ABSTRACT
BACKGROUND: Transgenic mice over-expressing SMAD7 in pancreatic beta-cells develop type 2 diabetes (T2D). The expression of SMAD7 is affected by KLF11, which contains gene variants that have previously been shown to be involved in genetic susceptibility to T2D, and by the highly homologous KLF10. This study aims to assess the genetic contribution of SMAD7 and KLF10 gene variants to T2D susceptibility in the French population. METHODS: We screened both genes to identify rare and frequent variants by direct sequencing and then genotyped these variants. Six frequent variants of SMAD7 and six of KLF10 were analyzed in 349 T2D patients and 349 normoglycaemic adult subjects. Variants with statistically significant differences in allele and/or genotype distribution were further analyzed in a population sample of 1.712 T2D patients and 1.072 normoglycaemic subjects. RESULTS: Two variants showed a significant association under a recessive model: The intronic SMAD7 IVS2 -21 had an odds ratio of 0.62 (P=0.007, 95% CI=0.44-0.88; P=0.034 when adjusting for age, sex and BMI by logistic regression), and the KLF10 3'UTR +1002 variant had an Odds Ratio of 0.81 (P=0.009, 95% CI=0.69-0.95; P=0.042 when adjusting for age, sex and BMI). CONCLUSION: Although the observed association of SMAD7 and KLF10 gene variants with T2D is modest, they may weakly contribute to a particular genetic background that increases the susceptibility to development of T2D.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Early Growth Response Transcription Factors/genetics , Genetic Predisposition to Disease , Genetic Variation , Kruppel-Like Transcription Factors/genetics , Smad7 Protein/genetics , Adult , Aged , Case-Control Studies , Female , France , Humans , Male , Middle Aged , Reference Values , White People/geneticsABSTRACT
AIMS/HYPOTHESIS: Morbid obesity (BMI>40 kg/m(2)) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. METHODS: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6+/-7.4 kg/m(2)), 808 non-obese subjects (BMI<30 kg/m(2)) and 493 obese subjects (30< or =BMI<40 kg/m(2)). RESULTS: Two 5'-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a "low-level" haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5'-ACDC "low-level" haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals. CONCLUSIONS/INTERPRETATION: These data clarify the contribution of the 5'-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.
Subject(s)
Diabetes Mellitus/genetics , Genetic Variation , Intercellular Signaling Peptides and Proteins/genetics , Obesity, Morbid/genetics , Promoter Regions, Genetic , Adiponectin , Diabetes Complications/genetics , Diabetes Mellitus/blood , Family , Female , France , Genotype , Humans , Intercellular Signaling Peptides and Proteins/blood , Intercellular Signaling Peptides and Proteins/deficiency , Male , Obesity, Morbid/blood , PPAR gamma/genetics , Polymorphism, Single Nucleotide , White PeopleABSTRACT
AIMS/HYPOTHESIS: The gene encoding HNF-4alpha, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4alpha P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. METHODS: Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4alpha region had been shown. RESULTS: The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4alpha was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. CONCLUSIONS/INTERPRETATION: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4alpha and type 2 diabetes in several ethnic groups.
