Biomedical subjects

G Siest

Publications and source records attributed to G Siest.

At least 37 records · Page 2Linked to original sources

PubMed2001

LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women.

BACKGROUND: In humans, a mutation of the leptin receptor gene (LEPR) leads to a rare obese syndrome of mendelian inheritance. However, obesity in humans results from interactions between genes and environment, mainly nutritional factors. Variations at the LEPR locus could be involved in the regulation of body weight. DESIGN: Genetic variations at the LEPR locus were screened in a selection of 30 French overweight subjects by Single Strand Conformation Polymorphism (SSCP) analysis, then an association study between genotypes and obesity phenotypes was performed in 179 French overweight patients recruited from the Nutrition Department of Bichat Hospital in Paris who were prescribed a low calorie diet and in 387 unrelated volunteers (98 overweight, 289 normal weight) drawn from the Stanislas Family Study in Nancy. RESULTS: Two new genetic variants were found: T + 70-->C (exon 1) and Asp (A) 96 Asp (G) (exon 4). In Nancy, the T + 70-->C polymorphism was associated with fat mass adjusted for BMI in women (P = 0.025). The genotype and allele frequencies of the Ser (T) 343 Ser (C) polymorphism (exon 9) were significantly different between normal and overweight women, with the T allele being more frequent in the overweight group (T frequency in Nancy, 0.82; in Nancy + Paris, 0.79) than in the normal weight group (0.69; P = 0.017 vs. Nancy overweight, P = 0.003 vs. Nancy + Paris overweight). In women from Nancy, fat mass adjusted for BMI was significantly associated with this polymorphism (P = 0.01). The overweight women carrying the C allele of this polymorphism lost more weight in response to low calorie diet than the non carriers (P = 0.006). CONCLUSIONS: In women, genetic variations at the LEPR gene level are associated with overweight and fat mass in a cross sectional study and with response to low calorie diet in an intervention study. These results indicate that variations at the leptin receptor locus are associated with common obesity phenotypes and are a part of the polygenic influences on the response to nutritional environment.

Adipose Tissue↗

PubMed2001

Candidate gene polymorphisms in cardiovascular disease: a comparative study of frequencies between a French and an Italian population.

A multilocus assay was used to genotype up to 27 variable sites in 15 genes in French and Italian, presumed to be healthy populations (n=1480, n=162, respectively). These genes are involved in lipid metabolism (APOE, APOB, APOC3, CETP, LPL, PON), homocysteine metabolism (CBS, MTHFR), blood viscosity (Fibrinogen, FV), platelet aggregation (GpIIIa), leukocyte adhesion (SELE), and renin-angiotensin system (AT1R, ACE, AGT). Allele frequencies for all the markers were compared between the two populations. Five allele frequencies differed between the two European countries: APOB 71Ile (p < 0.001), SELE 98T (p < 0.001), SELE 128Arg (p < or = 0.01), APOE E4 (p < or = 0.01) and MTHFR 677T (p < or = 0.01), suggesting the existence of a north-south gradient in European allele frequencies. The other allele frequencies : APOC3 -482T, -455C, 1100T, 3175G, 3206G; LPL -93G, 9Asn, 291Ser; CETP 405Val; PON 192Arg; ACE Del; AGT 235Thr; AT1R 1166C; CBS 278Thr, GpIIIa P1A2; Fibrinogen -455A, FV 506Gln and SELE 554Phe, were similar between the two populations. They were also similar to those observed in other European countries.

Alleles↗

PubMed2001

Determination of serum cystatin C: biological variation and reference values.

