摘要:

AbstractThiopurine methyltransferase (TPMT) catalyzes thiopurineS‐methylation, an important metabolic pathway for drugs such as 6‐mercaptopurine (6‐MP). Inherited differences in the activity of this enzyme are related to individual differences in the therapeutic efficacy and toxicity of 6‐MP and other thiopurine drugs. Variation of TPMT activity in the red blood cell (RBC) has been found to reflect activity differences in less accessible tissues. Previously reported qualitative analyses of inheritance of RBC TPMT in families suggested that a major gene plays a role in the regulation of activity of this enzyme. In the present study we completed complex segregation analyses of RBC TPMT activity of 213 individuals in 49 families that were randomly ascertained through children in the Rochester, MN, public school system. We found clear evidence of a major gene effect on RBC TPMT activity. Both transformed and untransformed data supported the segregation of a Mendelian major gene with frequency of 0.94 for the allele conferring high enzyme activity. The genotype distributions of individuals who were homozygous for the low activity allele, heterozygous, and homozygous for the high activity allele accounted for approximately 0.3%, 11.2%, and 88.5%, respectively, of the individuals in the sample. This major locus accounted for 66% of the total variance in untransformed RBC TPMT activity. Although there were significant residual family correlations among probable high activity homozygotes, there was insufficient power to detect additional major locus or polygenic inheritance effects on the residual variance. © 1995 Wiley

ISSN:0741-0395    

DOI:10.1002/gepi.1370120102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractWe present ARCAD, a method to estimate the disease risk associated with mutation carrier status using data on families ascertained by affected individuals, in which a germline mutation has been detected. Because the event of interest, the age of onset, is a censored variable, the method uses the survival analysis approach to formulate the likelihood. Provided that selection criteria are clearly defined, the ascertainment bias is removed by including a correction term in the likelihood computation. We simulated family data and selected those with a proband affected before age 17, and at least one or at least two relatives affected before age 46. We show that including the correction for the ascertainment provides reliable estimates of the risk, even when many individuals are not tested for the mutation. An application to cancer risk and germline p53 mutations is presented. We routinely investigate the p53 status for all the children treated in the Department of Pediatric Oncology at the Institute Gustave Roussy, whose family displays at least one relative affected by cancer before age 46. We identified 5 families with an inherited germline p53 mutation. The risk for any cancer for a mutation carrier estimated by ARCAD was 42% within the age class 0–16 years, 38% within the age class 17–45 years, and 63% after 45 years, with a lifetime risk of 85%. These risks are almost entirely explained by the occurrence of the six most frequent cancers encountered in the Li‐Fraumeni syndrome. © Wiley‐L

ISSN:0741-0395    

DOI:10.1002/gepi.1370120103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractIn order to investigate currently used model fitting strategies for twin data, analysis of variance (ANOVA) and path‐maximum‐likelihood (PATH‐ML) methods of analyzing twin data were compared using simulation studies of 50 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs. Phenotypic covariance was partitioned into additive genetic effects (A), environmental effects common to cotwins (C), and environmental variance unique to individuals (E). ANOVA and PATH‐ML had identical power to detect total covariance. The PATH‐ML AE model was much more powerful than ANOVA comparisons ofrMZ andrDZ to detect A. However, to be unbiased, the AE model requires the assumption that C = 0.0. To allow use of the AE model to estimate A, the null hypothesis C = 0.0 is tested by comparing the goodness of fit of the ACE and AE models. Simulation of 50 MZ and 50 DZ pairs revealed that C must be greater than 55% of total variance before the null hypothesis would be rejected (P<0.05) 80% of the time. Several recent publications were reviewed in which the null hypothesis C = 0.0 was accepted and apparently upwardly biased estimates of A, containing C, were presented with unrealisticPvalues. It was concluded that use of the AE model to estimate A gives an inflated view of the power of relatively small twin studies. It was recommended that ANOVA or comparison of the ACE and CE PATH‐ML models be used to estimate and test the significance of A as neither requires that C = 0.0. © Wil

ISSN:0741-0395    

DOI:10.1002/gepi.1370120104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe purposes of this study are to determine the frequencies of the different genetic forms of retinitis pigmentosa and to perform segregation analysis in the different genetic subtypes. Retinitis pigmentosa was diagnosed in 263 persons from 132 families. The frequency of the autosomal recessive type was the highest (31.8%) while the X‐linked type was very rare (1.5%). The frequency of autosomal dominant type was 14.4% and the simplex cases constituted half of the total cases of RP registered in our community. In conclusion, in our population the high proportion of simplex cases and the low number of X‐linked families are noticeable. The result of segregation analysis showed good agreement with expectation in autosomal dominant and autosomal recessive families but no more than 60% of all simplex cases were autosomal recessive. The proportion of sporadic cases was estimated statistically to be 39.9% of the total simplex cases. © Wiley‐Lis

