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PubMed1980

Cancer mortality in a human isolate.

Cancer mortality (1965--77) among 12,652 members of an inbred human religious isolate, the Hutterites, was compared with expectations based on mortality rates for the U.S. white population in 1970. Overall, Hutterites had significantly fewer deaths from cancer than expected (P < 0.01), due primarily to fewer lung cancers among males. Smoking is prohibited for this religious group. The most frequent types of cancers were leukemia and cancers of the digestive system, the prostate gland, and the female breast. Preliminary results suggest an association between recessive alleles and childhood leukemia. More stomach and rectal cancers were observed than expected, but differences were generally not significant. Familial aggregates of cancers of the stomach and breast are being investigated. The low frequency of cervical cancer is consistent with current evidence for an association of cervical cancer with early age at first intercourse and promiscuity, neither of which is characteristic of this population.

Canada↗

PubMed1996

Genetic variation and evolutionary stability of the FMR1 CGG repeat in six closed human populations.

In an attempt to understand the allelic diversity and mutability of the human FMR1 CGG repeat, we have analyzed the AGG substructure of this locus within six genetically-closed populations (Mbuti pygmy, Baka pygmy, R. surui, Karitiana, Mayan, and Hutterite). Most alleles (61/92 or 66%) possessed two AGG interspersions occurring with a periodicity of one AGG every nine or ten CGG repeats, indicating that this pattern is highly conserved in all human populations. significant differences in allele distribution were observed among the populations for rare variants possessing fewer or more AGG interruptions than the canonical FMR1 CGG repeat sequence. Comparisons of expected heterozygosity of the FMR1 CGG repeat locus with 30 other microsatellite loci, demonstrated remarkably similar levels of polymorphism within each population, suggesting that most FMR1 CGG repeat alleles mutate at rates indistinguishable from other microsatellite loci. A single allele (1 out of 92) was identified with a large uninterrupted tract of pure repeats (42 pure CGG triplets). Retrospective pedigree analysis indicated that this allele had been transmitted unstably. Although such alleles mutate rapidly and likely represent evolving premutations, our analysis suggests that in spite of the estimated frequency of their occurrence, these unstable alleles do not significantly alter the expected heterozygosity of the FMR1 CGG repeat in the human population.

Biological Evolution↗

PubMed1979

The Bowen-Conradi syndrome -- a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities.

This paper describes six Hutterite children from five families who appear to have been affected by the same syndrome that was described in two brothers by Bowen and Conradi [1]. Our additional cases confirm that the major features of the syndrome include porportionate intrauterine growth retardation, microcephaly, micrognathia, a prominent nose, rocker-bottom feet, joint limitation, and failure to thrive, with death within the first year of life. Bowen-Conradi syndrome is an autosomal recessive trait and pedigree records show that all six families now known are related to each other through two couples born in the late 1700s but that there are additional earlier possible sources of the responsible gene. The differential diagnosis of this syndrome is discussed.

Abnormalities, Multiple↗

PubMed2003

Finding starting points for Markov chain Monte Carlo analysis of genetic data from large and complex pedigrees.

Genetic data from founder populations are advantageous for studies of complex traits that are often plagued by the problem of genetic heterogeneity. However, the desire to analyze large and complex pedigrees that often arise from such populations, coupled with the need to handle many linked and highly polymorphic loci simultaneously, poses challenges to current standard approaches. A viable alternative to solving such problems is via Markov chain Monte Carlo (MCMC) procedures, where a Markov chain, defined on the state space of a latent variable (e.g., genotypic configuration or inheritance vector), is constructed. However, finding starting points for the Markov chains is a difficult problem when the pedigree is not single-locus peelable; methods proposed in the literature have not yielded completely satisfactory solutions. We propose a generalization of the heated Gibbs sampler with relaxed penetrances (HGRP) of Lin et al., ([1993] IMA J. Math. Appl. Med. Biol. 10:1-17) to search for starting points. HGRP guarantees that a starting point will be found if there is no error in the data, but the chain usually needs to be run for a long time if the pedigree is extremely large and complex. By introducing a forcing step, the current algorithm substantially reduces the state space, and hence effectively speeds up the process of finding a starting point. Our algorithm also has a built-in preprocessing procedure for Mendelian error detection. The algorithm has been applied to both simulated and real data on two large and complex Hutterite pedigrees under many settings, and good results are obtained. The algorithm has been implemented in a user-friendly package called START.

Algorithms↗

PubMed1991

Statistical analysis of outcomes from repeated pregnancies: effects of HLA sharing on fetal loss rates.