Human cystatin C is a low molecular weight protein which has been proposed as a better marker of glomerular filtration rate than creatinine. To be able to interpret results obtained in different patient populations it is necessary to define cystatin C reference values. We measured serum concentration of cystatin C in 1223 subjects using a particle-enhanced nephelometric assay. Subjects were aged 4 to 79 years and were selected among apparently healthy individuals who came to the Centre for Preventive Medicine in Vandoeuvre-Lès-Nancy, France. We observed a Gaussian distribution of cystatin C concentration in serum. We did not find any effect of age or gender in children, hormonal status in women (puberty, menopause, oral contraceptives or hormone replacement therapy) or alcohol intake. Cystatin C concentration was slightly lower in female than in male adults below the age of 60 years. Cystatin C levels significantly increased above the age of 60 in both males and females, probably due to physiological aging of renal function. No other significant differences were observed between males and females. Using multiple regression analysis, moderate correlations were observed between body mass index and cystatin C, and between smoking and cystatin C, but these were not biologically significant. According to the literature, only methylprednisolone and cyclosporin A increased and decreased cystatin C levels, respectively. The reference values for cystatin C obtained in a carefully selected population were 0.75+/-0.089 mg/l for children aged 4-19 years, 0.74+/-0.100 mg/l for males and 0.65+/-0.085 mg/l for females (aged 20-59 years), and 0.83+/-0.103 mg/l for older individuals (> or =60 years).

Adolescent↗

PubMed2001

Soluble transferrin receptor (sTfR): biological variations and reference limits.

The aim of this study was to establish soluble serum transferrin receptor (sTfR) reference limits. sTfR was measured in 885 healthy subjects from 3 to 91 years old (433 men, 409 women), without hematological abnormalities, using an immunonephelometric assay. The sTfR median concentrations in our population decreased gradually from the group aged 3-10 years to the group aged 21-40 years, then there were no changes in the older groups except for the females >60 years of age. The interindividual variability ranged from 12.6% to 30.3% among different age groups, and the analytical variability was 5%. Biological factors and other factors associated with sTfR concentration variation were examined and accounted for 35% of the sTfR variability in men aged 20 years or less, and 18% in those older than 20 years. Also, they accounted for 45% of the variability in women aged 20 years or less and 14% in those older than 20 years. The main factors statistically associated with sTfR concentration in males were ferritin, orosomucoid, hemoglobin, and tobacco in all age groups and only mean corpuscular volume (MCV) in males less than 20 years old. In the females the main factors were age, orosomucoid, and hemoglobin in all age groups, MCV and tobacco in females less than 20 years old, and ferritin and physical activity in females more than 20 years old. These factors were used to define the exclusion and partition criteria for obtaining the reference samples. Medians for reference values were: 1.60 mg/l in the 3-10-year old group (males and females); 1.42 mg/l in males between 11 and 20 years of age, and 1.33 mg/l in females of the same age. In the other age groups, the median of the reference values was 1.16 mg/l, except in females over 60 years old, for whom it was 1.26 mg/l.

Adolescent↗

PubMed2001

High sensitivity C-reactive protein (CRP) reference intervals in the elderly.

High sensitivity C-reactive protein is a useful marker in clinical practice; however, reference intervals are not available for all age groups. Therefore, the aim of this study was to determine reference intervals for elderly people. The non-parametric reference limits were calculated for the two genders, subdivided into two age classes (50-64 and 65-91 years). In our selected sample population, we did not observe significant gender differences.

Aged↗

PubMed2001

[APOC3, CETP, beta-fibrinogen and MTHFR are genetic determinants of carotid intim-media thickness (Stanislas cohort)].

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) interindividual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French cohort: the Stanislas cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analysis were done by ANOVA after adjustment of CIMT for age, BMI and smoking and by multiple regression analyses. No association was found with APOB Thr71 Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T and SELE Ser128Arg, polymorphism neither in men nor in women. Although, in women we found always no association for the APOC3 3206T/G, 3175C/G, 1100C/T, the CETP Ile405Val, the MTHFR 677C/T and the fibrinogen -455G/A polymorphism's, in men these polymorphism's were associated with CIMT variability (0.01 < or = p < or = 0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability.

Adult↗

PubMed2001

Genetic influences on lipid metabolism trait variability within the Stanislas Cohort.

