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At least 1,423 records · Page 79Linked to original sources
PubMed1993

Subtyping of alkylated human orosomucoid: evidence for a duplicated gene, ORM1*F2S.

Isoelectric focusing of human orosomucoid (ORM) was studied following different sample treatment. It is shown that: (i) alkylation with iodoacetamide leads to a drastic change in the isoelectric point (pI) of both ORM1 F2 and ORM2 A gene products and greatly improves the discrimination between ORM1 F1 and ORM1 F2; (ii) previous reduction of the molecule with dithiothreitol partially inhibits the pI transitions with resultant artifactual ORM1 F1F2S patterns that correspond in most cases to F2S phenotypes. With the technique now described, the persistence of three ORM1 gene products was found in only one individual and the segregation analysis is consistent with the existence of a rare ORM1*F2S haplotype.

Alkylation↗
PubMed2003

Polygenic inheritance of breast cancer: Implications for design of association studies.

Susceptibility to breast cancer is likely to be the result of susceptibility alleles in many different genes. In particular, one segregation analysis of breast cancer suggested that disease susceptibility in noncarriers of BRCA1/2 mutations may be explicable in terms of a polygenic model, with large numbers of susceptibility polymorphisms acting multiplicatively on risk. We considered the implications for such a model on the design of association studies to detect susceptibility polymorphisms, in particular the efficacy of utilizing cases with a family history of the disease, together with unrelated controls. Relative to a standard case-control association study with cases unselected for family history, the sample size required to detect a common disease susceptibility allele was typically reduced by more than twofold if cases with an affected first-degree relative were selected, and by more than fourfold if cases with two affected first-degree relatives were utilized. The relative efficiency obtained by using familial cases was greater for rarer alleles. Analysis of extended families indicated that the power was most dependent on the immediate (first-degree) family history. Bilateral cases may offer a similar gain in power to cases with two affected first-degree relatives. In contrast to the strong effect of family history, varying the ages at diagnosis of the cases across the range of 35-65 years did not strongly affect the power to detect association. These results indicate that association studies based on cases with a strong family history, identified for example through cancer genetics clinics, may be substantially more efficient than population-based studies.

Age Factors↗
PubMed1984

Genetic epidemiology of coeliac disease.

Segregation analysis favors a gene additive on liability with a frequency of 0.022, which is nearly recessive on the penetrance scale. Less than one-eighth of DR3 and DR7 haplotypes carry a determinant for coeliac disease. There is significant excess of DR3/7 heterozygotes among patients, indicating that the determinants are qualitatively different in DR3 and DR7 haplotypes. Linkage to HLA is highly significant (maximum lod score = 10.9). Evidence for recombination of 8% in males is attributed to residual errors in the model. We suggest an approach to a more precise model.

Celiac Disease↗
PubMed1985

Genetics of the Lp lipoprotein in Japanese-Americans.

Segregation analysis of four Lp assays on 557 children in 227 families reveals a dominant major gene and a residual heritable component that may reflect one or more alleles of weaker effect. Close or moderate linkage to esterase-D (ESD) is excluded.

Aged↗
PubMed1985

Demonstration of a common major gene with pleiotropic effects on immunoglobulin E levels and allergy.

Atopic disease is generally recognized to be familial, although specific genetic components have yet to be identified. High levels of a unique class of immunoglobulins, immunoglobulin E (IgE), have been shown to be associated with allergies. Several investigators have reported evidence indicating a recessive regulatory locus where an individual with the homozygous recessive genotype has persistently elevated levels of IgE. Willcox and Marsh [1978] have proposed a hypothesis relating IgE production and liability to become allergic. A test of this hypothesis was carried out in the present study. Bivariate segregation analysis of IgE levels and allergy was performed on 173 nuclear families, and the results indicate that an IgE regulatory locus contributes to the familial transmission of allergy. The results are further discussed in the context of the Willcox and Marsh hypothesis.

Adult↗
PubMed1986

Studies on an isolated West Indies population: IV. Genetic study of hearing loss.

