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PubMedDate not supplied

Genetic correlation in otosclerosis.

PURPOSE: The aim of this study was to determine the relationship of HLA typing in patients with otosclerosis. MATERIALS AND METHODS: We used a prospective study in which HLA typing of 100 surgically confirmed otosclerosis patients were compared with age and sex matched normal individuals. RESULTS: HLA-A3, HLA-A9, HLA-A11, and HLA-B13 were found to be significantly higher (P < .05, .01, and .01, respectively). HLA-A9 and HLA-A11 were found to be higher (P < .01) in patients with a positive family history, indicating genetic heterogenicity. CONCLUSIONS: Higher values of HLA-A9, HLA-11, and HLA-B13 in patients with otosclerosis compared with normal individuals strongly suggests a genetic, HLA-related component.

Adolescent↗

PubMed1991

Pathology of abortion: chromosomal and genetic correlations.

The examination of spontaneous abortion specimens is as important as doing perinatal autopsies or surgicals in today's practice of medicine. The results of the pathologist's examination assist obstetricians in specific follow-up of future pregnancies and geneticists in predicting the chances of specific developmental defects or repeat pregnancy loss. Without the information provided by the pathologist, the other specialists can offer no real assistance. More extensive use of cytogenetic analysis of placentas may help explain intrauterine fetal death in pregnancies with confined placental mosaicism, which complicates one to two percent of pregnancies. A brief review of morphologic and genetic differences between partial and complete moles emphasizes the disparate origins of these distantly related conditions.

Abortion, Spontaneous↗

PubMed1996

Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor.

Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.

Base Sequence↗

PubMed1998

The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates.

The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2 mutation in 31 out of 38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA III or ILOCA confirms the specificity of this mutation. A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes. However, these neurological signs were also seen in an ADCA I family in which the SCA2 mutation was not identified, illustrating the importance of a direct genetic test. The SCA2 families were from different geographical and ethnic backgrounds. However, haplotype analysis failed to show evidence of a founder mutation, even in families from the same geographical origin. The range of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for the pathological alleles. Similar to the other diseases caused by unstable trinucleotide repeats, a significant inverse correlation has been found between the number of repeats and age of onset, and there is a significantly higher paternal instability of repeat length on transmission to offspring. The SCA2 mutation is the most frequent amongst ADCA I patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectively.

Adolescent↗

PubMedDate not supplied

Cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder: clinical and genetic correlates.

BACKGROUND: Comorbidity of certain obsessive-compulsive spectrum disorders (OCSDs; such as Tourette's disorder) in obsessive-compulsive disorder (OCD) may serve to define important OCD subtypes characterized by differing phenomenology and neurobiological mechanisms. Comorbidity of the putative OCSDs in OCD has, however, not often been systematically investigated. METHODS: The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition , Axis I Disorders-Patient Version as well as a Structured Clinical Interview for Putative OCSDs (SCID-OCSD) were administered to 210 adult patients with OCD (N = 210, 102 men and 108 women; mean age, 35.7 +/- 13.3). A subset of Caucasian subjects (with OCD, n = 171; control subjects, n = 168), including subjects from the genetically homogeneous Afrikaner population (with OCD, n = 77; control subjects, n = 144), was genotyped for polymorphisms in genes involved in monoamine function. Because the items of the SCID-OCSD are binary (present/absent), a cluster analysis (Ward's method) using the items of SCID-OCSD was conducted. The association of identified clusters with demographic variables (age, gender), clinical variables (age of onset, obsessive-compulsive symptom severity and dimensions, level of insight, temperament/character, treatment response), and monoaminergic genotypes was examined. RESULTS: Cluster analysis of the OCSDs in our sample of patients with OCD identified 3 separate clusters at a 1.1 linkage distance level. The 3 clusters were named as follows: (1) "reward deficiency" (including trichotillomania, Tourette's disorder, pathological gambling, and hypersexual disorder), (2) "impulsivity" (including compulsive shopping, kleptomania, eating disorders, self-injury, and intermittent explosive disorder), and (3) "somatic" (including body dysmorphic disorder and hypochondriasis). Several significant associations were found between cluster scores and other variables; for example, cluster I scores were associated with earlier age of onset of OCD and the presence of tics, cluster II scores were associated with female gender and childhood emotional abuse, and cluster III scores were associated with less insight and with somatic obsessions and compulsions. However, none of these clusters were associated with any particular genetic variant. CONCLUSION: Analysis of comorbid OCSDs in OCD suggested that these lie on a number of different dimensions. These dimensions are partially consistent with previous theoretical approaches taken toward classifying OCD spectrum disorders. The lack of genetic validation of these clusters in the present study may indicate the involvement of other, as yet untested, genes. Further genetic and cluster analyses of comorbid OCSDs in OCD may ultimately contribute to a better delineation of OCD endophenotypes.