The contribution of 17 polymorphisms within 13 candidate genes on lipid trait variability was investigated by a multiplex assay in 772 men and 780 women coming for a health checkup examination. The studied genes were APOE, APOB, APOC3, CETP, LPL, PON, MTHFR, FGB, GpIIIa, SELE, ACE, and AGT. We found that APOB-Thr71Ile, APOE-(112/158), APOC3-1100C/T, and SELE-98G/T polymorphisms had a significant effect on lipid traits (P < or = 0.001 to P < or = 0.01). Genetic effects accounted for 3.5-5.7% of variation in apolipoprotein B (apoB)-related traits among men, and for 5.7-9.0% among women. The contribution of APOE polymorphism on apoB-related traits variability was two to three times more important in women than in men. We found suggestive evidence for interactive effects between genetics and age, smoking status, and oral contraceptives. Increase of LDL-cholesterol and apoB concentrations with age was stronger among the epsilon4 carriers in women, and apolipoprotein A-I (apoA-I) concentration decreased with age in epsilon4 male carriers. The effect of epsilon2 allele on LDL-cholesterol was more important in the oral contraceptive users. In nonsmokers only, the APOC3-1100C allele in women was related to lower apoB-related traits concentrations, and in men to higher apoA-I and HDL-cholesterol concentrations. In conclusion, this work, in addition to the reinforcement of the already known associations between APOB, APOE, and APOC3 genes and lipids, leads to new perspectives in the complex relationships among genes and environmental factors. The newly observed relationships between E-selectine gene and lipid concentrations support the hypotheses of multiple metabolic pathways contributing to the complexity of lipids variability.

Adult↗

PubMed2001

[Management of dyslipidemias diagnosed in general practice in France--The PRAGMA Study].

Several studies have reported the penetration and impact of national and international recommendations on the management of dyslipidaemia, a major cardiovascular risk factor. Most of them were carried out on patients participating in clinical trials or on in-hospital cases. The PRAGMA study was developed in order to evaluate management of this condition in general practice, at the heart of the health care system. From September to December 1998, 1,717 general practitioners were chosen randomly and included 6,623 patients considered to have a lipid disorder. In this sample, the prevalence of the main risk factors was as follows: hypertension: 39.6%, diabetes: 11.6%, obesity: 19.6%, past or present smokers: 33.8%. The main lines of management consisted in prescribing lipid lowering drugs (96.6%) with dietary recommendations (95.8%) and a fall lipid profile (59.9%). The main factors spontaneously cited by the general practitioners as being decisional were: the total cholesterol level (47.8%), diet (40.8%), body weight (29.4%) and drug therapy (19.2%). The cardiovascular risk factors were rarely taken into account in their totality. These results suggest that the management of dyslipidaemia patients by general practitioners is far from being optimal. Efforts should be made to change attitudes to take into consideration the global cardiovascular risk factors of patients with lipid disorders.

Adult↗

PubMed2000

Evidence for the pro-oxidant effect of gamma-glutamyltranspeptidase-related enzyme.

It has been previously reported that the metabolism of reduced glutathione (GSH) by gamma-glutamyltranspeptidase (GGT) in the presence of chelated metals leads to free radical generation and lipid peroxidation (LPO). The present study demonstrates for the first time that an established cell line expressing GGT-rel, a human GGT-related enzyme, metabolizes extracellular GSH to cysteinylglycine (CysGly) in a time-dependent manner when cells were incubated in a medium containing 2.5 mM GSH and 25 mM glycylglycine. Supplementation with 150-165 microM Fe(3+)-EDTA resulted in a reactive oxygen species (ROS) generation process. The resulting data showed a significantly higher level (7.6-fold) of ROS production in the GGT-rel positive cells in comparison with the GGT-rel negative control cells. CysGly and Cys, but not GSH, were responsible for the observed ROS production, as we confirmed by measuring the same process in the presence of Fe(3+)-EDTA and different thiols. A higher iron reduction and an increased LPO level determined by malondialdehyde HPLC measurement were also found in GGT-rel-overexpressing cells compared to GGT-rel negative cells. Our data clearly indicate that in the presence of iron, not only GGT, but also GGT-rel has a pro-oxidant function by generation of a reactive metabolite (CysGly) and must be taken into account as a potential physiopathological oxidation system.

