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Subjects Homozygous (subject + homozygous)
Selected AbstractsVariation in GABRA2 Predicts Drinking Behavior in Project MATCH SubjectsALCOHOLISM, Issue 11 2007Lance O. Bauer Background:, Previous studies demonstrated, and replicated, an association between single nucleotide polymorphisms (SNPs) within the GABRA2 gene and risk for alcohol dependence. The present study examines the association of a GABRA2 SNP with another definition of alcohol involvement and with the effects of psychosocial treatment. Methods:, European-American subjects (n = 812, 73.4% male) provided DNA samples for the analysis. All were participants in Project Matching Alcoholism Treatment to Client Heterogeneity (MATCH), a multi-center randomized clinical trial evaluating the efficacy of 3 types of psychosocial treatment for alcoholism: Cognitive Behavioral Therapy (CBT), Motivational Enhancement Therapy (MET), or twelve-step facilitation (TSF). The daily probabilities of drinking and heavy drinking were estimated during the 12-week treatment and 12-month post-treatment periods. Results:, Subjects homozygous for the allele associated with low risk for alcohol dependence in previous studies had lower daily probabilities of drinking and heavy drinking in the present study. This low-risk allele was also associated with a greater difference in drinking outcomes between the treatments. In addition, it enhanced the relative superiority of TSF over CBT and MET. Population stratification was excluded as a confound using ancestry informative marker analysis. Conclusions:, The assessment of genetic vulnerability may be relevant to studies of the efficacy of psychosocial treatment: GABRA2 genotype modifies the variance in drinking and can therefore moderate power for resolving differences between treatments. [source] Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmaticsCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2008T-H. Kim Summary Background Aspirin-intolerant asthma (AIA) refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). Angiotensin I-converting enzyme (ACE), a membrane-bound peptidase present in the lung, plays a pivotal role in the metabolism of the endogenous peptides involved in the pathogenesis of asthma. Methods We screened a Korean asthma cohort (581 asthmatics including 81 aspirin-intolerant asthmatics and 231 aspirin-tolerant asthmatics, and 181 normal controls) for four single nucleotide polymorphisms (SNPs; ,262 A>T and ,115 T>C in the 5,-flanking region and +5467 T>C [Pro450Pro] and+11860 A>G [Thr776Thr] in the coding region) and one ins/del (+21288 CT) in the ACE gene. Results None of the SNPs or haplotypes showed any association with the development of asthma, but they were significantly associated with the risk of AIA. Logistic regression indicated that the frequency of the rare alleles of ,262 A>T and ,115 T>C was higher in subjects with AIA than in subjects with aspirin-tolerant asthma (ATA) (P=0.003,0.01, P corr=0.015,0.05). Subjects homozygous for the rare alleles of ,262 A>T and ,115 T>C showed a greater decline in forced expiratory volume in 1 s (FEV1) after aspirin provocation than those homozygous for the common alleles (P<0.05). A luciferase reporter assay indicated that ACE promoters containing the rare ,262 A>T allele possessed lower activity than did those containing the common allele (P=0.009). In addition, ACE promoters bearing the rare ,115 T>C allele had no luciferase activity. DNA,protein binding assays revealed a band containing the ACE promoter region (including ,262 A) and a protein complex. Conclusion The ,262 A>T polymorphism in the promoter of the ACE gene is associated with AIA, and the rare allele of ,262 A>T may confer aspirin hypersensitivity via the down-regulation of ACE expression. [source] Peroxisome proliferator activated receptor delta genotype in relation to cardiovascular risk factors and risk of coronary heart disease in hypercholesterolaemic menJOURNAL OF INTERNAL MEDICINE, Issue 6 2003J. Skogsberg Abstract. Objectives., Peroxisome proliferator activated receptor delta (PPARD) is a transcription factor implicated in the regulation of genes involved in cholesterol metabolism. We recently discovered a common polymorphism in the 5,-untranslated region (5,-UTR) of the human PPARD, +294T/C, that is associated with an increased plasma low-density lipoprotein cholesterol (LDL-C) concentration in healthy subjects. Whether the +294C allele is associated with LDL-C elevation independently of the background lipoprotein phenotype