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Hereditary ataxia in the Jack Russell Terrier--clinical and genetic investigations.

Hereditary ataxia in the Jack Russell Terrier (JRT) is characterized by a gait disturbance with symmetric generalized ataxia and hypermetric and spastic movements. Histopathology shows a disease of the entire central nervous system, predominantly an axonopathy. In the present study, 35 clinically affected dogs were examined. Gait abnormalities began at 2-9 months of age. Generalized seizures occurred in 13 dogs in addition to the ataxia, and 7 dogs developed respiratory distress. Brain stem auditory-evoked potentials (BAEPs) were abnormal in 4 of 8 examined dogs, in which only waves I and II were detected. Abnormal BAEPs suggest the possibility of hereditary ataxia in the JRT. Investigations regarding the mode of inheritance were performed by complex segregation analyses on 3 pedigrees with a total of 115 JRTs (27 clinically affected dogs and 88 unaffected littermates and ancestors). Different modes of inheritance were tested, including monogenic, mixed, and polygenic models, as well as a model with environmental effects only. Models with genetic effects explained the data significantly better than the environmental model. The monogenic model had to be rejected in this study because of an insufficient match of data when compared to that of the most general model. The polygenic and mixed major gene models explained the pedigree data best and therefore have to be regarded as possible hypotheses for the mode of inheritance of hereditary ataxia in the JRT. The polygenic model proved best suited to explain the segregation pattern in the JRT, because it had the fewest number of parameters.

Animals↗

PubMed2026

Genetic Risk Factors for Kidney Function in Individuals with Type 1 Diabetes.

KEY POINTS: Previous research has identified polygenic risk scores that are associated with low eGFR and albuminuria in the general population. We observed that these eGFR and albuminuria polygenic risk scores were associated with eGFR and albuminuria, respectively, in type 1 diabetes. Associations were independent of glycemic control and suggest shared genetic kidney risk factors between type 1 diabetes and the general population. BACKGROUND: Genetic risk factors underlying kidney disease in type 1 diabetes (T1D) remain poorly understood. We examined whether previously established polygenic risk scores (PRS) for eGFR and albuminuria are associated with these measures in adults with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study. METHODS: We applied eGFR and albuminuria PRS derived in general population cohorts to 1304 DCCT/Epidemiology of Diabetes Interventions and Complications participants with genome-wide genotyping. We tested PRS associations with eGFR and urine albumin excretion rate (AER) as well as incident eGFR <60 ml/min per 1.73 m 2 , AER ≥30 mg/24 h, and AER ≥300 mg/24 h. For consistency, PRS values were linearly transformed so higher scores corresponded to higher eGFR and AER. We also examined associations of kidney outcomes with rs55703767 in COL4A3 , which has previously been associated with CKD in T1D. RESULTS: At DCCT baseline, participants had a mean age of 27 years; 53% were male. 49% of participants were randomized to intensive versus conventional glucose-lowering therapy. Participants were followed for median of (first-third quartiles) 35 (33-37) years. The eGFR PRS was significantly associated with continuous eGFR (per one SD higher PRS 2.72 ml/min per 1.73 m 2 higher [95% confidence interval (CI), 2.05 to 3.40]) and incident eGFR <60 ml/min per 1.73 m 2 (hazard ratio [HR]=0.82 [95% CI, 0.73 to 0.92]), but not consistently with albuminuria. There was no association with quantitative AER (2.42 mg/24 h [95% CI, -1.86 to 6.89]) or sustained AER ≥30 mg/24 h (HR=1.03; [95% CI, 0.94 to 1.14]). The albuminuria PRS was significantly associated with incident AER ≥30 mg/24 h (HR=1.12 [95% CI, 1.02 to 1.22]) but not continuous eGFR (0.49 ml/min per 1.73 m 2 higher [95% CI, -0.23 to 1.21]) or incident eGFR <60 ml/min per 1.73 m 2 (HR=0.96 [95% CI, 0.85 to 1.08]). Associations were similar in analyses stratified by DCCT treatment group assignment. rs55703767 was associated with lower incident macroalbuminuria in the overall cohort (HR=0.77 per minor allele [95% CI, 0.59 to 0.99]), and upon stratification by DCCT treatment group assignment, only within the conventional and not intensive glucose-lowering therapy group. CONCLUSIONS: PRS associated with eGFR and albuminuria in the general population were associated with corresponding measures in adults with T1D. The results suggest shared genetic risk factors for kidney disease between T1D and the general population but different genetic risk factors for albuminuria and eGFR in T1D. CLINICAL TRIALS REGISTRATION NUMBERS: NCT00360893 , NCT00360815 .