As part of our ongoing studies of genetic markers of reproductive outcome in the Hutterites, we have been analyzing potential risk factors for pregnancy outcomes. In particular, we are interested in the effects of HLA sharing between parents on fetal loss rates. Pregnancy outcome data such as these have two characteristics that create statistical challenges, i.e., repeated observations per couple and between-couple heterogeneity in risk. We critically examine four approaches based on the logistic model for the analysis of this and similar data: 1) unconditional likelihood analysis with and without fixed cluster effects; 2) conditional likelihood analysis; 3) mixed-effects analysis with random cluster effects; and 4) the robust generalized estimating equation (GEE) procedure. Of these approaches, the GEE method of Liang and Zeger would be best suited for the analysis of our data when the question of interest concerns a variable that is constant over all pregnancies, such as HLA sharing. If the question concerns a couple's risk associated with a changing variable such as maternal age, the mixed-effects analysis is the more appropriate.

Cluster Analysis↗

PubMed2001

The effect of pedigree complexity on quantitative trait linkage analysis.

Due to the computational difficulties of performing linkage analysis on large complex pedigrees, most investigators resort to simplifying such pedigrees by some ad hoc strategy. In this paper, we suggest an analytical method to compare the power of various pedigree simplification schemes by using the asymptotic distribution of the likelihood-ratio statistic. We applied the method to the large Hutterine pedigree. Our results indicate that the breaking and reduction of inbreeding loops can greatly diminish the power to localize quantitative trait loci. We also present an efficient Monte Carlo method for estimating identity-by-descent allele sharing in large complex pedigrees. This method is used to facilitate a linkage analysis of serum IgE levels in the Hutterites without simplifying the pedigree.

Adult↗

PubMed2001

Detection of mis-specified relationships in inbred and outbred pedigrees.

Genome screen data collected for linkage analysis can be used to detect pedigree errors. We have developed methods applicable to a broad range of relationships. We discuss applications of our methods to data on asthma, in which we detect a number of likely mis-specified relative pairs. We propose a graphical method for error detection in complex inbred pedigrees, with application to the Hutterites.

Adult↗

PubMed1990

A new syndrome with cerebro-oculo-skeletal-renal involvement.

We report on an infant male who presented with microcephaly of prenatal onset, schizencephaly, decorticated disturbance of the neurological function, congenital optic atrophy, abnormal eye movements and nystagmus. In addition, he had a skeletal dysplasia with predominant acromelic involvement and a renal disease characterized by both nephritic and nephrotic changes. The natural history of his condition included severe postnatal failure to thrive, lack of development of psychomotor milestones, intractable seizures, terminal renal insufficiency with early death. Such spectrum of phenotypic abnormalities has never been reported before and we suggest that it may represent a new syndromic entity. The differential diagnosis with the oculo-skeletal-renal syndromes, with the osteodysplastic primordial dwarfism of the Taybi-Linder type and with the Hutterite cerebro-osteo-nephrodysplasia, is discussed.

Abnormalities, Multiple↗

PubMed2005

High parity is associated with increased bone size and strength.

Some, but not all, studies report an association between decreased hip fracture risk and high parity despite similar bone mineral density (BMD). Our hypothesis was that bone size, a major determinant of bone strength, is greater in women with high parity compared with low parity or nulliparous women. A cross-sectional study of 168 Hutterite women aged 40-80 years was conducted. BMD, bone mineral content (BMC) and bone area of the total body (TB), hip, femoral neck (FN), and lumbar spine (LS) were measured, as well as bone geometry at the 4% and 20% distal radius and bending strength at 20% radius. Diet and activity recall and strength measurements were obtained. Of the 168 women, 42 (25%) were nulliparous while the remaining women reported 1 to 16 births (median=6). Of the 126 parous women, 122 (97%) breast-fed their infants (range 1.5-24 months). Hip, FN and LS BMD were not associated with either parity or months of breast-feeding. TB BMC and bone area (both, p<0.05) and FN bone area (p<0.01) were associated with parity. FN bone area was 4% greater in women with 7+ vs 1-4 children. Torsional bending strength, which includes structural and material bone properties, at the 20% distal radius was greater with higher parity (p=0.01). No bone measure was associated with average months of breast-feeding. High parity is associated with increased radial torsional bending strength and femoral neck size. The greater femoral neck size, without higher BMD, may explain the reduced hip fracture risk among women with high parity previously reported in some studies.

Adult↗

PubMed1998

Association and linkage of LDLR gene variation with variation in plasma low density lipoprotein cholesterol.