Adolescent↗

PubMed2002

A family with the branchio-oto-renal syndrome: clinical and genetic correlations.

BACKGROUND: The branchio-oto-renal (BOR) syndrome is an autosomal dominant disease characterized by hearing loss of early onset, preauricular pits, branchial clefts, and early progressive chronic renal failure in up to 40% of family affected members. So far, it has not received due attention in the adult European nephrology literature and because of the combination of deafness with chronic renal failure it may be confused with the Alport syndrome. The BOR syndrome is caused by mutations in the EYA1 gene that maps on chromosome 8q13.3. METHODS: A three-generation, 20-member large BOR Greek-Cypriot family has been studied and followed up clinically over a 27-year period. The findings in four individuals who developed early onset renal failure are described in detail. Genetic DNA linkage studies have also been carried out. RESULTS: Of the 15 family members at risk, 14 were tested with DNA linkage analysis. Ten members were genetically affected and four were normal. All 10 affected members developed early-onset deafness. Some had different ear lobe abnormalities. Nine affected members had preauricular pits. In some of the patients these pits were deep and prominent while in others they were minor and superficial. Eight affected members had early-onset branchial clefts that needed early corrective surgery without the correct familial diagnosis ever being made. End-stage renal disease (ESRD) developed in four members at ages 36, 14, 17, and 17 with minimal proteinuria, if any. This was due to unilateral renal agenesis with contralateral hypodysplasia or bilateral, severe renal hypodysplasia. CONCLUSION: The BOR syndrome is an infrequent but well-described entity that combines early-onset renal failure and deafness together with branchial clefts and preauricular pits. Renal agenesis and dysplasia are the causes of ESRD in these individuals. Other renal abnormalities include bifid kidneys with double ureters, vesico-ureteric reflux and pelvi-ureteric stenoses. The BOR syndrome should be included in the differential diagnosis of deafness and chronic renal failure in childhood and adolescence.

Adolescent↗

PubMedDate not supplied

[Clinico-morphological and molecular-genetic correlations in the stomach pathology associated with Helicobacter pylori].

Some clinicomorphological correlations are made in Helicobacter pylori (H. pylori) associated diseases of the gastroduodenal zone. Genes vacA and cagA in the H. pylori genome were revealed by PCR in stomach biopsies of infected patients and the results were compared with histological changes in the patients' mucous membrane. Specific IgG antibodies to some H. pylori antigens were detected in the serum and a comparative analysis of serological and histological data was performed. The findings suggest that H. pylori associated gastroduodenal pathology is determined by interaction between macro- and microorganisms taking account of genetic characteristics of the infective microorganism, its phenotypic variations and properties of inflammatory and immune response of the host.

Antigens, Bacterial↗

PubMed2005

Genetic correlational analyses of ethanol reward and aversion phenotypes in short-term selected mouse lines bred for ethanol drinking or ethanol-induced conditioned taste aversion.

Short-term selective breeding created mouse lines divergent for ethanol drinking (high drinking short-term selected line [STDRHI], low drinking [STDRLO]) or ethanol-induced conditioned taste aversion (CTA; high [HTA], low [LTA]). Compared with STDRLO, STDRHI mice consumed more saccharin and less quinine, exhibited greater ethanol-induced conditioned place preference (CPP), and showed reduced ethanol stimulation and sensitization under some conditions; a line difference in ethanol-induced CTA was not consistently found. Compared with LTA, HTA mice consumed less ethanol but were similar in saccharin consumption, sensitivity to ethanol-induced CPP, and ethanol-induced locomotor stimulation and sensitization. These data suggest that ethanol drinking is genetically associated with several reward-and aversion-related traits. The interpretation of ethanol-induced CTA as more genetically distinct must be tempered by the inability to test the CTA lines beyond Selection Generation 2.

Alcohol Drinking↗

PubMed2003

Approaches to mapping genetically correlated complex traits.