3T3 Cells↗

PubMed2000

Effect of apolipoprotein E on cell viability in a human neuroblastoma cell line: influence of oxidation and lipid-association.

Apolipoprotein E (apoE) whose polymorphic expression is widely associated with Alzheimer's disease (AD) is one of the most studied protein present in cerebral amyloid deposits. Native or fragments of apoE are known to exert neurotoxic effects. We evaluated the effects of apoE oxidation and lipid-association on the viability of human neuroblastoma IMR32 cells. We show that apoE affects cell viability only when it is lipid-associated and applied at a concentration near to that found in plasma, and this whatever the isoform. Oxidized phospholipid-associated apoE has a similar impact on cell viability. These findings show the necessity of including apoE into phospholipids when studying its effect on cell metabolism and underline the probable intervention of surface heparan sulfate proteoglycans (HSPG). It also warrants further studies in order to delineate the pathophysiological importance of apoE.

Apolipoprotein E2↗

PubMed2000

Conformation of apolipoprotein E both in free and in lipid-bound form may determine the avidity of triglyceride-rich lipoproteins to the LDL receptor: structural and kinetic study.

Slow refolding of human apolipoprotein E (apoE) in solution after guanidine- or cholate-induced denaturation followed by dialysis under controlled conditions was investigated using various spectroscopic properties of fluorescein- and dansyl-labeled apolipoprotein molecules. The results suggest that the last phase(s) of apoE refolding in solution include a slow (several hours at 24 degrees C) interconversion of a self-associated 'open' conformer into a more dense 'closed' conformer. The hydrophobic interactions are primarily responsible for the formation of this more compact apoE structure. To visualize the contribution of apolipoprotein conformation and/or the number of 'active' lipid-bound apoE molecules in the reaction of binding to the low density lipoprotein receptor (LDLr) by solid-phase binding assay, the complexes of human plasma apolipoprotein or recombinant (rec) apoE3 with dipalmitoylphosphatidylcholine (DPPC) or palmitoyloleoylphosphatidylcholine (POPC) varying in size were used. For seven complexes with plasma protein (four DPPC and three POPC complexes), the final phosphatidylcholine (PC)/protein mole ratio ranged from 117 to 279; affinity constant K(a) averaged for both PCs and plotted against this ratio abruptly increased from 3.8 x 10(7) to 3.8 x 10(8) M(-1) with a transition midpoint of 150-180 PC/apoE, mole ratio. Two DPPC complexes with rec protein bind much more efficiently. Complexes with both plasma and rec apoE were able to compete with very low density lipoproteins (VLDL) or low density lipoproteins (LDL) isolated from patients with E3/3 phenotype, for binding to the LDLr. Again, the competition efficiency abruptly increased at the increase in PC content with a transition midpoint of 130 PC/apoE, mole ratio. The transitions observed both in direct and competitive binding assay probably correspond to the abrupt increase in the number of 'active' apoE molecules on the complex surface accompanying the change in the size and/or in the shape of the complexes. The efficiency of apoE and apoB as the corresponding major ligands in the binding reaction of VLDL and LDL to the LDL receptor was compared. VLDL bind to LDLr following a simple encounter complex model, while LDL binding was characterized by a more complex two-step model with an additional isomerization step. The analysis of the binding data led us to suggest the existence of the continuum from several (2-3) apoE molecules on the surface of TG-rich particles that resulted in the increased binding affinity, on average 3.5-fold higher, compared to LDL. The existence of a complex equilibrium between aqueous and different lipid-bound forms of apoE is proposed, in particular, the formation of a transient disc-lipoprotein particle structure during the interaction with LDLr in vivo as well as in LPL-stimulated lipolysis of the lipid phase of the particle.

