Huntington’s Disease Genetics

Summary:Huntington’s disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children of HD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. HD is a “trinucleotide repeat” disorder, which is caused by an increase in the number of CAG repeats in the HD gene. Repeats of 40 or larger are associated with disease expression, whereas repeats of 26 and smaller are normal. Intermediate numbers of repeats, between 27 and 35, are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendents. Repeats of 36–39 are associated with reduced penetrance whereby some develop HD and others do not. The identification of the genetic defect in HD permits direct genetic testing for the presence of the gene alteration responsible for the disease. Tests may be performed in three circumstances: (1) confirmation of diagnosis, (2) predictive testing of persons at genetic risk for inheriting HD, and (3) prenatal testing. Testing is widely available and much experience has been gained with protocols that assist the individual in making an informed choice about test options, and minimize the occurrence of adverse emotional outcomes.     

CYP2A6基因多态性对丙戊酸钠血药浓度的影响

目的探讨细胞色素P4502A6(CYP2A6)基因多态性对丙戊酸钠血药浓度的影响。方法选择单药服用丙戊酸钠的癫患者98例,应用巢式PCR(nested-primerpolymerasechainreaction)方法分析其CYP2A6基因型,分析等位基因CYP2A6*1及CYP2A6*4;同时应用荧光偏振免疫法(FPIA)测定患者丙戊酸钠的血药浓度。结果98例患者中CYP2A6基因型为*1/*1者73例(74·5%),*1/*4者24例(24·5%),*4/*4者1例(1·0%),根据基因型分为A组(CYP2A6*1/*1)和B组(CYP2A6*1/*4或CYP2A6*4/*4)。B组患者丙戊酸钠的标准血药浓度平均值(4·1393±0·2793)较A组(3·3486±0·3919)高,差异有统计学意义(P<0·05)。结论CYP2A6基因多态性影响丙戊酸钠的血药浓度,含有CYP2A6*4等位基因的患者应用丙戊酸钠应较常规降低用量。     

A biometrical genetic approach to chromosome analysis inDrosophila: Detection of epistatic interactions in geotaxis

Chromosome analysis has been widely used as a first step in eclucidating the genetic architecture of several behaviors ofDrosophila melanogaster. These chromosome studies have generally used incomplete designs or fairly simple statistical analyses. Here I reanalyze two data sets on geotaxis from Pyle (1978) and Ksander (1966) using a biometrical genetic design. Results from the biometrical genetic reanalysis suggest that individual differences in geotaxis might be due to genes on all three major chromosomes which show extensive epistatic interactions.     

No evidence for association between the −112G/A polymorphism of UGRP1 and childhood atopic asthma

BACKGROUND: Susceptibility to asthma is known to involve genetic factors. Genome-wide screens have indicated that the chromosome 5q31-q34 region is linked to and/or associated with asthma. A new gene, named UGRP1 and reported by Niimi et al., encodes uteroglobin-related protein and is expressed in the lung and trachea. Niimi et al. showed the -112G/A polymorphism of the UGRP1 gene to be associated with asthma in a case-control study. OBJECTIVE: The objective of the present study was to replicate this association and confirm the possible role of the UGRP1-112G/A polymorphism in the aetiology of childhood asthma in a Japanese population. METHODS AND RESULTS: We conducted a transmission disequilibrium test (TDT) in 131 families identified through paediatric patients being treated for asthma. A case-control study was also carried out by comparing the probands and 137 unrelated non-atopic non-asthmatic Japanese children and 211 unrelated healthy Japanese adults. The -112G/A polymorphism was genotyped by the PCR-RFLP method. The TDT revealed that the -112A allele was not preferentially transmitted to asthma-affected children (P=0.85). Neither the presence of at least one A allele in an individual's genotype (sum of the G/A and A/A genotypes) nor the -112A allele was more prevalent among the asthma subjects than among the control subjects. CONCLUSION: Our findings indicate that the UGRP1-112G/A polymorphism does not play a substantial role in genetic predisposition to childhood asthma in this Japanese population.     