Our Markov chain Monte Carlo (MCMC) methods were used in linkage analyses of the Framingham Heart Study data using all available pedigrees. Our goal was to detect and map loci associated with covariate-adjusted traits log triglyceride (lnTG) and high-density lipoprotein cholesterol (HDL) using multipoint LOD score analysis, Bayesian oligogenic linkage analysis and identity-by-descent (IBD) scoring methods. Each method used all marker data for all markers on a chromosome. Bayesian linkage analysis detected a linkage signal on chromosome 7 for lnTG and HDL, corroborating previously published results. However, these results were not replicated in a classical linkage analysis of the data or by using IBD scoring methods.We conclude that Bayesian linkage analysis provides a powerful paradigm for mapping trait loci but interpretation of the Bayesian linkage signals is subjective. In the absence of a LOD score method accommodating genetically complex traits and linkage heterogeneity, validation of these signals remains elusive.

Cholesterol, HDL↗

PubMed1979

Population genetics of multigene family with special reference to decrease of genetic correlation with distance between gene members on a chromosome.

A mathematical method is developed which enables us to treat exactly the process of coincidental evolution under mutation, unequal intrachromosomal crossing-over as well as ordinary crossing-over between homologous chromosomes in a finite population of the effective size N. It makes use of finite difference equations involving two quantities denoted by fi and phi i, in which fi is the identity coefficient of two gene members that are i steps apart on the same chromosome and phi i is that of two members i steps apart on two homologous chromosomes. When the number of genes (n) per family is large, the finite difference equations can be approximately by ordinary second-order differential equations which can then be solved analytically. Results obtained by the present method are compared with the corresponding results previously obtained by one of us (T.O.) using conventional diffusion models of gene frequency changes in population genetics. It is shown that the previous results obtained by T.O. regarding second-order statistics are essentially valid, and they give good approximations particularly when N beta is small, where beta is the rate of ordinary interchromosomal crossing-over within the multigene family.

Base Sequence↗

PubMed1991

The relationship between ethanol-induced hyperglycemia and hypothermia: evidence of genetic correlation.

The hyperglycemic and hypothermic responses to acute ethanol exposure (0, 2, 4, 6 g/kg, intraperitoneally) were examined in non-fasted mice selectively bred for sensitivity (COLD line) or insensitivity (HOT line) to ethanol-induced hypothermia. Blood samples and rectal temperatures were obtained immediately before injection and hourly for 4 hr after injection. As expected, COLD mice demonstrated greater and more prolonged reductions in body temperature than HOT mice, especially at the 4 g/kg dose (HOT: -2.58 degrees C, COLD: -5.08 degrees C). Ethanol produced significant dose-dependent elevations in blood glucose levels over the 4-hr sampling period in both lines. The greatest elevations in blood glucose levels were seen at 4 g/kg, with COLD mice (mean = 225.1 mg/dl) showing significantly greater elevations in blood glucose levels compared to HOT mice (mean = 177.0 mg/dl). These results support the hypothesis that the thermic and glycemic effects produced by ethanol are due to related neural processes that share a common genetic component.

Animals↗

PubMed1998

Diffuse renal cystic disease in children: morphologic and genetic correlations.

During a 5-year period, we evaluated seven infants and two fetuses who presented with enlarged, hyperechoic kidneys. In each, the initial clinical diagnosis was autosomal recessive polycystic kidney disease (ARPKD). Among the seven unrelated infants were three Caucasian and four African-American infants. No syndromic stigmata were evident in any of these infants. At the time of the initial evaluation, the family data were incomplete for four infants. The two fetuses were presumed to be at-risk for ARPKD based on the diagnosis in previous siblings. Renal histopathology was evaluated in all nine cases and revealed a spectrum of cystic disease ranging from ARPKD to glomerulocystic kidney disease to autosomal dominant polycystic kidney disease to diffuse cystic dysplasia. In the eight cases for whom liver histopathology was available, varying degrees of biliary dysgenesis were evident. We present a detailed analysis of the key histopathological features in each case and discuss the histopathological findings in an embryological context. In addition, we address the current role of molecular genetics in the diagnostic evaluation.

Female↗

PubMed2003

Cribriform-morular variant of papillary carcinoma: the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma. A case report with clinical and molecular genetic correlation.