Adult↗

PubMed1990

Mapping genes in diabetes. Genetic epidemiological perspective.

Research on mapping diabetes-susceptibility genes is dependent on several factors, including the existence of a single major gene for susceptibility, genetic homogeneity, and the existence of appropriate clinical material. The power to detect susceptibility genes is dependent on the risks in relatives and the distance of genetic markers from the susceptibility genes. For insulin-dependent diabetes mellitus (IDDM), the best-fitting risk models are those with a single major locus with residual polygenic factors. The major locus effect is likely represented by genes in the HLA complex, because specific genotypes have been found to affect IDDM risk significantly. Thus, mapping the remaining polygenic IDDM susceptibility factors--each of small effect--is a difficult and long task. For non-insulin-dependent diabetes mellitus (NIDDM), the likely risk models result in few genes with moderate effect. Models of NIDDM have significant residual polygenic variation remaining, reflecting the importance of multiple loci with small effect, environmental effects, or genetic heterogeneity; however, the prospects for mapping genes that provide at least moderate susceptibility for NIDDM now appear promising.

Chromosome Mapping↗

PubMed2001

Potential gain from optimizing multigeneration selection on an identified quantitative trait locus.

The potential extra response that can be obtained from the optimal use of a known QTL in selection by optimizing weights in an index of breeding value for the QTL and polygenic EBV was investigated for a range of parameters. Optimal strategies were derived for a deterministic model of simultaneous selection on a QTL and polygenic effects using optimal control theory. Responses over 10 generations to the following selection strategies were compared: 1) standard QTL selection, with QTL weights equal to 1, 2) optimal QTL selection, 3) stepwise single-generation optimal QTL selection, and 4) non-QTL selection based on phenotype. Cumulative discounted response with discount rates of 10 or 30% per generation were evaluated and used as objective for optimal selection strategies. Optimal selection balanced the conflict between short- and long-term responses and gave greater cumulative discounted response than standard QTL selection of up to 20%, but less than 5% for most cases. Discount rate had limited impact. For a QTL with an additive effect of one polygenic standard deviation, cumulative discounted response from optimal QTL selection was less than 5% greater than response for non-QTL selection for most cases. Exceptions were traits with low heritability and recessive QTL at low frequency, for which extra response was up to 55% greater. Stepwise optimal selection resulted in less cumulative discounted response than standard QTL selection for QTL with negative dominance. The benefit of optimal over stepwise optimal selection was limited (less than 4%) for most cases, except for overdominant QTL. These results indicate that optimizing selection on an identified QTL can result in greater responses to selection but that extra responses tend to be limited for the situations studied here of single-stage purebred selection on a single QTL for a trait observed on both sexes.

Animals↗

PubMed2003

Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning.

Inflammatory bowel disease (IBD) includes two clinical subtypes: Crohn disease (CD) and ulcerative colitis (UC). The general prevalence is about 1.0-2.0 % in Western countries. It is predominantly regarded as a multifactorial disorder involving environmental factors and polygenic defects. The view was confirmed by a lot of evidences from clinical attributions and animal models, especially from epidemiological investigations. So the etiological study of IBD has been focused on searching for susceptibility genes by positional cloning, which consists of two steps: linkage analysis and association analysis. Linkage analysis has been an important method of searching for susceptibility genes to polygenic diseases as well as single-gene disorders. IBD, as a polygenic disease, has been widely investigated by linkage analysis for susceptibility gene since 1996. The paper reviewed 38 articles, which covered almost all original researches in relation to IBD and linkage analysis. So far, several loci, such as 16q, 12q, 6p and 3p, have been identified by the studies. The most striking is 16q12 (IBD1), which linked only with CD not UC in the majority of studies. Association analysis, as one essential step for positional cloning, is usually carried out by genotyping candidate genes selected by means of linkage analysis or other methods, for figuring out the frequencies of alleles and comparing the frequencies between IBD group and healthy control group to identify the specific allele. It has been established that IBD is implicated in immune disorder. So the studies were centered on the genes of NOD2/CARD15, HLA-II, cytokine, cytokine receptor and adhesion molecule. This paper reviewed 14 original articles on association between NOD2 and IBD that have been published since 2001. All results, with the exception of one report from a Japanese group, provide evidences that the three kinds of variants of NOD2 are susceptibility factors for IBD. This article also comprehensively analyzed 18 original researches of HLA gene polymorphism in IBD. We found extensive discrepancy among the conclusions and a novel hypothesis was put forward to explain the discordance. Most studies published recently on association between IBD and cytokine gene polymorphism were reviewed.