鄂尔多斯沙地草场小毛足鼠种群数量动态分析

目的 了解小毛足鼠种群数量变动因素。方法 1991-1998年4-10月在中国农业科学院草原研究所鄂尔多斯沙地草场改良试验站，利用直线夹日法调查。结果 小毛足鼠为该地区优势种，该鼠数量变化季节性明显，年间变化差异较大。经过8年调查，小毛足鼠数量变化经历了低谷(1991—1992年)、高峰(1993年)、下降(1994年)和低谷(1995—1998年)4个时期。结论 影响种群数量变动的主要因素有种群年龄组成中幼年组的百分比、怀孕率、鳖殖指数以及该地区子午沙鼠、三趾跳鼠和黑线仓鼠的数量。     

Lipid metabolism and occurrence of post-percutaneous transluminal coronary angioplasty restenosis: role of cholesteryl ester transfer protein and paraoxonase/arylesterase

Summary.  Plasma lipid metabolic and transfer processes have recently been suggested to play an important role in the development of early restenosis, a major complication of percutaneous transluminal coronary angioplasty (PTCA); in particular, the common variants of genes for cholesteryl ester transfer protein (CETP) and paraoxonase (PONA) have been implicated. We had the opportunity to investigate this question in a large, prospective cohort characterized by quantitative coronary angiography in all subjects. The CETP-Taq IB (intron 1), CETP-Msp I (intron 8), and PONA-Alw I (exon 2) polymorphisms were characterized in a cohort of 779 patients of whom 342 ('cases') had developed restenosis (as defined by > 50% loss of lumen compared with immediate postprocedure results) at repeat angiography at 6 months post PTCA. Selected frequencies for CETP B1 and B2 alleles (absence/presence of Taq IB site) were 0.65 and 0.35 (cases) and 0.65 and 0.35 (controls), respectively; frequencies for CETP M1 and M2 alleles (absence/presence of Msp I site) were 0.20 and 0.80 (cases), 0.21 and 0.79 (controls), respectively; frequencies for PONA A and B alleles (absence/presence of Alw I site) were 0.73 and 0.27 (cases), 0.72 and 0.28 (controls), respectively. All observed genotype frequencies were in Hardy–Weinberg equilibrium. There was no evidence for gene–gene interaction, or an association between genotype and restenosis or degree of lumen loss (adjusted for covariates). Our data, collected in the largest study of its kind so far, indicate that the common variants for CETP and PONA are not associated with incidence of restenosis after PTCA, and are therefore not useful markers for risk assessment.     

Is there a ‘Basque’ profile regarding autosomal recessive deficiencies of coagulation factors?*

When excluding haemophilia and von Willebrand disease, coagulation factors deficiencies constitute rare autosomal recessive disorders (<1 in 500,000) of less precisely defined epidemiology. We have reported herein the distribution of these entities in the French Basque Country, a genetic isolate of very old individualization with peculiar biological specificities. The prevalence of these disorders was markedly high, especially, as already shown, factor XI deficiency. This unusual profile needs to be discussed in the view of population genetics.     

Cystitis as a correlate of female urinary incontinence

The objectives of the research were to study the association between prevalent urge and stress urinary incontinence (UI) and a history of cystitis in adult females. A cross-section of the adult female population, aged 30–59 years, in the Municipality of Aarhus, Denmark, was studied, using self-reported data based on postal questionnaires. The sample consisted of 3114 women, out of whom 2613 (84%) delivered the information requested. The main outcome measures were period prevalence in 1987 of episodes of UI provoked by physical stress and UI associated with a feeling of urge, prevalence of experience of episodes of cystitis and UI related to cystitis in adult life, and prevalence of relative risks, as indicated by odds ratio (OR), of UI conditional on cystitis experience. Results indicated that the 1987 period prevalences of UI provoked by physical stress and UI associated with a feeling of urge were 15% and 9%, respectively. Forty-five per cent reported a history of cystitis and 10% of UI during episodes of cystitis. Both UI provoked by stress and UI associated with a feeling of urge were significantly correlated to cystitis (OR 2.1, P<0.0001, and 1.8, P<0.0001, respectively) and to UI during episodes of cystitis (OR 7.1, P<0.0001, and 5.7, P<0.0001, respectively). When corrected for the stress aspect, UI being associated with a feeling of urge showed no association of its own to a history of cystitis. However, stress and urge aspects were both correlated to the experience of UI during episodes of cystitis. The prevalence of experience of cystitis increased with increasing number of urologic (per operation OR 2.1, P<0.0001) and gynecologic operations (per operation OR 1.5, P<0.0001), e.g. curretage (per operation OR 1.2, P<0.001), but not with the number of abdominal operations or the number of childbirths. It was concluded that cystitis may be an important component of UI etiology. Stress and not urge UI seems to be the key type related to a history of cystitis in general. The experience of UI during cystitis is connected to both stress and urge UI. A history of cystitis may possibly itself by initiated by surgery.     