The increased incidence of thyroid carcinomas in familial adenomatous polyposis (FAP) patients is well recognised. These thyroid neoplasms display distinctive clinicopathological features and generally show good prognostic outcome. Recently, unusual sporadic tumours that share the morphological features of FAP-associated thyroid carcinomas have also been described. In this report, we document a case of a thyroid tumour in a previously well, 46-year-old female. Histology revealed a circumscribed neoplasm composed of tubular, papillary, cribriform and solid areas. The pseudostratified columnar tumour cells showed occasional nuclear grooves and rare nuclear inclusions. Immunohistochemistry showed positive staining with antibodies to cytokeratin AE1/AE3, oestrogen and progesterone receptor proteins. Focal immunoreactivity was also noted with antibodies to thyroglobulin, epithelial membrane antigen, 34betaE12 and cytokeratin CK7. The absence of polyps on colonoscopy and germline mutation in the adenomatous polyposis coli (APC) gene provides evidence that this tumour represents the sporadic counterpart of FAP-associated thyroid carcinoma. The patient is well with no evidence of disease 7 months following resection of the tumour. The differential diagnoses and molecular genetics of this unusual tumour are discussed.

Adenocarcinoma, Papillary↗

PubMed1999

Population, habitat and genetic correlates of mycorrhizal specialization in the 'cheating' orchids corallorhiza maculata and C. mertensiana

Unlike photosynthetic plants, several distantly related nonphotosynthetic plants are highly specialized toward their mycorrhizal fungi. It is unknown whether this specialization varies geographically or is influenced by the environment. We have investigated these questions in the nonphotosynthetic orchids Corallorhiza maculata and C. mertensiana by amplifying fungal internal transcribed spacer (ITS) fragments from widespread mycorrhiza samples and then discriminating putative fungal species using ITS restriction fragment length polymorphisms (RFLPs). Three fungal species were found across 27 plants representing seven populations of C. mertensiana; 20 species were found across 104 plants and 21 populations of C. maculata. All fungi belonged to the Russulaceae, an ectomycorrhizal family. Partitioning of Simpson's diversity showed that 48% of the variance in occurrences of fungal species coincided with population boundaries in C. mertensiana, vs. 68% in C. maculata. This differentiation coincided with geography but not habitat in C. mertensiana. In contrast, likelihood ratio tests showed strong associations between fungal occurrence and both habitat and phenotype in C. maculata. For example, C. maculata populations growing under oaks had no fungi in common with nearby populations growing under conifers, and those above 2000 m had no fungi in common with those below 2000 m. However, plant genetic differentiation may underlie some of these patterns. C. mertensiana and C. maculata never shared fungal species, even when growing intermixed at the same site, demonstrating genetic control that was independent of habitat. Similarly, intermixed normal and pale-coloured variants of C. maculata had no fungal species in common. These results demonstrate fine-scale genetic influences and geographical mosaicism in a mycorrhizal interaction.

Journal Article↗

PubMed1976

[Multiple sclerosis with reduced and with normal levels of complement in the blood. Clinical and genetic correlation].

The authors describe the results of immunological assay of complement factors C3, C4 (the usual path of activation of complement) and of B factor (the alternate path of activation) in 61 multiple sclerosis patients not receiving corticoids, 52 normal controls and 217 patients with other neurological disorders. Hypocomplementaemia (fall in factor C3 related to a fall in total haemolytic activity) was found in 29.5 p. 100 of the patients not on corticotherapy at the first assay, and in 36 p. 100 of the patients when repeated assays were carried out. Hypocomplementaemia is significantly more frequent in multiple sclerosis than in the normal population (0 p. 100) and in neurological patients (9.6 p. 100). In 13.1 p. 100 of the multiple sclerosis patients there was a decrease in B factor: 50.3 p. 100 of the multiple sclerosis patients exhibited no quantitative abnormality of the main factors of complement (normocomplementary multiple sclerosis). The group of multiple sclerosis patients with hypocomplementaemia was characterized by the incidence of other abnormalities in the complement system: cleavage of the C3 factor and a fall in B factor in 60 p. 100 of the cases. A more frequent increase in IgE and measles antibodies was found also while the normocomplementary multiple sclerosis patients more frequently had higher levels of IgA. Genetically, the group with hypocomplementaemia is related to a significant increase in the incidence of the HL-A W18 group while the normocomplementary multiple sclerosis patients appear closely related to the HL-A7 group. Familial investigations show that hypocomplementaemia is usually present in the ascendents and collaterals and that it seems to be transmitted with the HL-A haplotypes. Four families gave evidence of transmission with the W18 group. This transmission sometimes occurs together with transmission of an increase in IgE and/or of measles antibodies. In two pedigrees, one of the ascendents carried in his serum an activator of the alternate path of complement. There does not appear to be any prognostic difference between the two groups. In multiple sclerosis with hypocomplementaemia, the facts suggest a complex immunological abnormality, transmitted genetically to the subject and existing prior to the illness, comprising both elements of deficient and excessive immune response. The recognized presence of a gene of immunological reactivity and of genes of synthesis of complement on the 6th chromosome, in proximity with genes of histocompatability (HL-A and M.L.C.) provides a theoretical basis for this supposition.