Apolipoproteins E↗

PubMed2000

Structural peculiarities of the binding of very low density lipoproteins and low density lipoproteins to the LDL receptor in hypertriglyceridemia: role of apolipoprotein E.

Very low (VLDL) and low density lipoproteins (LDL) were isolated from plasma of patients with the E3/3 phenotype which were divided into three groups based on their plasma triglyceride content: low (TG<200 mg/dl, TG(l)), intermediate (200<300 mg/dl, TG(i)300 mg/dl, TG(h)). The protein density (PD) on the VLDL and LDL surface was calculated from lipoprotein composition and protein location was studied by tryptophan fluorescence quenching by I(-) anions at 25 degrees C and 40 degrees C. A comparison of the TG(h) with the TG(l) group revealed a significant (<0.05) increase of the PD parameter as much as 21% for VLDL, but not for LDL where this parameter did not change for any group; generally, PD(LDL) values were 3.2-3.8-fold lower than PD(VLDL). In accordance with this difference, the tryptophan accessibility f in VLDL vs. LDL was lower at both temperatures. There were temperature-induced changes of the f parameter in opposite directions for these lipoproteins. The difference in f value gradually decreased for VLDL in the direction TG(l)TG(i)TG(h) while for LDL there was a U-shaped dependence for these groups. The Stern-Volmer quenching constant K(S-V) which is sensitive to both temperature and viscosity, did not change for VLDL, but K(S-V)(LDL) was 2-3-fold higher for the TG(i) group compared to the other two. The efficiencies of VLDL and LDL binding to the LDL receptor (LDLr) in vitro were compared by solid-phase assay free of steric hindrance observed in cell binding. The maximal number of binding sites did not change for either type of particles and between groups. The association constant K(a) and apolipoprotein (apo) E/apoB mole ratio values all increased significantly for VLDL, but not for LDL, in comparison of the TG(i+h) with the TG(l) group. Based on VLDL and LDL concentrations in serum and on the affinity constant values obtained in an in vitro assay, VLDL concentrations corresponding to 50% inhibition of LDL binding (IC(50)) were calculated in an assumption of the competition of both ligands for LDLr in vivo; the mean values of IC(50) decreased 2-fold when plasma TG exceeded 200 mg/dl. The functional dependences of K(a)(VLDL), IC(50) and apoE content in VLDL (both fractional and absolute) and in serum on TG content in the whole concentration range studied were fitted to a saturation model. For all five parameters, the mean half-maximum values TG(1/2) were in the range 52-103 mg/dl. The efficiency of protein-protein interactions is suggested to differ in normolipidemic vs. HTG-VLDL and apoE content and/or protein density on VLDL surface may be the primary determinant(s) of the increased binding of HTG-VLDL to the LDL receptor. ApoCs may compete with apoE for the binding to the VLDL lipid surface as plasma triglyceride content increases. The possible competition of VLDL with LDL for the catabolism site(s) in vivo, when plasma TG increases, could explain the atherogenic action of TG-rich lipoproteins. Moreover, the 'dual action' hypothesis on anti-atherogenic action of apoE-containing high density lipoproteins (HDL) in vivo is suggested: besides the well-known effect of HDL as cholesteryl ester catabolic outway, the formation of a transient complex of apoE-containing discs appearing at the site of VLDL TG hydrolysis by lipoprotein lipase with VLDL particles proposed in our preceding paper promotes the efficient uptake of TG-rich particles; in hypertriglyceridemia due to the diminished HDL content this uptake seems to be impaired which results in the increased accumulation of the remnants of TG-rich particles. This explains the observed increase in cholesterol and triglyceride content in VLDL and LDL, respectively, due to the CETP-mediated exchange of cholesteryl ester and triglyceride molecules between these particles.