A -243A-->G polymorphism upstream of the gene encoding GAD65 associates with lower levels of body mass index and glycaemia in a population-based sample of 5857 middle-aged White subjects.

AIMS: The glutamate decarboxylase gene (GAD2) encodes GAD65, an enzyme catalysing the production of the gamma-aminobutyric acid (GABA) which interacts with neuropeptide Y to stimulate food intake. It has been suggested that in pancreatic islets, GABA serves as a functional regulator of pancreatic hormone release. Conflicting results have been reported concerning the potential impact of GAD2 variation on estimates of energy metabolism. The aim of this study was to elucidate potential associations between the GAD2-243A-->G polymorphism and levels of body mass index (BMI) and estimates of glycaemia. METHODS: Using high-throughput chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, the GAD2-243A-->G (rs2236418) polymorphism was genotyped in a population-based sample (Inter99) of 5857 middle-aged, unrelated Danish White subjects. RESULTS: The G-allele was associated with modestly lower BMI (P = 0.01). In a case-control study of obesity, the G-allele frequency in 2582 participants with BMI < 25 kg/m2 was 19.5% (18.4-20.6) compared with 17.1% (15.5-18.8) in 968 participants having BMI > or = 30 kg/m2 (P = 0.03), odds ratio 0.9 (0.7-1.0). Of the 5857 subjects, GG carriers had lower fasting plasma glucose levels (mmol/l) [AA (n = 3859) 5.6 +/- 0.8; AG (n = 1792) 5.5 +/- 0.8; GG (n = 206) 5.5 +/- 0.8, P = 0.008] and lower 30-min oral glucose tolerance test (OGTT)-related plasma glucose levels (AA 8.7 +/- 1.9; AG 8.6 +/- 1.9; GG 8.6 +/- 2.0, P = 0.04), adjusted for sex, age and BMI. Analysing subjects who were both normoglycaemic and glucose tolerant (n = 4431) GG carriers still had lower fasting plasma glucose concentrations: AA (n = 2895) 5.3 +/- 0.4; AG (n = 1383) 5.3 +/- 0.4; GG (n = 153) 5.2 +/- 0.4 (P = 9.10(-5)). CONCLUSION: The present study suggests that the GAD2-243A-->G polymorphism in a population of middle-aged White people associates with a modest reduction in BMI and fasting and OGTT-related plasma glucose levels.     

Genetic susceptibility to type 2 diabetic nephropathy in human and animal models

SUMMARY:   Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Japan, Western Europe, and the United States. Mega studies such as Diabetes Control and Complication Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) clarified that poor glycemic and blood pressure control are undoubtedly involved in the development of nephropathy. However, these factors are not sufficient to predict which diabetic patients will develop renal disease, because not all patients with poor glycemic and blood pressure control develop renal disease. Since ethnic variations and familial clustering of diabetic nephropathy have been observed, genetic factors might contribute to susceptibility to this disease. Several methods such as (genome wide) association studies, sib-pair analysis, and quantitative trait loci (QTLs) analysis are available to examine polygenic diseases. However, no mutations that could explain the majority of nephropathy cases have been identified so far. The development of most diabetic nephropathy might be explained by the polygenic effect (i.e. many minor gene-gene interactions might be very important in the development of nephropathy). Identification of candidate genes of nephropathy enables targeting of therapy in patients at risk and development of novel therapeutic agents.