ISSN:0741-0395    

DOI:10.1002/gepi.1370120105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractHLA‐A, ‐B, ‐C, ‐DR, and ‐DQ typings of the Schmiedeleut Hutterites of South Dakota were collected as part of an ongoing genetic‐epidemiologic study of HLA and fertility. A total of 1,082 individuals, including 852 married adults representative of the reproductive population of this isolate, were characterized for five‐locus HLA haplotypes. HLA‐A1, A2, A3, and A24 accounted for 75% of observed HLA‐A alleles and HLA‐B27, B35, B51, and B62 accounted for 55% of observed HLA‐B alleles. S‐leut Hutterites are derived from 68 or fewer ancestors. However, only 48 ancestral HLA haplotypes were observed and nine of these accounted for over 52% of the observed haplotypes. Measures of two‐locus linkage disequilibrium derived from these haplotypes indicated that one‐third to half of the observed HLA‐A/B, B/DR, and A/DR allele combinations exhibited highly statistically significant linkage disequilibrium. Allele and haplotype frequencies did not differ between males and females. Recombination rates of 0.004% and 0.005% between HLA‐A and ‐C and between HLA‐B and ‐DR, respectively, were observed. This HLA profile points out a paucity of HLA alleles and haplotypes in this population and marked linkage disequilibrium among the HLA allele

ISSN:0741-0395    

DOI:10.1002/gepi.1370120106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractTo investigate the nature of the genetic component controlling susceptibility to leprosy and its subtypes, 402 nuclear families were ascertained through a leprosy patient followed at the Dermatology Hospital in Ho Chi Minh City, Vietnam; 285 families were of Vietnamese origin and 117 were of Chinese origin with a higher proportion of lepromatous forms among Chinese patients. Segregation analyses were conducted using the model developed by Abel and Bonney [(1990)Genet Epidemiol7:391–407], which accounted for variable age of onset and time‐dependent covariates. Three phenotypes were considered: leprosy per se (all forms of leprosy together), nonlepromatous leprosy, and lepromatous leprosy. For each of this phenotype, analyses were performed on the whole sample and separately on the Vietnamese and the Chinese families. The results showed that a single Mendelian gene could not account for the familial distributions of leprosy per se and its two subtypes in the whole sample. However, these results were different according to the ethnic origin of the families. In the Vietnamese subsample, there was evidence for a codominant major gene with residual familial dependences for the leprosy per se phenotype, and borderline rejection of the Mendelian transmission hypothesis for the nonlepromatous phenotype. In Chinese families, strong rejection of Mendelian transmission was obtained in the analysis of leprosy per se, and no evidence for a familial component in the distribution of the nonlepromatous phenotype was observed. For the lepromatous phenotype, the discrimination between models was poor, and no definitive conclusion could be reached. Referring to immunological data, we suggest that these results could be explained by a heterogeneity in the definition of the lepromatous phenotype. It is likely that progress in the understanding of the genetic components involved in the expression of leprosy will come from a better definition of the phenotype under study, and immunological studies are ongoing in this population to investigate this hypothesis. © Wiley‐Lis

ISSN:0741-0395    

DOI:10.1002/gepi.1370120107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractAn increased frequency of the apolipoprotein E type 4 allele (APOE‐4) has previously been associated with both late‐onset sporadic and late‐onset familial Alzheimer disease (AD) [Strittmatter et al. (1993)Proc Natl Acad Sci USA90:1977–1981; Saunders et al. (1993a)Neurology43:1467–1472]. To further investigate this association we genotyped affected individuals from 92 separate AD pedigrees including both early‐ and late‐onset cases. An increased frequency of the APOE‐4 allele was found only among the late‐onset cases, both familial and sporadic, confirming the earlier reports. In addition, age at onset was significantly decreased in the APOE‐4 homozygotes (in late onset families) compared to either APOE‐4 heterozygotes or individuals not carrying an APOE‐4 allele. We also observed a significantly decreased frequency of the APOE‐2 allele in both the early‐and late‐onset familial cases. These results strengthen the argument for a direct role of APOE in susceptibi

ISSN:0741-0395    

DOI:10.1002/gepi.1370120108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe genetic control of the total IgE, the immunoglobulins E involved in allergy, remains still unclear. Although high IgE levels were found to be determined by a recessive major gene in several studies, other modes of inheritance were also reported. Moreover, at least two different genetic mechanisms controlling the IgE regulation have been suggested: one involved in the specific IgE response and the other one in the nonspecific response. To better understand the genetic mechanisms controlling IgE variation, we performed segregation analysis of IgE levels by ignoring or taking into account the specific response to allergens (SRA). Analyses were conducted using the class D regressive model, in a sample of 234 Australian nuclear families randomly selected during the winter months, when IgE levels are the lowest (basal). SRA, when included as a covariate in the model, was defined by one of the three following criteria: (1) raised specific IgE level for one or more allergens, (2) positive skin test for one or more allergens, and (3) at least one of the (1) or (2) criteria. When the presence of SRA is ignored, the familial transmission of total IgE level is compatible with the segregation of a recessive major gene and residual familial correlations. When the presence of SRA is accounted for in the analysis, whether defined by criteria (1), (2), or (3), there is still evidence for a recessive major gene controlling IgE levels but residual familial correlations are no longer significant. In addition, no interaction between this major gene and SRA is shown here. Our results suggest that this gene, which accounts for 28% of the variation of the trait, may be involved in the control of basal IgE production, independently of specific response to allergens. © Wiley‐Liss, I

ISSN:0741-0395    

DOI:10.1002/gepi.1370120109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

ISSN:0741-0395    

DOI:10.1002/gepi.1370120110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

ISSN:0741-0395    

DOI:10.1002/gepi.1370120101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY