Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation.

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

How obesity relates to socio-economic status: identification of eating behavior mediators.

BACKGROUND: Socio-economic status (SES) is a strong determinant of eating behavior and the obesity risk. OBJECTIVE: To determine which eating and lifestyle behaviors mediate the association between SES and obesity. METHODS: We performed a case-control study of 318 obese people and 371 non-obese people in northern France. Ten eating behavior traits were assessed using the Three-Factor Eating Questionnaire Revised 21-Item and an eating attitude questionnaire (on plate size, the number of servings, reasons for stopping eating and the frequency of eating standing up, eating in front of the television set (TV) and eating at night). The SES score (in three categories) was based on occupation, education and income categories. Mediation analysis was performed using the test of joint significance and the difference of coefficients test. RESULTS: The age- and gender-adjusted obesity risk was higher for individuals in the low-SES groups (odds ratio (OR) (95% confidence interval (CI)=1.82 (1.48-2.24), P<0.0001). Additional servings were associated with a higher obesity risk (OR=3.43, P<0.0001). Cognitive restraint (P<0.0001) and emotional eating (P<0.0001) scores were higher in obese participants than in non-obese participants but did not depend on SES. Of the 10 potential factors tested, eating off a large plate (P=0.01), eating at night (P=0.04) and uncontrolled eating (P=0.03) significantly mediated the relationship between SES and obesity. CONCLUSION: Our results highlighted a number of obesogenic behaviors among socially disadvantaged participants: large plate size, uncontrolled eating and eating at night were significant mediators of the relationship between SES and the obesity risk.

Effects of established blood pressure loci on blood pressure values and hypertension risk in an Algerian population sample.

Genome-wide association studies and subsequent replication studies have pinpointed 29 genetic variants associated with blood pressure (BP). None of these studies included North African populations. We therefore looked at whether or not these genetic variants modulated BP and hypertension (HTN) risk in an Algerian population sample. Twenty-nine single-nucleotide polymorphisms (SNPs) were genotyped in a representative sample of 787 subjects from the InSulino-résistance à ORan (ISOR) study (378 men and 409 women aged between 30 and 64 years and recruited from within the city of Oran, Algeria). Genetic variants were considered both individually and when combined as genetic predisposition scores (GPSs) for systolic BP (SBP), diastolic BP (DBP) and HTN risk. The SNPs in CYP1A1-ULK3, HFE and SH2B3 were significantly associated with BP and/or HTN. The SBP-GPS, DBP-GPS and HTN-GPS were associated with higher levels of DBP (+0.24 mm Hg P=0.05, +0.23 mm Hg P = 0.05 and +0.26 mm Hg P = 0.03, respectively). Moreover, the three GPSs tended to be associated with a 6% higher risk of HTN. Our study is the first to show that some of the BP loci validated in subjects of European descent were associated (either individually or when combined as GPSs) with BP traits and/or the HTN risk in an Algerian population, but to a lesser extent than in European populations. Although larger studies and meta-analyses of North African populations are needed to confirm the present results, our data contribute to a better understanding of genetic susceptibility to HTN.

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene-diet interactions.

OBJECTIVE: Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. DESIGN AND SUBJECTS: THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). RESULTS: The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. CONCLUSIONS: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

Impact of REV-ERB alpha gene polymorphisms on obesity phenotypes in adult and adolescent samples.