Carrier Proteins↗

PubMed2000

[A study on the inheritance of dried tofu output of soybean].

The P1, P2, F1, F2 and F2:3 in plant generation of three crosses of Liuhexiaoyeqing x Xinyixiaohedou, Shangraoganbusi x Huaiyinqiuhedou and Liuhexiaoyeqing x Nannong 73-935 were used to study the inheritance of dried tofu output. The results of the joint analyses of multiple plant generations showed a consistant one major gene plus polygene mixed inheritance model. The heritability values for dried tofu output were as high as 87.84%-99.98%. In plant generation F2:3 of these crosses, the heritabilities of major gene were 51.80%-61.85%, and those of polygene were 36.12%-48.03%. Therefore, both major gene and polygene effects were important and should be utilized in breeding program.

Glycine max↗

PubMed2001

Inherited genetic susceptibility to breast cancer.

Inherited genetic susceptibility to breast cancer can be due both to genes which confer a high degree of risk and to polygenes which have a smaller effect on disease risk. An estimated 5-10% of breast cancer is considered to be due to mutations in genes conferring high risk which results in hereditary patterns of disease. Two major breast cancer susceptibility genes, BRCA1 and BRCA2, which were identified using linkage analysis in large extended breast and/or ovarian cancer pedigrees, are estimated to account for the majority of large families with breast/ovarian cancer predisposition and about two-thirds of large breast cancer families. The associated lifetime risk for breast cancer in mutation carriers ranges from 40% to 90%, depending on the extent of family history and the population. Other genetic factors, such as HRAS or CAG repeats of AR, as well as reproductive and hormonal factors may therefore modify cancer risk. Women at particularly high risk of developing breast cancer represent a group in whom expensive and rigorous screening programmes are cost-effective and who may benefit from trials of chemoprevention. There are only preliminary data on the efficacy of increased surveillance and on risk reduction due to prophylactic surgery. However, for chemoprevention to be equivalent to prophylactic mastectomy, it will be necessary to strive for an equivalent reduction. The efficacy of chemoprevention in this high-risk population is unknown. Existing and new agents for chemoprevention need to be carefully assessed in properly designed clinical trials among such women. In the process, other factors modifying the penetrance in mutation carriers need to be taken into account in order to evaluate the true effect of the chemopreventive agents. Polygenes confer much lower levels of risk and may be relevant for risk assessment when the effects of multiple loci, possibly in conjunction with environmental factors, are understood and quantified. At present, it seems unlikely that the genetic information at single polygenes will be clinically relevant for risk assessment and management.

Biomarkers, Tumor↗

PubMed2001

[Major gene plus poly-gene inheritance of erucic acid content in Brassica napus L].