Hearing troubles were found to be very frequent among inhabitants of French origin in a small Caribbean island. Segregation analysis of hearing loss was performed in 165 complete nuclear families and revealed that familial aggregation could be entirely explained by a single recessive gene with high frequency (0.40). Homozygous individuals for this gene would probably be more susceptible to ototoxic agents than other individuals. High frequency of this gene may be due to a founder effect.

Audiometry↗
PubMed1986

Familial aggregation of cancer in Laredo, Texas: a generally low-risk Mexican-American population.

Genealogies for the Mexican-American city of Laredo, Texas, have been assembled by computer from individual civil and church records of birth, marriage, and death. Documentation is available on vital events in the lives of over 300,000 individuals, about 80% of the city population from 1870-1981. These data were collected to determine the degree to which death from cancer is more clustered in families than would be expected by chance alone; methods specific to this data base have been developed to accomplish this task. A statistically significant excess of familial cancer was observed overall when all cancer sites were pooled, but no evidence was observed for excess familial risk at single sites except for breast cancer and perhaps for ovarian cancer. The excess of breast cancer risk is comparable to that observed in other populations. A few site-combinations manifest excess familial risk, most notably those involving and dominated by breast cancer and certain digestive system sites. We do not confirm the degree of familiarity observed elsewhere for cancers of the lung, colorectum, stomach, or other sites in this generally low-risk population. Even where we find evidence of excess risk, the degree of excess is small and the number of multiply affected families too small to test etiologic models by segregation analysis. The absence of excess familial risk does not appear to be due to inadequate numbers of cases, since breast cancer is familial with no more occurrences in Laredo than other sites. These results differ to some extent from those found in a similar study of Utah Mormons, but it is unclear whether this is because of differences in risk patterns or statistical properties of the analytic methods used in the two studies.

Adolescent↗
PubMed1986

Genetic etiology of gastric carcinoma: I. Chronic atrophic gastritis.

Scientific evidence has accumulated to show that chronic atrophic gastritis (CAG) is a precursor of gastric carcinoma, especially its intestinal histologic type; thus the etiology of CAG is of interest. Data on 110 families (557 individuals) collected as part of a large cohort from the Narino region of Colombia, South America, are analyzed to determine the familiality of CAG as a risk factor, and the possible involvement of a major gene in its etiology. We found that age and having an affected mother are important risk factors. In the sample, 45% are affected; 56% of individuals above 30 are affected, whereas only 28% of those 30 and under are affected; 48% of those with affected mothers are affected, but only 7% of those with unaffected mothers are affected. A positive spouse association was confounded with age. Sex and an affected father are not significant risk factors. The genetic (segregation) analysis showed Mendelian transmission of a recessive autosomal gene with penetrance dependent on age and mother's CAG status. Homozygous recessives account for an estimated 61% of the sampled population and have penetrance reaching 72% at age 30 if the mother is affected, and 41% if the mother is not affected. Carriers and non-carriers, who make up an estimated 39% of the sampled population, have an appreciable estimated risk after age 50. The environment, particularly diet, as the sole determinant of CAG needs reevaluation; some combined action of genes and environment seems more plausible.

Age Factors↗
PubMed1986

Genetic epidemiology of Menkes disease.

Copper incorporation studies were performed on individuals from 58 pedigrees, comprising 140 sibships. As previously reported, there is considerable overlap between heterozygotes and normal homozygotes. Segregation analysis supports recessive inheritance of disease, with residual heritability for 64Cu uptake in cultured cells. The population frequency of sporadic cases is compatible with the 1/3 expected for an X-linked lethal with equal mutation rates in egg and sperm, which implies a mutation rate of 6.7 X 10(-6)/gamete/generation. The parameters estimated here are likely to provide the best basis for genetic counseling until more reliable carrier tests are performed on a systematic sample from a large, defined population.

Brain Diseases, Metabolic↗
PubMed1987

Genetic epidemiology of myotonic dystrophy.