Apolipoproteins B↗

PubMed2000

Heparin specifically inhibits binding of apolipoprotein E to amyloid beta-peptide.

Apolipoprotein E (apoE) binds to non-fibrillar amyloid beta-peptide with high affinity. We find here that heparin specifically inhibits apoE-amyloid beta-peptide (1-40) interaction. Low molecular weight heparins reduce the affinity of this interaction 3-fold as it was estimated by surface plasmon resonance. The binding is not affected by high salt concentration, which prevents heparin-induced changes of apoE conformation. We propose that rigid protein conformation, induced by high affinity heparin binding to apoE, is unfavorable for its interaction to amyloid beta-peptide. Using thioflavin T assay, we find that heparin promotes fibrillogenesis of amyloid beta-peptide whereas apoE abolishes this effect. The data suggests that the relationship between apoE and glycosaminoglycans may be important for amyloid beta-peptide fibril formation.

Amyloid beta-Peptides↗

PubMed2000

Differential oxidation of apolipoprotein E isoforms and interaction with phospholipids.

Accumulation of oxidized proteins has been demonstrated in the brain of patients suffering from Alzheimer's disease (AD). Among the proteins found in cerebral amyloid deposits, apolipoprotein (apo) E is a polymorphic protein which one specific isoform, apo E4, has been widely associated with AD. Apo E may be linked with AD by its isoform-specific interaction with lipids or other proteins in amyloid plaques. Using the myeloperoxidase oxidative system, we report that oxidation of the three recombinant apo E isoforms is differential (as estimated using immunoblot and high-performance liquid chromatography analysis), with apo E4 being more susceptible than apo E3, which in turn is much more susceptible than apo E2. In addition, susceptibility to thrombin proteolysis is reduced when apo E is oxidized, and oxidation of apo E decreases its incorporation into phospholipid discs by approximately 50%. Oxidation of apo E may contribute to inefficient lipid recycling in the brain, particularly regarding apo E4 and E3. Our results link and strengthen both the E4 allele linkage with AD and the role of protein oxidation in AD. The cerebral mechanisms underlying apo E oxidation and/or myeloperoxidase functions in vivo remain to be assessed.

Alleles↗

PubMed2000

Effects of pro-inflammatory cytokines on apolipoprotein E secretion by a human astrocytoma cell line (CCF-STTG1).

Apolipoprotein (apo) E has been implicated in Alzheimer's disease; however, little is known about the regulation of its secretion in astrocytes. To investigate the effects of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on apoE secretion by CCF-STTG1 cells, a sensitive and specific double sandwich Enzyme-Linked ImmunoSorbent Assay (ELISA) was developed. Using a monoclonal anti-human apoE antibody as the capture antibody, this assay was carried out with commercially available reagents. The assay had a sensitivity of 0.013 ng per well, within-run and between-run variation coefficients of 6.0 and 8.6 per cent respectively. There was no cross-reactions between antibodies used and apoAI, apoAII, apoB, apoCI, apoCII and apoCIII. Low apoE concentrations were assessed using a serum-free HepG2 culture medium as secondary calibrator, containing 59 microg l(-1) of apoE. In serum-free medium, CCF-STTG1 cells secreted apoE, the accumulation of which in the cell medium increased linearly with time (27 microg per 48 h). After 48 h of incubation, apoE secretion was inhibited by TNF-alpha but not affected by IL-1beta and IFN-gamma. However, the effect of regulatory factors may depend upon culture conditions since in the presence of 10 per cent fetal calf serum, IFN-gamma significantly inhibited apoE secretion. Thus, apoE secretion by CCF-STTG1 cells is inhibited by specific pro-inflammatory cytokines. This new apoE ELISA presents the great advantage of using commercially available reagents which permit inter-laboratory comparability of results, involves relatively low cost and is adaptable for the measurement of low levels of apoE.