Inheritance of erucic acid content in the cross of HSTC14 x Ningyou 7 (Brassica napus L.) was investigated by applying the major gene plus poly-gene model of quantitative traits to a joint analysis of multi-generations (P1, F1, P2, B1:2 B2:2 and F2:3). The results showed that erucic acid content in the cross of HSTC14 x Ningyou 7 was controlled by two major genes with additive-dominance-epistatic effects plus polygenes with additive-dominance effects (the E-1 model). Heritability values of the major genes of B1:2, B2:2 and F2:3 population were estimated as 69.47%, 28.25% and 51.33% respectively, while those of polygene were 29.81%, 70.39% and 47.86%. This results demonstrated that erucic acid content level in the cross was mainly controlled by two major genes mixed with the effect of polygenes. The estimated additive effects of the two major genes, da and db, were -12.1712 and -6.5423 respectively. The dominant effect of the first major gene was 9.1011, much higher than that of the second one. The interaction effect of the first major gene's additive effect and the second major gene's dominance effect was 22.4400, while that between the second major gene's additive effect and the first major gene's dominance effect was only 1.0317. There were obvious differences in genetic effects between the two major genes. The effect of db was only about 53.75% that of da, indicating that the contributions to erucic acid level of the two major genes was not equal in the cross. The possible reasons resulting in the difference was discussed in this paper.

Brassica↗

PubMed2001

Hypertension exacerbates coronary artery disease in transgenic hyperlipidemic Dahl salt-sensitive hypertensive rats.

BACKGROUND: The mechanisms underlying the known interaction of two complex polygenic traits, hypertension and hyperlipidemia, resulting in exacerbation of coronary artery disease have not been elucidated. Identification of critical pathways underlying said exacerbation could identify mechanism-based targets for intervention and prevention. MATERIALS AND METHODS: To investigate hypertension- atherosclerosis interaction, we studied the inbred transgenic atherosclerosis-polygenic hypertension Dahl salt-sensitive (S) rat model (Tg53), which over-expresses human cholesteryl ester transfer protein (hCETP) in the liver, and exhibits coronary artery disease and decreased survival compared with control non-transgenic Dahl S rats. Using serial-section histopathological and immunohistochemical analyses, we analyzed the coronary artery disease phenotype of Tg53 rats at end-stage marked by cardio-respiratory compromise as the experimental equivalent of acute coronary syndromes, and determined the effects of reduction of blood pressure through low salt diet (0.008% NaCl) on the coronary artery disease phenotype and survival. RESULTS: End-stage Tg53 rats exhibit coronary artery lesions in the proximal right coronary artery system which exhibit "culprit plaque" features such as plaque inflammation, matrix degradation, apoptosis, neovascularization, thrombosis and hemorrhage recapitulating said features and heterogeneity of human coronary "culprit plaques". Comparative analysis of 6 month vs end-stage lesions reveals distinct lesion development profiles of proximal coronary lesions which quickly progress from eccentric non-occlusive foam-cell rich lesions at 6 months to occlusive "culprit plaques", compared with more distal coronary lesions which exhibit occlusive thick-cap atheroma that remain relatively unchanged from 6 months to end stage. Reduction of hypertension through a low-salt (0.008% NaCl) diet increased survival (P < 0.0001) of Tg53 rats and significantly attenuated the coronary artery disease phenotype detected at 10 months of age marked by diminished apoptosis, neovascularization, matrix degradation compared with end-stage lesions detected at <8 months of age. CONCLUSIONS: End stage coronary lesions in the Tg53 rats recapitulate many, albeit not all, features of "culprit plaques" in humans supporting proposed paradigms of plaque vulnerability implicating lesion macrophage enrichment, apoptosis, matrix degradation and pathological neovascularization. Comparative time course analysis of coronary lesions reveals that plaques which develop into end-stage "culprit plaques" are distinct from "stable plaques" by location and early lesion morphology, suggesting distinct lesion development and progression pathways. The significant effects of low-salt diet-induced decrease in hypertension on right coronary disease phenotype provides compelling evidence that polygenic hypertension accelerates coronary plaque progression and complication independent of cardiac hypertrophy, and more importantly provides paradigmatic support for public health policy.

Animals↗

PubMed2004

[A study on risk factors among 125 type 2 diabetes mellitus with familial tendency].