Prevalence rate of myotonic dystrophy (DM) was estimated in a large sample of the Italian population. Segregation analysis of the affected families suggests that subjects showing minor clinical signs, even in the absence of myotonic features, should be considered as bearers of the DM trait. An apparent excess of normal sibs among the offspring of DM subjects may be due to the late onset of the disease and possibly to a partial loss of affected individuals from the sample before diagnosis. Prevalence rate of DM in this study is estimated between 69 to 90 per million inhabitants; accordingly, DM might be the most frequent inherited neuromuscular disorder in human populations.

Adult↗
PubMed1988

Genetic factors influencing apolipoprotein AI and AII levels in a kindred with premature coronary heart disease.

A single 51-member kindred, ascertained on the basis of a normotriglyceridemic proband with depressed high-density lipoprotein cholesterol (HDL-C) and myocardial infarctions at ages 40 and 42, was studied with respect to quantitative variation in HDL-C and apolipoprotein (apo) AI and AII levels. The results of bivariate segregation analysis suggest that the etiology of depressed HDL-C involves one or possibly two major loci: one has a pleiotropic effect on apo AI and apo AII levels and, possibly another one that affects apo AI levels. Both the major loci were characterized as having a dominant allele leading to depression of the respective trait(s). In addition, analysis of the cosegregation of HDL-C and apo AI levels gave evidence of residual nonfamilial factors common to both traits, leading to a positive covariance between them. This could reflect the role of apo AI in the transformation of nascent HDL-C particles into mature ones via its cofactor activity to lecithin cholesterol acyltransferase. The proposed two-locus model represents one possible etiology for the heterogeneous disorder of hypoalphalipoproteinemia. This analysis of a single pedigree does not completely define the genetic mechanism, but it does illustrate a useful new analytic approach.

Apolipoprotein A-I↗
PubMed1989

Linkage data on affective disorders in an epidemiologic context.

Recent data on chromosomal linkage markers in affective disorders indicate that single locus inheritance is involved in these disorders. The presence of a single locus has not been detectable using segregation analysis on family study data from large populations, possibly because of both heterogeneity and birth cohort and sex differences in diagnostic frequencies.

Affective Disorders, Psychotic↗
PubMed1989

Phenylthiocarbamide taste sensitivity revisited: complete sorting test supports residual family resemblance.

Phenylthiocarbamide (PTC) taste thresholds were determined in 100 nuclear families using the complete sorting test. Segregation analysis using the mixed model suggested that the variability in PTC thresholds is controlled by a major locus with incomplete dominance as well as by a multifactorial component with significant residual heritability. Such a model explained nearly 96% of the variance, leaving only 4% of the variance in thresholds arising from measurement error and other environmental factors.

Adolescent↗
PubMed1989

Alternative genetic models for the inheritance of the phenylthiocarbamide taste deficiency.

Pedigree segregation analysis was used to examine several one- and two-locus models of the inheritance of phenylthiocarbamide (PTC) taste deficiency that extend the traditional one-locus recessive model by the addition of either another allele or another locus, and in some cases predict two types of nontasters. These models allow nontaster by nontaster matings to produce taster offspring, consistent with our data and several previous studies which use the Harris and Kalmus [Annals of Eugenics 15:24-32, 1949] dilution method. The models fit our data set of 1,152 individuals from 120 families significantly better than the one-locus recessive model. The best fit was obtained with a two-locus model in which one locus controls PTC tasting and the other locus controls a more general taste ability. This model is consistent with research on the physiology of PTC tasting and with results from genetic linkage studies. Further study is suggested to evaluate better the accuracy of the proposed model.

Alleles↗
PubMed1989

Test of genetic heterogeneity of cleft lip with or without cleft palate as related to race and severity.

The question of possible heterogeneity among population groups and phenotypic groups on the role of major gene in the etiology of cleft lip with or without cleft palate [CL(P)] was examined using the uniformly collected data in Hawaii. Complex segregation analysis was used to analyze patterns of family resemblance under the mixed model incorporating the effects of major gene and multifactorial inheritance. Analysis of the entire data showed superior fit of the mixed model including the effects of both major gene and multifactorial inheritance over the model of major gene alone or multifactorial inheritance alone. No significant heterogeneity could be detected between the high-incidence group (Oriental or Japanese) and the low-incidence group (non-Oriental) in the underlying general model, although higher heritability was observed in general. When families were classified into "severe" and "mild" phenotypes based on cleft lip vs. cleft lip and palate or unilateral vs. bilateral cleft in the proband, no significant differences could be detected between the two types in the underlying genetic model.