Subject(s)
DNA-Binding Proteins/genetics , Diabetes Mellitus, Type 2/genetics , Phosphoproteins/genetics , Polymorphism, Genetic , Polymorphism, Single Nucleotide , Transcription Factors/genetics , Case-Control Studies , Female , Finland , France , Gene Frequency , Genetic Predisposition to Disease , Genotype , Hepatocyte Nuclear Factor 4 , Humans , Linkage Disequilibrium , Male , Middle Aged , White PeopleABSTRACT
AIM: Anti-inflammatory effects of moderate alcohol consumption have been proposed to explain why moderate alcohol intake lowers coronary heart disease risk. We investigated the relationship between overall alcohol, beer or wine consumption and markers of systemic inflammation in three different geographical areas in Europe. METHODS AND RESULTS: Cross-sectional samples, each representative of the general population from Germany, Scotland, and France (MONICA Augsburg 1994/95, 2275 men and 2186 women, 25-74 years; Glasgow MONICA 1994/95, 561/616, 25-74 years, and MONICA Lille 1994/95, 581/574, 35-64 years) were studied. Alcohol intake was assessed by standardized interview. Adjusted means of C-reactive protein (CRP), fibrinogen, white blood cell (WBC) count, plasma viscosity (PV), and albumin were calculated among categories of alcohol intake, and separately for beer or wine consumption, by multiple linear regression. Self-reported moderate daily alcohol intake up to 40 g was associated with lower concentrations of CRP, fibrinogen, PV and WBC count, compared to non-drinking and heavy drinking, even after adjustment for various potential confounders. CONCLUSIONS: Moderate consumption of either wine or beer is associated with lower levels of systemic inflammatory markers in three different European areas, suggesting that ethanol itself might be largely responsible for the potential anti-inflammatory effects of these beverages.
Subject(s)
Alcohol Drinking/blood , Arteriosclerosis/blood , Inflammation/blood , Adult , Aged , Beer , Biomarkers/blood , Coronary Disease/blood , Cross-Sectional Studies , Female , France , Germany , Humans , Male , Middle Aged , Risk Factors , Scotland , WineABSTRACT
Cerebral accumulation of beta-amyloid peptide (A beta) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate A beta-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to A beta deposition, further suggesting a physiological role in A beta clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR=0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical A beta clearance and offer new potential targets for therapeutic interventions in AD.
Subject(s)
Alzheimer Disease/enzymology , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Cerebral Cortex/metabolism , Neurons/metabolism , Adult , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Case-Control Studies , Cerebral Cortex/cytology , Endothelin-Converting Enzymes , Genetic Predisposition to Disease , Hippocampus/metabolism , Humans , In Vitro Techniques , Metalloendopeptidases , Reference Values , Risk Factors , Tissue DistributionABSTRACT
Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a -499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the -499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.
Subject(s)
Adaptor Proteins, Signal Transducing , Alzheimer Disease/genetics , Carrier Proteins/genetics , Nuclear Proteins/genetics , Promoter Regions, Genetic , Trans-Activators/genetics , Alzheimer Disease/enzymology , Alzheimer Disease/pathology , Autopsy , Base Sequence , Brain/pathology , Cognition , DNA Primers , France , Genetic Variation , Humans , Neuroblastoma , Reelin Protein , Transfection , Tumor Cells, CulturedABSTRACT
OBJECTIVE: To assess whether the -455 and -482 mutations in APOC-III gene insulin response element affect the relationships between plasma insulin and triglyceride-rich lipoprotein levels. DESIGN: Population-based studies. SUBJECTS: The population sample was composed of 983 subjects (485 men and 498 women), aged between 35 and 65 y, randomly sampled from the electoral rolls in Northern France and stratified on gender and 10 y age groups. MEASUREMENTS: Plasma triglyceride, apolipoprotein C-III, apoB, LpC-III:B and LpE:B lipoprotein particles and insulin levels were measured. Two polymorphisms in APOC-III gene insulin response element (T-->C at -455 and/or C-->T at -482) were determined. RESULTS: Plasma insulin was positively correlated to triglyceride levels (P<0.0001), apo C-III (P<0.003), LpC-III:B (P<0.0001), apoB (P<0.0001) and LpE:B (P<0.0001). This association differed significantly according to APOC-III insulin response element polymorphisms. The relationship between insulin and LpC-III:B (P<0.02) or apoB (P<0.02) was greater in women bearing the C allele of -455 than the T allele. Similarly, the relationship between insulin and LpC-III:B (P<0.02) or LpE:B (P<0.05) was greater in women bearing the T allele of -482 than the C allele. There was no evidence for any effect in men. CONCLUSION: These results suggest that the relationship between plasma insulin and triglyceride-rich lipoprotein levels is partly influenced by polymorphisms in APOC-III insulin response element.