OBJECTIVE: To study the risk factors regarding heredity and environment in familial incident type 2 diabetes mellitus (DM). METHODS: To compare the difference of environmental risk factors between type 2 DM, impaired glucose tolerance (IGT) and normal persons through study on familial information and environmental risk factors in 125 familial incident type 2 DM in-patients and out-patients from 1999 to 2001. Falconer was used to estimate heritability. Penrose was used to study the heredity damagers by polygene analysis. RESULTS: There was a significant constituent ratio diversity (P < 0.01) in triglyceride, body mass index, waist to hip ratio, hypertension history and physical activities history among 3 groups, while no significant diversity in blood lipids and history of coronary heart disease. 83.42% +/- 5.84% heritability of type 2 DM in 125 familial predigree indicated that dominant major gene might exist in these familiar pedigrees. Analysis of polygene in these groups showed type 2 DM might conform to the model of polygene heredity. CONCLUSION: This study suggested that type 2 DM had significant heritability and genetic heterogeneity, which generally appeared to be a disease of multi-factorial inheritance. Environmental risk factors, genetic factors and their interactions were due to type 2 DM.

Adult↗

PubMed2005

[Identification of drought tolerant germplasm and inheritance and QTL mapping of related root traits in soybean (Glycine max (L.) Merr.)].

Fifty nine accessions of soybean (Glycine max (L.) Merr.) selected from 301 ones in Huang-Huai-Hai and Middle-Lower Changjiang Valleys were tested in two years for their tolerance to drought by using the mean membership index value averaged over those of plant height,leave number,dry root weight and dry stem and leaf weight. Four most tolerant accessions (Rank 1) and two most sensitive ones (Rank 5) were identified. There existed very significant correlations between drought tolerance and relative values of dry root weight,total root length, and root volume (per plant dry weight basis), respectively,which could be used as root indicators of drought tolerance. The RIL population derived from Kefeng 1 x Nannong 1138-2 was used to analyze the inheritance of the three related root traits by using the segregation analysis of quantitative traits under the major gene plus polygene mixed inheritance model. The results showed that between the two parents (Rank 1 x Rank 4), the relative values of dry root weight,total root length and root volume were respectively controlled by two major genes (linked together for the latter two traits, recombination value being 4.30% and 1.93%, respectively) plus polygenes with their major gene heritability values of 62.26%-91.81% and polygene heritability values 2.99%-24.75%, indicating that the major genes,especially the one with larger effect,accounted for a major part of the genetic variation between the two parents. It was identified that five, three, and five QTLs located on N6-C2, N8-D1b + W, N11-E, and N18-K linkage groups for relative dry root weight, total root length and root volume, respectively. Each of the traits appeared to have one locus (Dw1, R/1, and Rv1) with relatively large effect in comparison with their other loci, and those major ones were located near the same site of the same linkage group N6-C2. The results of segregation analysis and QTL mapping appeared pretty consistent with each other, which could be used as a demonstration of each other.

Adaptation, Physiological↗

PubMed1991

Pravastatin vs gemfibrozil in the treatment of primary hypercholesterolemia. The Italian Multicenter Pravastatin Study I.

This study compared the efficacy and safety of pravastatin and gemfibrozil in the treatment of primary hypercholesterolemia. Three hundred eighty-five outpatients from 13 lipid clinics in Italy participated in this randomized double-blind study. Patients were assigned to receive either 40 mg once daily of pravastatin or 600 mg of gemfibrozil twice daily after an initial diet lead-in period. After 24 weeks, mean reductions from baseline values of plasma total and low-density lipoprotein cholesterol were, respectively, 23% and 30% with pravastatin and 14% and 17% with gemfibrozil. Significant lipid-lowering effects were noted within 4 weeks. Apolipoprotein B decrease was 21% with pravastatin and 13% with gemfibrozil. A statistically significant increase of high-density lipoprotein cholesterol of 5% was achieved with pravastatin compared with a 13% increase for gemfibrozil. Serum triglyceride values decreased 5% with pravastatin and 37% with gemfibrozil. Familial and polygenic hypercholesterolemic patients were also examined separately. Pravastatin effectiveness in reducing low-density lipoprotein cholesterol was greater by 6% in polygenic than in familial hypercholesterolemic patients. Treatment for 25 patients (eight treated with pravastatin and 17 treated with gemfibrozil) was discontinued during the study. The incidence of clinical symptoms and laboratory alterations was low for both treatment groups. Pravastatin and gemfibrozil were well tolerated, but pravastatin was significantly more effective in reducing total and low-density lipoprotein cholesterol levels in primary (either familial or polygenic) hypercholesterolemias than gemfibrozil.