BACKGROUND: REV-ERBα has been shown to regulate adipogenesis and lipid metabolism as well as to link the circadian timing system to whole body metabolic homeostasis. We thus tested whether polymorphisms in REV-ERBα could be associated with metabolic phenotypes in human population samples. METHODS: We analyzed the associations between 5 REV-ERBα polymorphisms and anthropometric (body weight, body mass index (BMI), waist and hip circumferences), biochemical (plasma lipid, glucose and insulin levels) and clinical (systolic and diastolic blood pressure) variables in three population-based studies (MONICA Lille n=1155 adults, MONA LISA Lille n=1170 adults and HELENA n=1155 adolescents). We assessed in vitro, the potential influence of one REV-ERBα polymorphism in transient transfection assays using two different cell lines. RESULTS: We observed significant and consistent associations between the T minor allele of the REV-ERBα rs2071427 polymorphism (located in intron 1) and higher BMI (mean allele effect=+0.33 kg m(-2)) in the MONICA Lille (P=0.02), MONA LISA (P=0.02) and HELENA (P=0.03) studies. The odds ratios for obesity associated with this allele were 1.67 (1.00-2.79) (P=0.05) in MONICA Lille, 1.29 (1.01-1.65) (P=0.04) in MONA LISA Lille and the odds ratio for overweight was 1.48 (1.08-2.03) (P=0.01) in HELENA. In transfection experiments in human hepatocyte-derived cell lines, the REV-ERBα intron 1 directed the transcription of a luciferase reporter gene independently of the rs2071427 polymorphism. CONCLUSION: Our results suggest that the REV-ERBα rs2071427 polymorphism modulates body fat mass in both adult and young people.

Association between angiopoietin-like 6 (ANGPTL6) gene polymorphisms and metabolic syndrome-related phenotypes in the French MONICA Study.

AIM: Although the ANGPTL6 (angiopoietin-like 6) gene product is now known to be involved in the regulation of fat mass and insulin sensitivity in mice, its physiological functions in humans have yet to be determined. METHODS: Subjects from the population-based French MONICA Study (n=3402) were genotyped for single nucleotide polymorphisms (SNPs) in ANGPTL6, and associations with anthropometric or biochemical phenotypes were looked for. RESULTS: On evaluating the frequency of 17 ANGPTL6 SNPs in 100 randomly selected subjects on the basis of linkage disequilibrium mapping, four SNPs (rs6511435, rs8112063, rs11671983 and rs15723) were found to cover more than 95% of the known ANGPTL6 genetic variability. Subjects from the entire MONICA Study were then genotyped for these four SNPs. No significant association was detected for rs11671983 and rs15723. In contrast, the G allele of rs8112063 was associated with lower plasma glucose levels (P=0.009). Also, obese subjects carrying the G allele of rs6511435 had higher plasma insulin levels than AA subjects (P=0.0055). Moreover, the G allele of rs6511435 tended to be associated with a 20% higher risk of the metabolic syndrome (P=0.034). However, when false discovery rate testing (40 tests) was applied, these associations were no longer statistically significant. CONCLUSION: These findings constitute the first study in humans of ANGPTL6 genetic variability. Although there was no evidence that polymorphisms in ANGPTL6 might be significantly associated with the metabolic syndrome-related phenotypes, a weak association of these polymorphisms with these parameters cannot be excluded. Further association studies are needed to arrive at any definite conclusions.

Variations in the APP gene promoter region and risk of Alzheimer disease.

We genotyped five polymorphisms, including two polymorphisms with known effects on transcriptional activity, in a large cohort of 427 Alzheimer disease (AD) cases and 472 control subjects. An association between rs463946 (-3102 G/C) and AD was found and was confirmed in a replication sample of a similar size. By contrast, analysis of three recently described rare mutations influencing APP transcription did not confirm their association with AD risk.

[Genetic complexity of Alzheimer's disease]. / Complexité génétique de la maladie d'Alzheimer.

The discovery of pathogenic mutations in the amyloid precursor protein (APP) gene and the presenilin (PS1, PS2) genes, causing familial early-onset AD has lead to the hypothesis of the amyloid cascade. The epsilon4 allele of the apolipoprotein E (APOE) gene, the only recognized genetic risk factor for AD, may be involved in the mechanism. However, to date, search for new genetic determinants has been hampered by methodological limitations. Some loci, for instance on chromosome 12, have been characterized by linkage studies performed in familial cases, but the regions of interest are very large and contain numerous genes. Furthermore, search for polymorphisms implicated in the development of AD, should not be limited to the coding part of the genes, but should also involve the non-translated sequences of the genes, for instance in the regions regulating gene expression. Indeed, these genetic variations may have important impact on key proteins of the pathologic process. Although this task is difficult, the identification of new susceptibility genes should lead to a better understanding of the development of AD.

Association study of Notch 4 polymorphisms with Alzheimer's disease.

BACKGROUND: The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have significant linkage with Alzheimer's disease. OBJECTIVE: To investigate the potential impact of two polymorphisms within this gene on the risk of developing Alzheimer's disease. METHODS: Genotyping of promoter and 5'-UTR polymorphisms was done in Scottish, English, and French populations. The potential functionality of the 5'-UTR polymorphism was assessed by testing its impact on A beta load in Alzheimer brains and also by undertaking electrophoretic mobility shift assays and transfection experiments. RESULTS: No association of the Notch4 polymorphisms alone with the disease was observed in any of the populations. However, an interaction of the 5'-UTR C/T polymorphism with the epsilon 4 allele of the APOE gene was detected in United Kingdom populations but not in the French. No relation between the 5'-UTR polymorphism and A beta loads was detected overall or in the presence or absence of the epsilon 4 allele. No DNA protein specific binding was found with proteins from neuroblastoma, glioma, or astrocytoma cells, and no allele dependent transcriptional activity was detected. CONCLUSIONS: No association between two NOTCH4 polymorphisms alone and Alzheimer's disease was observed in the three populations, but there was evidence of an increased risk associated with the 5'-UTR CC genotype in epsilon 4 bearers in the United Kingdom. As no functionality for this polymorphism could be determined, it is likely that the interaction is spurious or results from a linkage disequilibrium of this 5'-UTR polymorphism with another marker elsewhere in the 6p21.3 locus.

No association of the HLA-A2 allele with Alzheimer's disease.

A possible association of the human leucocyte antigen (HLA)-A2 allele with increased susceptibility to Alzheimer's disease (AD) has been the subject of debate for more than 20 years. We compared the presence of the HLA-A2 allele in a sample from the French population composed of 451 patients and 477 controls. There was no evidence of an association of this allele with increased risk of AD. Moreover, no effect was observed when we stratified the case-control sample on gender, age of onset or presence of an APOE epsilon4 allele. We conclude that HLA-A2 allele is not a major risk factor for sporadic AD.

No association of the -48CT polymorphism of the presenilin 1 gene with Alzheimer disease in a late-onset sporadic population.

Recently, a polymorphism located in the promoter of the presenilin 1 gene was associated with early-onset Alzheimer disease (EOAD). To determine if this polymorphism is also a risk factor for late-onset Alzheimer's disease (LOAD), we analysed its potential impact in a French population of LOAD patients only. Genotype and allelic distributions of the -48CT polymorphism were similar for controls and AD patients. Our result suggests that this polymorphism may not influence the development of LOAD. Other studies need to be undertaken to confirm this association restricting the impact of this polymorphism to EOAD patients.

Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.

OBJECTIVE: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. BACKGROUND: Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. METHODS: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. RESULTS: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. CONCLUSION: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.

Association study of three polymorphisms of TGF-beta1 gene with Alzheimer's disease.

BACKGROUND: There is evidence that inflammatory processes may contribute to the development of Alzheimer's disease through production of cytokines and free radicals that damage neurones. A recent study has shown that transforming growth factor beta1 (TGF-beta1) signalling in astrocytes promotes Abeta production and could play a critical role in the formation of amyloid plaques in the brain. OBJECTIVES: To explore the impact of the -800 and -509 TGF-beta1 promoter polymorphisms and the +25 polymorphism on the risk of occurrence of Alzheimer's disease in a large population of sporadic cases and controls, and on the amyloid beta (Abeta) load in the brains of Alzheimer patients. METHODS: The TGF-beta1 genotypes of the three polymorphisms were determined in 678 sporadic Alzheimer's disease patients and 667 controls. They were also characterised, along with Abeta load, in the brains of 81 necropsy confirmed Alzheimer patients. RESULTS: No significant variations in the distribution of the genotypes and haplotypes were observed between Alzheimer patients and controls, or in the amount of Abeta deposition. CONCLUSIONS: These results do not suggest an influence of genetic variability at the TGF-beta1 gene locus on the occurrence of Alzheimer's disease.