and whether it confers increased risk of coronary heart disease (CHD) is unknown. Against this background, we investigated the relationships between the PPARD polymorphism and plasma lipoprotein concentrations and the risk for contracting CHD in the West of Scotland Coronary Prevention Study (WOSCOPS). Design., A nested case,control study of participants in a randomized double-blind placebo-controlled trial of pravastatin in mildly-to-moderately hypercholesterolaemic men. Subjects., A total of 580 cases of incident CHD and 1160 individuals who remained free of CHD (controls). Main outcome measures., Plasma lipoprotein con-centrations and risk of CHD according to PPARD genotype. Results., Individuals carrying the rare PPARD +294C allele had a significantly lower high-density lipoprotein cholesterol (HDL-C) concentration than subjects homozygous for the common T-allele. Homozygous carriers of the C-allele also showed a tendency towards higher risk of CHD compared with homozygous carriers of the T-allele. In addition, a gene,gene interaction involving the PPARD polymorphism and the PPAR alpha L162V polymorphism may influence the plasma LDL-C concentration. Conclusions., PPARD plays a role in cholesterol metabolism in man. [source] Homozygosis for (12) CA repeats in the first intron of the human IFN- , gene is significantly associated with the risk of aplastic anaemia in Caucasian populationBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2004Carlo Dufour Summary Interferon- , (IFN- ,) mediates the final damage of the stem cell compartment in Aplastic Anaemia (AA). Normal subjects homozygous for 12 (CA) repeats of polymorphism variable number of dinucleotide (CA) repeat (VNDR) in position 1349 of the IFN- , gene (IFNG) were shown to overproduce IFN- ,in vitro. We studied the distribution of polymorphism VNDR 1349 of IFNG in 67 Caucasian AA patients and in normal controls. Genotype (CA)12-12, (homozygosis for allele 2) and the single allele 12 were significantly more frequent (P = 0·005 and 0·004 respectively) in patients versus controls. The polymorphism was equally distributed in AA patients regardless of their response to immunosuppression. Homozygosity for 12 (CA) repeats of polymorphism VNDR 1349 of IFNG is strongly associated with the risk of AA in Caucasian subjects. [source] Aldosterone synthase gene variation and adrenocortical response to sodium status, angiotensin II and ACTH in normal male subjectsCLINICAL ENDOCRINOLOGY, Issue 2 2004Brian Kennon Summary objective, Aldosterone synthase, a key enzyme in the terminal steps of aldosterone synthesis, is encoded by the CYP11B2 gene. A polymorphism in the 5, coding region of this gene (,344 C/T) is associated with hypertension, particularly with elevation of the aldosterone to renin ratio. A second polymorphism (a conversion in intron 2 to resemble that of the neighbouring 11,-hydroxylase (CYP11B1) gene) is found in close linkage dysequilibrium with the variant at ,344 C/T. The mechanism by which these variants predispose to cardiovascular disease and the precise intermediate phenotype associated with them remains speculative. design, We performed a focused physiological study in normal volunteers stratified by CYP11B2 genotype. patients, Twenty-three subjects homozygous for the T allele and 21 homozygous for the C allele of the ,344 C/T polymorphism of CYP11B2 were studied. measurements, Basal and angiotensin II stimulated plasma and 24-h urinary steroid excretion during low (60 mmol/day) and high (160 mmol/day) sodium intake and plasma steroids after ACTH stimulation were measured. results, No influence of polymorphic variation on basal or stimulated plasma cortisol or aldosterone or other plasma steroid concentrations during either dietary phase was seen. However, excretion of tetrahydro-11-deoxycortisol (the urinary metabolite of 11-deoxycortisol), which is the precursor of cortisol) was increased in TT subjects during sodium restriction, consistent with impairment of zona fasciculata 11,-hydroxylation. conclusions, We conclude that this polymorphism has no major influence on normal zona glomerulosa function but is associated with a change in 11,-hydroxylation in the zona fasciculata. The mechanism remains uncertain, but alteration of 11-deoxycortisol levels without change in cortisol suggests altered efficiency of 11,-hydroxylation. In the long term, this may lead to a minor but chronic increase in ACTH drive to the gland, which may have consequences for steroid synthesis and predispose to the risk of cardiovascular disease. [source] | ||||||||||