Adult↗

PubMed1989

Genetic determination of plasma apolipoprotein AI in a population-based sample.

Apolipoprotein AI (apo AI) is the major protein of high-density lipoprotein (HDL). Using radioimmunoassay, we measured plasma apo AI levels in 1,880 individuals in 283 pedigrees randomly selected from the population with respect to disease status and risk factors for coronary artery disease. Apo AI levels were first adjusted for date of assay (6.8% of apo AI variation) and then adjusted for variability in age and body mass index (an additional 6.6%, 20.4%, and 23.0% of apo AI variations for males, females not using exogenous hormones, and females using exogenous hormones, respectively). A mixture of two normal distributions fit the adjusted data better than did a single normal distribution. Genetic and environmental models that could explain the mixture of normal distributions were investigated using complex segregation analysis. Heterogeneous etiologies for individual differences in adjusted apo AI levels were suggested by the data in the 283 pedigrees. In a subset of 126 pedigrees, there is evidence for the major effect of a nontransmitted environmental factor that explains the mixture of distributions as well as polygenic loci that influence apo AI levels within each distribution. The environmental factor and polygenic loci account for 32% and 65% of the adjusted variation, respectively. In the other 157 pedigrees there is strong support for a single locus with a major effect that accounts for 27% of the adjusted variation. The effect of the polygenic loci is not different from zero in these 157 pedigrees. This is the first study to present evidence for the segregation of a single unmeasured locus with a major effect on levels of apo AI in a population-based sample of pedigrees.

Adolescent↗

PubMed1989

Inheritance of immune responsiveness, life span, and disease incidence in interline crosses of mice selected for high or low multispecific antibody production.

High (H) and low (L) antibody responder lines of mice separated by selective breeding present a maximal interline difference in antibody (Ab) response to Ag of different specificities (general genetic regulation). The analysis of SRBC agglutinin response in H line, L line, F1 hybrids, F2, and backcross segregants demonstrates that Ab responsiveness is a polygenic trait regulated by the additive interaction of 5 to 7 independent loci, with an incomplete dominance (44% +/- 7%) of the high response character, and a 30% +/- 10% impact of the environmental factors. The life span of H, L, F1, F2, and backcross populations is correlated positively with 2-ME-resistant agglutinin response (r = 0.97, p less than 0.001) and negatively with 2-ME-sensitive agglutinin response (r = 0.95, p = 0.01) (interpopulation correlation). Similar correlations are also observed in individuals of the various populations, especially in F1 x L backcross, in which the largest phenotypic variance is found. The positive correlation between Ab responsiveness and life span was confirmed by ELISA titration for distinct IgG isotypes (intrapopulation correlation). Malignant lymphomas and chronic nephritis were the two most common diseases observed. The age-adjusted incidence of such diseases, which is largely affected by environmental factors, accounts for the longer life span of H, as compared with L, mouse populations. The longevity of the 30% or less survivors, chiefly determined by the rate of physiologic aging, is a polygenic character regulated by the cumulative interaction of 3 to 7 independent loci, with a complete dominance of the long life trait and an impact of the environmental factors of about 60%. Thus we have grounds for regarding general Ab responsiveness and life span as polygenic traits regulated by a small number of identical or closely linked gene loci, and immune responsiveness as a defense mechanism against neoplastic and inflammatory diseases.

Aging↗

PubMed1987

Complex segregation analysis of febrile convulsions.

Complex segregation analysis was performed on 467 nuclear families ascertained through febrile-convulsion probands. The probands were identified as having their first febrile convulsion while residents of Rochester, MN, during the years 1935-64. Parents and first- and second-degree relatives of probands were identified through the Olmsted County, MN, record-linkage system. Diagnoses of convulsive activity were made from review of medical records. The genetic models investigated included both single-major-locus and polygenic models, with likelihoods computed jointly on children and parents as well as being conditioned on parental phenotype. Possible heterogeneity was investigated by means of analyses of frequency of febrile convulsions in the proband. Analyses of the entire data set indicated that the single-major-locus models could be rejected. The most parsimonious model for these data was the pure polygenic (or common familial environment) model with a large heritable component (68% +/- 7%). However, when families were partitioned on the basis of frequency of febrile convulsions in the proband, significant heterogeneity was present. Our results indicated that the polygenic model was strongly corroborated in families of probands with a single febrile convulsion. In families of probands with multiple febrile convulsions, evidence was consistent with a single-major-locus model with nearly dominant seizure susceptibility.