Adult↗

PubMed2000

Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency.

Adenylosuccinate lyase (ADSL) deficiency (MIM 103050) is an autosomal recessive inborn error of purine synthesis characterized by the accumulation in body fluids of succinylaminoimidazolecarboxamide (SAICA) riboside and succinyladenosine (S-Ado), the dephosphorylated derivatives of the two substrates of the enzyme. Because ADSL-deficient patients display widely variable degrees of psychomotor retardation, we have expressed eight mutated ADSL enzymes as thioredoxin fusions and compared their properties with the clinical and biochemical characteristics of 10 patients. Three expressed mutated ADSL enzymes (M26L, R426H and T450S) were thermolabile, four (A2V, R141W, R303C and S395R) were thermostable and one (del206-218), was inactive. Thermolabile mutations decreased activities with SAICA ribotide (SAICAR) and adenylosuccinate (S-AMP) in parallel, or more with SAICAR than with S-AMP. Patients homozygous for one of these mutations, R426H, displayed similarly decreased ADSL activities in their fibroblasts, S-Ado:SAICA riboside ratios of approximately 1 in their cerebrospinal fluid and were profoundly retarded. With the exception of A2V, thermostable mutations decreased activity with S-AMP to a much more marked extent than with SAICAR. Two unrelated patients homozygous for one of the thermostable mutations, R303C, also displayed a much more marked decrease in the activity of fibroblast ADSL with S-AMP than with SAICAR, had S-Ado:SAICA riboside ratios between 3 and 4 in their cerebrospinal fluid and were mildly retarded. These results suggest that, in some cases, the genetic lesion of ADSL determines the ratio of its activities with S-AMP versus SAICAR, which in turn defines the S-Ado:SAICA riboside ratio and the patients' mental status.

5' Untranslated Regions↗

PubMed2003

[Population genetic correlation of vitamin D receptor polymorphisms with clinical disorders].

Calcitriol, the active metabolite of Vitamin D (1,25(OH)2D3) has several major roles in the body: hormonal regulation of calcium and phosphate-homeostasis, regulation of parathormone synthesis and modulation of the immune and endocrine systems. Due to its antiproliferative effects it also plays a role in tumour development. The calcitriol can have these differential effects as it is modulating gene expression in the cell nucleus. The effects of vitamin D are mediated by the nuclear vitamin D receptor, which heterodimerizes with the retinoid X receptor and changes gene transcription. Until now 5 single nucleotide polymorphisms of the vitamin D receptor gene have been identified. This review summarizes the identified effects of vitamin D receptor polymorphisms on bone homeostasis, on the parathyroid function, on diversal tumours and on diabetes.

Bone and Bones↗

PubMed2006

Energetic efficiency under stress underlies positive genetic correlations between longevity and other fitness traits in natural populations.

Evolutionary relationships among fitness traits are considered in terms of the near-to-universal scenario of stressful environments leading to a resource-deficient and hence energy-deficient world. Fitness approximates to energetic (and metabolic) efficiency under this environmental model. When fitness is high, stress resistance (reducible to oxidative-stress resistance) and metabolic stability are maximal, and energy expenditure is minimal. Rapid development should then be favored followed by a long lifespan and high adult survival. Positive associations among diverse fitness or life-history traits are expected, controlled by stress-resistant 'good genotypes'. Heterozygotes tend to show higher energetic efficiency and hence higher fitness than do corresponding homozygotes under extreme environments, and to give parallel associations among life-history traits. Energy budgets under abiotic environments are pivotal for integrative evolutionary studies of life histories in natural populations.

Animals↗