ABSTRACT
Genetic linkage studies indicate evidence for one or more Alzheimer's disease (AD) genes on chromosome 19 independently of the apolipoprotein E gene, a well-characterized AD-risk factor. Recently, the PIN1 gene on chromosome 19p13.2 has been proposed as a candidate gene for AD. Here, we have investigated the potential impact of two promoter polymorphisms (rs2233678 and rs2233679) within this gene on the risk of developing AD. No association of these polymorphisms or haplotypes with the disease was observed in a large French case-control population. Our data suggest that these genetic variants in PIN1 do not make a significant contribution to AD risk.
Subject(s)
Alzheimer Disease/genetics , Peptidylprolyl Isomerase/genetics , Aged , Case-Control Studies , Chromosomes, Human, Pair 19 , Female , Genetic Linkage , Genetic Predisposition to Disease , Humans , Male , NIMA-Interacting Peptidylprolyl Isomerase , Polymorphism, Genetic , Promoter Regions, Genetic , RiskABSTRACT
Recently, a region encompassing the promoter and intron 1 of the paraoxonase 1 gene (PON1) have been associated with the risk of developing Alzheimer's disease (AD) in a large pan-ethnic (Caucasian and African-American) dataset. We attempted to replicate this observation in a large French study of sporadic cases and controls. We confirmed that the proximal promoter and 5' sequence of the PON1 gene may harbor unknown functional variant(s) associated with the risk of developing AD.
Subject(s)
Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Aryldialkylphosphatase/genetics , Polymorphism, Single Nucleotide/genetics , Risk Assessment/methods , Aged , Female , France/epidemiology , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Humans , Male , Prevalence , Risk FactorsABSTRACT
BACKGROUND: Previous studies have suggested that the activity of enzymes involved in the urea cycle may modulate nitric oxide (NO) production, arterial vasomotion, and hypertension. Our aim was to determine whether hypertension and coronary vasomotion could be associated with polymorphisms within the ornithine transcarbamylase (OTC) gene, located on chromosome X and coding for a key-enzyme of the urea cycle. METHODS: Among 11 OTC polymorphisms that were originally selected from databases, the tag single-nucleotide polymorphism (SNP) rs5963409 and the independent SNP rs1800321 were tested for association with hypertension in two independent population samples recruited in Northern (Multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) study, n = 1,138) and Western (Etude du Vieillissement Artériel (EVA) study, n = 1,166) France. The vasomotor response of coronary arteries to methylergonovine maleate and isosorbide dinitrate was also evaluated in an independent sample (the vasomotion study, n = 121). RESULTS: In males, the frequency of the rs5963409 minor allele was consistently higher in hypertensive (HT) than in normotensive subjects in the MONICA and EVA studies. In the combined sample, the rs5963409 minor allele was associated with an increased risk of hypertension (odds ratio (OR) (95% confidence interval (CI)) = 1.45 (1.10-1.90); P = 0.008). This association was independent of classical confounding factors. Consistently, rs5963409 minor allele was associated with a greater susceptibility to vasoconstriction in response to methylergonovine maleate (P = 0.0072). In contrast, no significant association between rs5963409 and hypertension could be detected in females. CONCLUSION: Our results suggest that the OTC rs5963409 polymorphism may be associated with hypertension and coronary vasomotion in males.
Subject(s)
Coronary Vasospasm/genetics , Coronary Vessels/physiopathology , Hypertension/genetics , Ornithine Carbamoyltransferase/genetics , Vasoconstriction/drug effects , Vasodilation/drug effects , Adult , Aged , Blood Pressure/genetics , Coronary Vasospasm/epidemiology , Coronary Vasospasm/physiopathology , Female , France/epidemiology , Gene Frequency , Humans , Male , Middle Aged , Molecular Epidemiology , Polymorphism, Single Nucleotide , Sex FactorsABSTRACT
Numerous observations indicate that cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Converging evidence points to a pivotal role for vascular endothelial growth factor (VEGF) in neuronal protection, and the lack of activity of this in neurodegenerative disorders. The VEGF gene is located at 6p21.3, a site several studies have shown to have significant linkage with AD, and a functional polymorphism within the VEGF promoter may alter the risk of developing AD. We assessed the potential impact of this polymorphism on the risk of developing AD in a large French case-control population, and investigated its association with the severity of brain vascular lesions (arteriosclerosis, white matter loss and cerebral amyloid angiopathy) in several brain regions (frontal, temporal, parietal and occipital cortex) in AD. No association of the VEGF promoter polymorphism with the risk of developing AD was observed. No relationship between this polymorphism and vascular pathological changes in AD was detected. Our data indicate that although this polymorphism is functional, it does not confer greater risk for AD, nor modulate the extent of vascular pathology.
Subject(s)
Alzheimer Disease/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Vascular Endothelial Growth Factor A/genetics , Aged , Alzheimer Disease/pathology , Brain/pathology , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Risk , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Recently, the ubiquilin 1 gene has been proposed as a major candidate gene for AD. Here, we have investigated the potential impact of the UBQ-8i polymorphism (rs12344615) within this gene on the risk of developing AD. No association of this polymorphism with the disease was observed in a large French case-control population. Furthermore, no relationship between this polymorphism and Abeta load or degree of neurofibrillary degeneration in the brains of 114 patients with AD was detected.