The role of common variation in the low density lipoprotein (LDL) receptor gene (LDLR) as a determinant of variation in plasma LDL cholesterol in normolipidemic populations is not well established. To address this question, we used both association and linkage analysis to evaluate the relationship between plasma LDL cholesterol and genetic variation in LDLR and in three other candidate genes for lipoprotein metabolism, namely, APOE, PONI, and LPL. We studied a sample of 719 normolipidemic Alberta Hutterites, who comprised 1217 sib pairs. Variation in each of the four candidate genes was significantly associated with variation in plasma LDL cholesterol, but the average effects of the alleles were small. In contrast, sib pair analysis showed that only the LDLR gene variation was linked with variation in plasma LDL cholesterol (P = 0.026). Thus, the common LDLR gene variation was both associated with and linked to variation in plasma LDL cholesterol, suggesting that there is a functional impact of structural variation in LDLR on plasma LDL cholesterol in this study sample. However, the absence of linkage of variation in LDL cholesterol with the other three candidate genes, in particular APOE, is consistent with a lower sensitivity of linkage analysis compared with association analysis for detecting modest effects on quantitative traits. Attributes such as the genetic structure of the study sample, the amount of variance attributable to the locus, and the information content of the marker appear to affect the ability to detect genotype-phenotype relationships using linkage analysis.

Adult↗

PubMed2006

Sex-specific genetic architecture of asthma-associated quantitative trait loci in a founder population.

Identifying genes that influence susceptibility to asthma-related and atopy-related phenotypes has been challenging, owing to clinical heterogeneity and a complex underlying genetic architecture that includes both gene-gene and gene-environment interactions. In this article, we report the results of genome-wide linkage and association studies of eight asthma-associated quantitative traits in the Hutterites, a founder population of European descent. Our study revealed significant sex-specific genetic architecture for at least five of these traits, and identified 13 genome-wide significant quantitative trait loci (QTL) by linkage or association that are present in only one of the sexes (nine in males, four in females).

Asthma↗

PubMed1987

Religion and differences in morbidity and mortality.

Religion and its effects on morbidity and mortality (with particular emphasis on mortality) are reviewed as are special issues which have in the past made the study of religion and death difficult. The morbidity and mortality experience of various religious groups is portrayed, including Protestants, Catholics, Jews, Muslims, the clergy, Seventh-day Adventists, Latter-day Saints, Parsis, Jehovah's Witnesses and Hutterites. Studies of religious effects on morbidity and mortality have broadened in focus from the study of specific health practices, or health-related behaviors, to include the study of social support, religious participation and health-related attitudes. Gaps in the literature are identified and a preliminary model of religion's effect on morbidity and mortality is discussed.

Attitude to Death↗

PubMed2006

Divergent risk of multiple sclerosis in two anabaptist communities in America.

A lowered risk of multiple sclerosis (MS) has been reported in the Hutterite community residing mainly in southern Canada. In another anabaptist community, the Old Colony Mennonites (OCM), settled in Canada and spread to Latin America, only a large pedigree with an increased risk of autoimmune diseases, including type I diabetes and three cases of MS, was reported. The prevalence of MS in the pedigree (3,158 per 100,000), even when observing its confidence interval, seems rather high, and the MS prevalence in the Mennonite general population is assumed at least to be equal to the Canadian rates. Based upon an extended study of the literature, the hypothesis that smoking and curing with nitrate/nitrite plays any role, by interaction with inflammatory intestinal changes in childhood infections, is supported. In addition, tobacco smoking and short-term breast-feeding as possible risk factors are also in line with a higher MS risk in OCM, whereas insecticides and herbicides can be excluded as risk factors in MS.

Americas↗

PubMed2004

Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency.

Liver carnitine palmitoyltransferase I (CPT I) deficiency is a rare disorder of hepatic mitochondrial long-chain fatty acid oxidation. It characteristically presents with symptoms associated with failure of ketogenesis (hypoketotic hypoglycemia). The disorder is due to mutations in the CPT 1A gene for which few patients have been characterized. We present here four novel mutations in five patients from four families with severe enzyme deficiency. Three of these are missense mutations (G465W, R316G, and F343V) and the fourth a nonsense mutation (R160X). Other than small Inuit and Hutterite populations in Canada and the Northern plains, there is complete heterogeneity of disease-causing mutations within CPT I deficient families with each demonstrating unique mutations. Because there are no easily recognizable disease-specific metabolite markers, diagnostic confirmation of this disorder requires a combination of enzymatic analysis and whole gene sequencing.

Adolescent↗

PubMed1981

Cancers of the breast and female genital system: search for recessive genetic factors through analysis of human isolate.