Subject(s)
Apolipoproteins C/genetics , Insulin/blood , Polymorphism, Genetic , Triglycerides/blood , Adult , Aged , Alleles , Apolipoprotein C-III , Apolipoproteins/blood , Apolipoproteins/genetics , Female , France , Humans , Insulin/genetics , Male , Middle Aged , Sex Factors , Surveys and Questionnaires , Triglycerides/geneticsABSTRACT
The frequency of a genetic susceptibility vascular factor, the deletion (D) allele of the angiotensin I converting enzyme gene (ACE), coding for a key enzyme of the renin angiotensin system, was characterized in two independent case--control studies. The results of the current study suggest that bearing at least one ACE D allele is a risk factor to develop dementia for subjects older than 74 years. This observation reinforces the hypothesis of a major implication of vascular risk factors in the occurrence of all types of dementia.
Subject(s)
Dementia/epidemiology , Dementia/genetics , Peptidyl-Dipeptidase A/genetics , Aged , Alleles , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Male , Risk FactorsABSTRACT
AIMS: Abnormal coronary vasomotion plays a role in the clinical expression of coronary artery disease. We hypothesized that the functional C825T polymorphism located in the ubiquitous G-protein beta3 subunit, implicated in the cellular signal transduction of many receptors, could modify artery coronary vasomotion. We assessed the potential association of the pertussis toxin-sensitive G protein beta3 subunit (GNB3) gene C825T polymorphism on coronary vasomotion in humans. METHODS AND RESULTS: We examined the response of angiographically normal human coronary arteries (n=131) after intravenous injection of methylergonovine maleate, a vasoconstrictor, followed by injection of isosorbide dinitrate, a vasodilator, according to GNB3 genotypes. Coronary vasomotion was assessed with quantitative coronary angiography. Subjects bearing at least one T allele had greater susceptibility to vasoconstriction in response to methylergonovine maleate than CC subjects, whereas vasodilation in response to isosorbide dinitrate did not differ among the different genotypes. CONCLUSION: The C825T polymorphism of the G-protein beta3 subunit may be a genetic determinant of coronary artery vasomotion in humans.
Subject(s)
Coronary Vasospasm/genetics , Heterotrimeric GTP-Binding Proteins/genetics , Polymorphism, Genetic/genetics , Vasoconstriction/genetics , Coronary Angiography , Coronary Vasospasm/diagnostic imaging , Coronary Vasospasm/physiopathology , Coronary Vessels/drug effects , Coronary Vessels/physiopathology , Diuretics, Osmotic , Female , Humans , Isosorbide , Male , Methylergonovine , Middle Aged , Vasoconstriction/drug effects , Vasoconstriction/physiology , Vasodilator AgentsABSTRACT
OBJECTIVE: Clinical, epidemiologic, and pathologic observations suggest that vascular risk factors are associated with impaired cognition. Previous studies supported an association between cognitive decline and APOE. Although the underlying mechanism is not clear, it might involve apoE receptors, such as the very low density lipoprotein receptor. METHODS: The impact of a polymorphic triplet repeat in the very low density lipoprotein receptor gene (VLDLR) on cognitive function was examined in two independent studies: a population study involving 221 demented subjects compared with 249 control subjects and a clinical study involving 124 demented subjects compared with 179 control subjects. RESULTS: In the population study, the presence of the VLDLR-5-repeat allele was associated with a relative risk of dementia (OR, 1.9; 95% CI, 1.2 to 3.0). This result was confirmed in the clinical study (OR, 8.1; 95% CI, 4.4 to 15.1) and was more pronounced in subjects with mixed or vascular dementia than in patients with AD. CONCLUSION: The VLDLR-5-repeat allele may constitute a genetic susceptibility factor for dementia, particularly in the presence of vascular risk factors. This observation suggests the influence of vascular risk factors in the occurrence of dementia.