Apolipoproteins E↗

PubMed2000

Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project.

As part of the ApoEurope Project, the apolipoprotein E (apo E) serum concentration and polymorphism were determined in 6934 healthy subjects aged 25-64 years recruited in six European countries: Finland; France; Greece; Northern Ireland; Portugal and Spain. Age and sex influenced apo E concentration with concentrations being significantly higher in men than in women for those aged between 25 and 44 years. The age effect differed between the sexes after the age of 44 years, displaying a linear increase in women and a plateau in men. As expected, the serum apo E concentration was highest in varepsilon2 carriers and lowest in varepsilon4 carriers in each country with a significantly higher frequency of the varepsilon4 allele in the northern regions. The main finding of this study was a clear increasing North-South gradient in serum apo E concentration independent of age, sex and apo E genotype. In subjects aged <45 years and with the varepsilon3/varepsilon3 genotype, apo E concentration was higher in the South-East (Greece) as compared to the North by 20% for men and 32% for women. In addition to the genetic polymorphism, the geographical area is an important factor to take into account when studying serum apo E concentration in multicentre studies and defining reference values.

Adult↗

PubMed2000

Association of the G-2548A polymorphism in the 5' region of the LEP gene with overweight.

Mutations in the translated part of the leptin gene (LEP) have been found in only two families. Nevertheless DNA polymorphisms in the LEP region are linked to extreme obesity. We previously found in the 5' region of LEP a polymorphism, G-2548A, associated with a differerce in BMI reduction following a low calorie diet in overweight women. Recently, this polymorphism was associated with extreme obesity in women. In this work, we genotyped a new sample from the general population including 314 normal weight (BMI < 27 kg/m2) and 109 overweight subjects (BMI > or = 27 kg/m2). The genotype and allele frequencies were significantly different between groups, with the G-2548 allele being more frequent in the overweight subjects (p < 0.01). In men, carriers of this allele had lower leptin concentrations adjusted for fat mass (p = 0.05). Our results indicate that variations at the leptin locus are associated with common obesity phenotypes, and not only with extreme obesity or the rare mendelian obesity syndromes.

Adult↗

PubMed2000

5-HT2A receptor gene polymorphism is associated with food and alcohol intake in obese people.

OBJECTIVE: To test the association between a polymorphism of the 5-HT2A receptor gene, -1438G/A, and energy and nutrients intake, including alcohol. SUBJECTS: Two hundred and seventy six unrelated overweight subjects (180 women, 96 men) were recruited from the Nutrition Department of Bichat Hospital in Paris on the basis of 120% of ideal body weight (body mass index, BMI=33.3+/-4.8 kg/m2). A second overweight sample (31 women, 49 men) was drawn from the Stanislas Family Study, composed of volunteers for a free health examination in Nancy (BMI=29.6+/-3.1 kg/m2). MEASUREMENTS: Energy and nutrients intake were assessed using the diet history method in Paris and the 3-day record method in Nancy. We analyzed the polymorphism by PCR followed by MspI digestion. Statistical differences between genotypes were assessed by using the non-parametric Kruskal-Wallis test. RESULTS: In the whole overweight population, the A allele was associated with lower energy intake 10. 3+/-2.8, 9.9+/-2.8, 9.3+/-2.9 MJ/day for GG, GA and AA genotypes respectively (P<0.05). This association was significant in the patient sample from Paris and in the overweight male volunteers from Nancy. Allele A-related lowering in energy intake was due to a trend to lower intakes in all the main nutrients. The A allele was also associated with a lower alcohol consumption: 18.4+/-19.7, 15.3+/-21. 2 and 12.3+/-17.5 g/day for GG, GA and AA genotypes, respectively (P<0.05). CONCLUSIONS: These data indicate that a gene polymorphism may influence food and alcohol intake in overweight humans. This could be explained by the role of the serotonergic system as a determinant of food intake.

Adult↗