To investigate the importance of recessive genes in female breast and genital cancers, we have conducted investigations in the Hutterites, a highly inbred genetic isolate in North America. The homogeneous life style of this group, which lives on communal farms, also facilitates distinction between shared environmental and genetic factors. We ascertained 177 cases of cancer (all organ systems) through Canadian and United States cancer registries, field trips, and searches of death certificates. Breast cancer and endometrial cancer mortalities were those expected for 1970 United States whites, but no deaths due to squamous cervical carcinoma were ascertained in this monogamous population. Inbreeding coefficients (F) for cases were higher than means for matched controls for each of the four cases of breast cancers that occurred in younger women (less than 45 years of age), for four of five cases of endometrial cancer, and for the single cases of uterine leiomyosarcoma, dysgerminoma, and ovarian adenocarcinoma. By contrast, in cases of breast cancer that occurred in women 45 years of age or older, only four of 15 F's were above those for controls. There is a significant difference between the two breast cancer age groups with respect to the likelihood that the F of cases was higher than the F of controls (chi 2 = 6.99, p less than 0.01). However, grouping cases by type, none of the F distributions were significantly different from those of their matched controls. These preliminary genetic investigations thus conform certain concepts concerning breast and female genital cancer but also suggest the desirability of further studies to elucidate the role of genetic factors in premenopausal breast cancer.

Adult↗

PubMed1999

Absence of association between genetic variation in the LIPC gene promoter and plasma lipoproteins in three Canadian populations.

The promoter sequence variant -480T in the hepatic lipase gene (LIPC) has been shown to be significantly associated with low post-heparin hepatic lipase activity. Some studies have also found that the -480T variant is associated with elevation in plasma HDL cholesterol. We tested for associations of LIPC -480T with plasma lipoprotein traits in samples taken from three distinct Canadian populations: 657 Alberta Hutterites, 328 Ontario Oji-Cree and 210 Keewatin Inuit. Plasma HL activity was not available for analyses. The LIPC -480T allele frequencies in these three groups, respectively, were 0.219, 0.527 and 0.383, and the prevalence of LIPC -480T/T homozygotes was, respectively, 0.042, 0.274 and 0.167. No significant association was found between LIPC -480T and plasma HDL cholesterol or apolipoprotein AI concentration, after adjusting for covariates including gender and body mass index. There was no consistent relationship between the population mean plasma HDL cholesterol concentration and the population LIPC -480T frequency. Our findings are consistent with the idea that the common promoter variation in LIPC, which has been reported to be associated with variation in post heparin HL activity and HDL triglyceride concentration, is not always associated with variation in plasma HDL cholesterol concentration, possibly due to yet unspecified environmental or genetic factors.

Adolescent↗

PubMed1996

Population genetic studies of HLA-G: allele frequencies and linkage disequilibrium with HLA-A1.

HLA-G is a class I gene that is expressed in the extravillous cytotrophoblast. Although the function of this gene is still unknown, its expression at the maternal-fetal interface suggests that HLA-G may play a key role in the induction of tolerance during pregnancy. Preliminary to our studies of the effects of HLA-G polymorphisms on pregnancy outcome, we have defined HLA-G alleles in the Hutterites. We report here the presence of nine HLA-G alleles that differ with respect to nucleotide sequences, including four groups of alleles that differ with respect to amino acid sequences, and striking linkage disequilibrium between HLA-G and HLA-A alleles. The levels and sites of polymorphism in HLA-G suggest that this gene had a unique evolutionary history and may perform nonclassical functions at the maternal-fetal interface.

Adult↗

PubMed1997

Population genetic studies of HLA-E: evidence for selection.

HLA-E is a nonclassical, class I gene (Ib) of unknown function. The study was initiated to determine the amount and nature of the variation in the class Ib gene HLA-E in diverse ethnic groups. A single base-pair substitution (A-->G at 382, exon 3) resulting in a change from an arginine (R) to a glycine (G) at codon 107 was found. A glycine was present at position 107 in individuals from four ape species, suggesting that EG107 is the older of the two alleles. The two human alleles were present in all samples studied. The alleles were in linkage disequilibrium with HLA-A (W = 0.58), HLA-B (W = 0.59) and HLA-C (W = 0.55) in the Hutterites. The frequencies of the two HLA-E alleles were more equal than expectations based on neutrality in inbred and outbred Caucasian samples (Watterson's F = 0.506, p = 0.02 and F = 0.512, p = 0.047, respectively) and nearly significant in African-American and Hispanic samples (F = 0.513, p = 0.063 and F = 0.508, p = 0.053). These data suggest that this polymorphism arose before the expansion of Homo sapiens and has been maintained in diverse populations by stabilizing selection.

Alleles↗