Subject(s)
Cognition Disorders/genetics , Dementia/genetics , Receptors, LDL/genetics , Aged , Aged, 80 and over , Cognition Disorders/psychology , Female , Genotype , Humans , Male , Odds Ratio , Polymorphism, Genetic , Psychiatric Status Rating ScalesABSTRACT
The high affinity sulfonylurea receptor 1 (SUR1) is involved in the metabolism of glucose in pancreatic beta-cells. We investigated the impact of the SUR1 intron 16-3t-->c polymorphism on non-insulin-dependent diabetes mellitus (NIDDM) prevalence in a large representative sample of French men and women, 35-64 years old, and explored potential relationships between the SUR1 intron 16 -t-->c polymorphism and sulfonylurea therapy efficiency. This study took place in Lille (northern), Strasbourg (eastern), and Toulouse (southern France). One hundred and twenty-two subjects with NIDDM were registered. We stratified NIDDM subjects according to their medical treatment: sulfonylureas (n = 70) versus other treatments (n = 50). From the three populations, a control group was selected (n = 1,250). Subjects carrying the cc intron 16 genotype had an increased risk of NIDDM [odds ratio (OR) = 1.76, 95% confidence interval (CI) 1.10-2.80; P = 0.017]. Subjects bearing at least one -3c allele and treated with sulfonylurea agents had fasting plasma triglyceride concentrations 35% lower than subjects that were tt homozygous (P = 0.026), whereas no difference could be detected between genotypes in NIDDM subjects treated with other treatments. The SUR1 intron 16 -3t-->c polymorphism was associated with an increased susceptibility to NIDDM in this population study, and seems to modulate the sulfonylurea therapy efficiency on hypertriglyceridemia reduction. This observation may help to better target the various therapies available for treatment of NIDDM.
Subject(s)
ATP-Binding Cassette Transporters , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Hypoglycemic Agents/therapeutic use , Potassium Channels, Inwardly Rectifying , Potassium Channels/genetics , Receptors, Drug/genetics , Sulfonylurea Compounds/therapeutic use , Data Interpretation, Statistical , Diabetes Mellitus, Type 2/epidemiology , Female , Genetic Predisposition to Disease , Humans , Hypoglycemic Agents/metabolism , Introns , Male , Middle Aged , Polymorphism, Genetic , Potassium Channels/metabolism , Prevalence , Receptors, Drug/metabolism , Sulfonylurea Compounds/metabolism , Sulfonylurea ReceptorsABSTRACT
AIMS/HYPOTHESIS: The UCP2-UCP3 gene region has been previously associated with obesity and diabetes. In a large representative cohort of Northern France (MONICA project), we studied the effect of a recently reported C/T polymorphism located in the 5' sequences of the UCP3 gene on anthropometric measurements and lipid profile. We also examined the association of this polymorphism with obesity and Type II (non-insulin-dependent) diabetes mellitus. METHODS: The -55 C/T polymorphism of the UCP3 gene has been genotyped in 1155 subjects from the MONICA project. Association studies were done with diabetes, obesity and related phenotypes. Results were ascertained in a second cohort of well-characterized Type II diabetic and control subjects. RESULTS: The variant T allele was associated with a decreased risk of developing Type II diabetes. Frequencies of the T allele were 13.3% compared with 22%, p = 0.04, in the diabetic and control groups, respectively. This observation was confirmed in the second cohort of French Type II diabetic (n = 171) and control (n = 124) subjects: 17.8% compared with 25%, p = 0.03. Moreover, subjects bearing the TT genotype had higher plasma total cholesterol and LDL-cholesterol concentrations (p = 0.0006 and p = 0.001, respectively) than subjects bearing wild or heterozygous genotypes. CONCLUSION/INTERPRETATION: The UCP3 -55 C/T polymorphism was associated with a higher atherogenic profile and modified the risk for the development of Type II diabetes.