Cleft Lip↗
PubMed1991

Genetic epidemiology of childhood brain tumors.

The study goal was to determine the genetic (heritable) contribution to childhood brain tumors (CBT) which cause nearly one quarter of all childhood cancer deaths. Their etiology remains unknown, but previous studies have suggested a proportion of CBT may be heritable. In this study we collected family histories of 243 confirmed CBT patients referred to The University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed before age 15, and residents of the United States or Canada. Family histories were obtained for all the probands' first degree relatives (parents, siblings, and offspring) and extended to include selected second degree relatives (aunts, uncles, grandparents) using sequential sampling. To determine if these CBT families exhibited excess cancer, we compared their cancer experience to age-, race-, sex-, and calendar-year specific rates from the Connecticut Tumor Registry. No cancer excess was observed among 1,099 first and second degree relatives [39 cancers observed (O) and 44 expected (E) for a standardized incidence ratio (SIR) of 0.88]. For colon cancer, although small numbers, five cases were observed among the probands' first degree relatives with 1.6 expected, for a significant SIR of 3.10. Segregation analysis demonstrated that chance alone could not account for the observed cancer distribution with a multifactorial model providing the best overall explanation of the data. Overall, heredity played a role in the etiology of CBT in 4% of the study families: four (1.7%) due to known hereditary syndromes (nevoid basal cell carcinoma syndrome and von Recklinghausens neurofibromatosis--NF-1), four (1.7%) with multifactorial inheritance, and two additional families with cancers aggregating similar to the clinical criteria described for the Li-Fraumeni cancer family syndrome.

Adolescent↗
PubMed1991

Lack of evidence for linkage between low-density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia.

Low-density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, appears to be a genetically influenced risk factor for coronary heart disease. Phenotype B, as determined by gradient gel electrophoresis, appears to be inherited in a manner consistent with the presence of a single major genetic locus, based on complex segregation analysis. Familial combined hyperlipidemia (FCHL) is a disorder characterized by elevations in total plasma cholesterol and/or triglyceride levels in probands and family members, variable lipoprotein phenotypes over time, and elevations in apolipoprotein B levels. Because apo B is the primary protein component of LDL particles, the present study was undertaken to determine whether LDL subclass phenotypes are controlled by the APOB locus in FCHL families. The evidence against linkage was very strong based on lod score analyses (total lod = -13.3), under assumptions that LDL subclass phenotypes are influenced by a major genetic locus and that the mode of inheritance and penetrance functions are known. Other methods requiring fewer assumptions also provided evidence against linkage, although the strength of this evidence was weaker. Thus the results demonstrate that the proposed gene responsible for LDL subclass phenotypes is unlikely to be the APOB gene in families with FCHL.

Alleles↗
PubMed1992

Two-locus mitochondrial and nuclear gene models for mitochondrial disorders.

Stimulated by a large pedigree with a cochlear form of deafness, for which we considered a two-locus mitochondrial and nuclear gene model, we have extended the classic methods of segregation analysis to these classes of two-locus disorders. Based on the unique maternal transmission pattern of the mitochondria, we demonstrate that utilization of the maternal line pedigree allows us to simplify the various two-locus mitochondrial models to "one nuclear locus" models. Classifying the nuclear families into different independent groups by the mother's phenotypes allows us to estimate the nuclear gene frequency in one group and to use this estimate as the expected value to test the fitness of the model on the other group. In addition, if we restrict the analysis to specific subsets of the mating type(s), we can also test the model on specific groups of nuclear families without estimating the gene frequency. Goodness-of-fit tests can be performed on pooled sibship data as well as individual sibship data. These methods of analysis should assume increasing importance as more disorders with features of mitochondrial inheritance are identified.

Cell Nucleus↗