Child, Preschool↗

PubMed1986

Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia.

We previously reported the finding of phytosterolemia, xanthomatosis, and hyperapobetalipoproteinemia (hyperapoB) in five siblings in a large Amish pedigree ascertained through a 13-year-old boy who died suddenly from advanced coronary atherosclerosis. Here, we present further analyses of the plasma levels of the plant sterol, sitosterol, of low density (beta) lipoprotein (LDL) sterol, and of LDL B protein. Of 254 relatives and spouses of the proband, 90.5% were examined. A series of genetic models were explored using a pedigree analysis where parameters reflecting frequency, transmission, and penetrance of putative genotypes were examined simultaneously using a maximum likelihood approach. Segregation analysis of the sitosterol levels showed that the phenotype of sitosterolemia was controlled by a rare autosomal recessive gene. There was also significant familial correlation in plasma sitosterol levels that was attributed to a polygenic component under a mixed model but could also be due to shared environments such as diets. The recessive model was supported by our finding that the plasma sitosterol levels in the parents and in six children born to three of the five sitosterolemics were less than 1 mg/dl, well within the normal range. The phenotype of hyperapoB is based on an elevated level of LDL B protein in the presence of a normal LDL cholesterol level (low LDL sterol to LDL B ratio). For both LDL sterol and LDL B, a polygenic model showed a slightly greater improvement in ln likelihood than did the Mendelian single locus model when both were compared to a sporadic model. Similar results were obtained for sterol levels of high density (alpha) lipoprotein (HDL) sterol. When segregation analysis was performed using the ratio of LDL sterol to LDL B, the Mendelian single locus model gave a slightly better fit to the data than did the polygenic model. While the analyses presented here provided unequivocal evidence for the recessive phenotype of phytosterolemia, we also identified a possible single gene factor that could account for the major portion of the strong familial aggregation in the ratio of LDL sterol to LDL B, and to a lesser extent LDL B. However, there is clear evidence of familial aggregation for these traits in this pedigree beyond that due to Mendelian components.

Adolescent↗

PubMed1979

Quantitative characters of potential value in studying mutagenesis.

The use of polygenic characters in testing for mutagenicity appears promising. Characters chosen should be easily measured and highly heritable, with a reasonable proportion of the genetic variance being of the additive type, as this implies that polygenic mutations affecting the character would be detectable in the heterozygous state. Changes in such characters may arise as a result of pleiotropic effects of major gene mutations that affect early steps in metabolic pathways.--No single character is likely to be entirely satisfactory; rather a diverse group of biochemical, anatomical and physiological characters, including growth and behavior, should be studied. Mandible shape appears to be particularly promising. The characters may be analysed simultaneously using multivariate techniques. Special attention should be paid to the detection of outliers, which may then be investigated by more classical methods for the presence of mutants. Thus, easily measured, highly heritable polygenic characters may be useful in screening animals for the presence of mutations.

Animals↗

PubMed1979

["Teratologic series" and their genetics].

Isolated cyclopia is one of the members of the prosencephalic teratologic series. In some families with cyclopian monster other types of prosencephalic malformations are found in sibs or more distant relatives. All these malformations occur more frequently in females. Different forms of prosencephalies are observed in the same type of chromosome disbalance. These data suggest that morphogenesis and etiology of the prosencephalic malformations are common. Therefore a whole teratologic series but not a single member-malformation must be an object of genetic analysis. The same data are found for another teratologic series: bilateral renal agenesis--unilateral one--aplastic variant of the cystic dysplasia of kidneys. Polygenic inheritance with the threshold phenomenon is the most probable type of genetic determination of such malformations. The more frequent occurrence of polygenic malformations in families with the studied malformation whose inheritance is not yet established may be an indirect indication for the polygenic determination of the latter.

Abnormalities, Severe Teratoid↗