Subject(s)
Carrier Proteins/genetics , Diabetes Mellitus, Type 2/blood , Lipids/blood , Polymorphism, Genetic , Adult , Alleles , Blood Glucose/analysis , Body Constitution , Body Mass Index , Cholesterol, LDL/blood , Cohort Studies , Female , France , Genetic Predisposition to Disease , Genotype , Humans , Insulin/blood , Ion Channels , Male , Middle Aged , Mitochondrial Proteins , Obesity/blood , Obesity/genetics , Risk Factors , Uncoupling Protein 3ABSTRACT
The apolipoprotein (APO) E4 isoform is associated with an accelerated rate of Alzheimer disease (AD) expression in sporadic as well as late-onset familial forms of the disease but the precise mechanism is unknown. In an attempt to approach the possible mechanisms involved, APOE receptors have been studied. They all belong to the low density lipoprotein (LDL) receptor family and share the same structural motifs. Some of them are preferentially expressed in the brain such as the LDL receptor related protein, the apolipoprotein E receptor 2, and the very low density lipoprotein (VLDL) receptor. These receptors have been suspected to be involved in Alzheimer disease at various levels. Among them, the VLDL receptor was extensively explored. Although genetic studies conducted on a polymorphism in the promoter of the VLDL receptor in Japanese and Caucasian populations gave divergent results, this does not exclude a possible involvement of the VLDL receptor in AD.
Subject(s)
Alzheimer Disease/metabolism , Lipoproteins, VLDL/metabolism , Receptors, LDL/metabolism , Alzheimer Disease/ethnology , Alzheimer Disease/genetics , Asian People/genetics , Chromosomes, Human, Pair 9 , Humans , Lipoproteins, VLDL/genetics , Receptors, LDL/genetics , Signal Transduction , White People/geneticsABSTRACT
Fatty acids play important biological roles in cells. The precise mechanism whereby fatty acids cross the plasma membrane is still poorly understood. They can cross membranes because of their hydrophobic properties and/or be transported by specific proteins. Recently, a gene coding for fatty acid transport protein 1 (FATP1), an integral plasma membrane protein implicated in this process, was cloned in humans. We screened the gene by single-strand conformation polymorphism analysis and detected an A/G polymorphism in intron 8. We analyzed the potential relations of this genetic polymorphism with various obesity markers and with plasma lipid profiles in a random sample of 1144 French subjects aged 35 to 64 years. We detected statistically significant associations between this FATP1 A/G polymorphism and an increase in plasma triglyceride levels, mainly in women. These results suggest that genetic variability in the FATP1 gene may affect lipid metabolism, especially in women, and reinforce the potential implication of FATP1 in lipid homeostasis.
Subject(s)
Carrier Proteins/genetics , Fatty Acids/genetics , Introns , Membrane Transport Proteins , Polymorphism, Genetic , Triglycerides/blood , Adult , Base Sequence , Diabetes Mellitus, Type 2/genetics , Fatty Acid Transport Proteins , Female , France , Genotype , Humans , Male , Middle Aged , Polymorphism, Single-Stranded Conformational , Regression Analysis , Sex CharacteristicsABSTRACT
Several clinical, epidemiological, and pathological observations suggest that vascular risk factors are associated with cognitive performances. The renin-angiotensin system components, major determinants of the cardiovascular system, are expressed in the brain. To estimate their potential impact on cognitive performances, we studied the association between cognitive functioning and an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene. In a sample of 1168 highly performing subjects (59-71 years), DD homozygotes had the lowest cognitive scores as evaluated by the Mini-Mental State Examination. Cognitive decline at 4-year follow-up (defined as the loss of at least 3 points in Mini-Mental State Examination score) was more prevalent in these subjects, the odds ratio being equal to 1.53 (95% CI: 1.04-2.24) with subjects ID as reference class. Moreover, the combined effect of the presence of at least one APOE epsilon4 allele and ACE DD homozygosity was a risk factor for cognitive decline. This report reinforces the hypothesis of an influence of cardiovascular risk factors on cognitive performances.
