefs and religious perspectives.

BACKGROUND: Immunization is a necessary component of well child services within public health. Despite the documented effectiveness of vaccines, some parents choose to refuse or delay immunization for their children. Adherence to different beliefs has affected immunization coverage in one Regional Health Authority in Southwest Alberta. METHODS: This qualitative study involved exploratory, descriptive open-ended interviews with a sample of 47. The sample included people of Dutch ethnic background, Hutterites, and parents and practitioners who engage in alternative health beliefs and practices. RESULTS: Major findings include: 1) among the Dutch, most noted their decision to refuse to immunize was based on religious beliefs; 2) the Hutterites' decision not to immunize was due to their experiences with adverse reactions but was further supported by their use of alternative health; and, 3) the alternative health group are more concerned with the safety of vaccines with regard to the short- and long-term effects on their children's health. DISCUSSION: All three groups conveyed a common concern of child health and safety. Educational initiatives need to be implemented to allay parents' fears. Community development activities with individuals of the groups included here who support immunization will increase acceptance of immunization.

Adult↗