Effect of the APOE promoter polymorphisms on cerebral amyloid peptide deposition in Alzheimer's disease.

Polymorphisms in the promoter region of the apolipoprotein E gene (APOE) affect the amount of amyloid peptide (Abeta) in the brains of patients with Alzheimer's disease. We measured Abeta load immunohistochemically in regions 8 and 9 of Brodman's area in 74 people with Alzheimer's disease. The amount of Abeta deposition was independent of APOE genotype in our cohort. These findings in patients with confirmed Alzheimer's disease are consistent with the hypothesis that variation in APOE expression directly affects Alzheimer's disease pathology.

Alzheimer disease is not associated with polymorphisms in the angiotensinogen and renin genes.

Hypertension has been implicated as a risk factor for Alzheimer disease (AD) and dementia in epidemiological studies of humans. It is thus possible that there are common genetic determinants for hypertension and AD. Epidemiological, clinical, and experimental data suggest that the renin-angiotensin-aldosterone system is a critical regulator of blood pressure. The presence of an MboI site in an RFLP in the renin gene and the Thr at the Met/Thr polymorphism at codon 235 (M235T) of the angiotensinogen gene have been reported to be associated with hypertension. These variants were studied in autopsy-confirmed AD cases and matched controls from the U.K. While no association was detected with the renin polymorphism, a weak deleterious effect was observed in cases homozygous for the angiotensinogen Thr allele. However, this association was not observed in a French cohort of clinically diagnosed AD cases and controls, suggesting that the initial observation was a type I error. Thus, these polymorphisms are unlikely to be associated with AD risk.

A FE65 polymorphism associated with risk of developing sporadic late-onset alzheimer's disease but not with Abeta loading in brains.

The FE65 protein was previously described interacting with amyloid protein precursor (APP) and mediating its internalization. Hu et al. (Hum. Genet., 103 (1998) 295) recently reported that a deletion polymorphism in intron 13 of the FE65 gene may be protective for sporadic Alzheimer's disease (AD) forms and suggested that this deletion may modify splicing between exon 13 and 14 (the two exons encoding the interaction domain of FE65 with APP). We tested the impact of this polymorphism in 646 controls and 639 sporadic AD cases. We were only able to detect a protective effect of the deletion in the population over 75 years (odds ratio = 0.53, 95% confidence interval (0.35-0.82), P= 0.002). Furthermore, no association of this polymorphism with Abeta40, Abeta42(43) and total Abeta loads were detected in 74 AD brains, although, we could expect that this deletion was associated with modifications of the APP metabolism. In conclusion, the FE65 gene may be a minor genetic determinant only for sporadic late-onset AD forms, although, we cannot conclude that this impact is mediated by a modulation of the APP process and/or Abeta peptide deposition.

The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease.

Although the varepsilon4 allele of the apolipoprotein E gene appears as an important biological marker for Alzheimer's disease (AD) susceptibility, other genetic determinants are clearly implicated in the AD process. Here, we propose that a genetic variation in the transcriptional factor LBP-1c/CP2/LSF gene, located close to the LRP locus, is a genetic susceptibility factor for AD. We report an association between a non-coding polymorphism (G-->A) in the 3'-untranslated region of this gene and sporadic AD in French and British populations and a similar trend in a North American population. The combined analysis of these three independent populations provides evidence of a protective effect of the A allele (OR = 0.58, 95% CI 0.44-0.75). We describe a potential biologically relevant role for the A allele whereby it reduces binding to nuclear protein(s). The absence of the A allele was associated with a lower LBP-1c/CP2/LSF gene expression in lymphocytes from AD cases compared with controls. Our data suggest that polymorphic variation in the implication of the LBP-1c/CP2/LSF gene may be important for the pathogenesis of AD, particularly since LBP-1c/CP2/LSF interacts with proteins such as GSKbeta, Fe65 and certain factors involved in the inflammatory response.