Subject(s)
Cognition Disorders/epidemiology , Cognition Disorders/genetics , Peptidyl-Dipeptidase A/genetics , Age Distribution , Aged , Apolipoproteins E/genetics , Cognition Disorders/enzymology , Educational Status , Female , Follow-Up Studies , Heterozygote , Homozygote , Humans , Logistic Models , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Polymorphism, Genetic/genetics , Sex DistributionABSTRACT
Recent reports sustain the hypothesis of tight links between vascular and neurodegenerative diseases: associations between atherosclerosis lesions and Alzheimer's disease (AD), increased risk of AD for hypertensive subjects, decreased risk of dementia for elderly treated with hypotensive drugs, and a major impact of apolipoprotein E polymorphism, a protein of the lipid metabolism, on the occurrence of AD. All these results suggest that vascular determinants, both environmental and genetic, may predispose to or speed up dementia. As a major player of vascular homeostasis, the renin angiotensin system (RAS) proteins constitute an interesting source of candidate genes. Among these, the angiotensin I-converting enzyme gene (ACE), a central enzyme of the RAS, presents in its sequence a deletion (D)/insertion (I) polymorphism associated with variations of plasma ACE levels and with the risk of myocardial infarction. We explored the impact of this genetic polymorphism on the risk of cognitive impairment and of dementia in several epidemiological studies. Physiopathological hypotheses suggest a possible involvement of the RAS proteins in the occurrence and evolution of AD. Moreover, although inconsistent, several results of case-control studies tend to suggest that the ACE I/D genetic polymorphism may constitute a genetic susceptibility factor for dementia, reinforcing the hypothesis of a major implication of vascular risk factors in the occurrence of dementia.
Subject(s)
Alzheimer Disease/epidemiology , Alzheimer Disease/physiopathology , Peptidyl-Dipeptidase A/genetics , Renin-Angiotensin System/physiology , Aged , Alzheimer Disease/genetics , Arteriosclerosis/complications , Arteriosclerosis/physiopathology , Humans , Middle Aged , Polymorphism, Genetic , Risk Factors , United KingdomABSTRACT
The goal of the present study was to assess the impact of variability at the APOC-III insulin response element (APOC-III IRE) genetic locus on lipid, lipoprotein and complex lipoprotein particle levels as well as on the risk of dyslipidemia, in the population of northern France. To this end, 590 men and 579 women were randomly selected in the urban community of Lille in the framework of the MONICA project. Three polymorphisms, -482, -455 in the APOC-III insulin response element (IRE) and SstI in the 3'-noncoding region of the APOC-III gene locus were assessed. Compared to the most common alleles, the rare alleles of -482 and -455 were associated with increased levels of apoB-containing particles (LDL-cholesterol, apoB) and of triglyceride-related markers (apoC-III and LpC-III:B) in women, but not in men, suggesting a gender-related impact of APOC-III polymorphisms on these variables. Similarly, triglycerides, LpC-III:B and apoB were higher in women bearing the rare allele of SstI than in those with the most common allele. There was no evidence for any significant association between any of the -482, -455, and SstI alleles and lipid disorders (mixed hyperlipidemia, hypertriglyceridemia and hypercholesterolemia) in this sample of randomly selected men and women from northern France. In contrast, the prevalence of the haplotype that combined the rare alleles of the -482 and -455 sites was increased only in women with hypertriglyceridemia. Therefore, although the individual risk of hypertriglyceridemia is increased in women with the haplotype T, C at -482, -455, it appears that the -482, -455 and SstI APOC-III gene polymorphisms are not major contributors to the risk of dyslipidemia in the population of northern France.
Subject(s)
Apolipoproteins C/genetics , Genetic Variation , Hyperlipidemias/genetics , Polymorphism, Genetic , Adult , Aged , Alleles , Apolipoprotein C-III , Apolipoproteins/blood , Female , France , Humans , Hyperlipidemias/blood , Insulin/genetics , Male , Middle Aged , Sex FactorsABSTRACT
OBJECTIVE: To investigate the impact of two common polymorphisms in the human beta2-adrenoceptor gene (Gly16Arg and Gln27Glu substitutions) on obesity and anthropometric measurements as well as blood variables in a large sample of a French population. DESIGN AND SUBJECTS: Within the framework of the WHO-MONICA project, a population study composed of 1195 subjects aged 35-64 y was randomly sampled from the electoral rolls of the Urban Community of Lille, in northern France. Subjects without any medical treatment (for hypercholesterolaemia, hypertension or diabetes mellitus) susceptible to interfere with body weight and biological variables were selected (n = 836, 419 men/417 women, age = 49.5+/-8.1 y, body mass index (BMI) = 25.7+/-4.4 kg/m2). Subjects with a body mass index > or = 30 kg/m2 were considered as obese (n = 119, age = 49.5+/-8.2 y, BMI = 33.9+/-3.3 kg/m2 range 30-44). MEASUREMENTS: Genotyping was carried out with allele-specific oligonucleotides hybridization. Association between genotypes and various obesity markers (body weight, body mass index, waist and waist-to-hip ratio), lipid, glucose and insulin variables were studied. RESULTS: The Gly16Arg and Gln27Glu polymorphisms were in complete linkage disequilibrium. Gln27Gln subjects had an increased risk of obesity (odds ratio (OR) = 1.77, 95% CI 1.19-2.62, P = 0.005). This effect was mainly detected in men (OR = 2.40, 95% CI 1.34-4.27, P = 0.003). Men bearing the Gln27Gln genotype had higher body weight, BMI, waist and hip circumferences and waist-to-hip ratio than others. Moreover, if Gln27Gln men carried in addition the Arg16 allele, the increase in body weight, BMI and waist-to-hip ratio was more important. CONCLUSION: Our results suggest that genetic variability of the beta2-adrenoceptor gene is implicated in body weight regulation and in the onset of obesity in French men.
Subject(s)
Obesity/genetics , Polymorphism, Genetic , Receptors, Adrenergic, beta-2/genetics , Adult , Arginine , Body Constitution , Body Mass Index , Body Weight , Female , France , Genotype , Glutamic Acid , Glutamine , Glycine , Humans , Linkage Disequilibrium , Male , Middle Aged , Nucleic Acid HybridizationABSTRACT
BACKGROUND: Apolipoprotein(a) [apo(a)], the distinctive, highly polymorphic glycoprotein of lipoprotein(a), shares a series of common features with apolipoprotein E (apoE), which is implicated in the development of Alzheimer disease. OBJECTIVE: To determine whether apo(a) is associated with Alzheimer disease. DESIGN: Case-control study. SETTING: University hospitals in Europe. PARTICIPANTS: 285 patients with Alzheimer disease and 296 controls. MEASUREMENTS: Plasma lipoprotein(a) levels, size of the apo(a) isoforms, and apoE and apo(a) genotyping. RESULTS: Among carriers of the apoE epsilon4 allele, lipoprotein(a) was associated with a progressive, age-dependent increased risk for late-onset Alzheimer disease (odds ratio for patients >80 years of age, 6.0 [95% CI, 1.2 to 30.8]; P<0.01). Among noncarriers older than 80 years of age, lipoprotein(a) was associated with a reduced risk for Alzheimer disease (odds ratio, 0.4 [CI, 0.2 to 0.91; P<0.05). CONCLUSIONS: In this convenience sample, lipoprotein(a) was an additional risk factor for late-onset Alzheimer disease in carriers of the apoE epsilon4 allele. However, lipoprotein(a) may protect against late-onset Alzheimer disease in noncarriers.