Dietary fat intake modifies the influence of the FTO rs9939609 polymorphism on adiposity in adolescents: The HELENA cross-sectional study.

BACKGROUND AND AIMS: The fat mass and obesity associated gene (FTO) has been associated with obesity and dietary intake. The aims were: (i) To assess whether energy and macronutrient intakes were different across the FTOrs9939609 genotypes in adolescents, and (ii) to explore whether dietary fat intake modified the association of the rs9939609 polymorphism with adiposity. METHODS AND RESULTS: The FTOrs9939609 polymorphism was genotyped in 652 adolescents (53% females, 14.8 ± 1.2 years, TT = 246, TA = 296, AA = 110). Energy and macronutrient intake were assessed by two non-consecutive 24 h-recalls. Weight, height, waist circumference and skinfold thicknesses were measured and body fat percent was calculated. Energy and macronutrient intake were similar across the FTOrs9939609 genotypes (P > 0.2). There were significant interactions between the FTO polymorphism and fat intake on adiposity estimates (P < 0.05). In adolescents whose fat intake was below 30% (N = 203), the A allele of rs9939609 was not associated with adiposity indices. In contrast, in adolescents whose fat intake was between 30% and 35% of energy (N = 190), the rs9939609 polymorphism was associated with a 1.9% higher body fat per risk allele (95%CI: 0.39, 3.33; P < 0.05), and in those whose fat intake was higher than 35% (N = 259), it was associated with a 2.8% higher body fat per risk allele (95%CI: 1.27, 4.43; P < 0.001). CONCLUSIONS: These findings support the concept that the deleterious effect of the FTOrs9939609 polymorphism on adiposity is exacerbated in adolescents consuming high fat diets. In contrast, the consumption of low fat diets (<30% of energy) may attenuate the genetic predisposition to obesity in risk allele carriers.

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.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.

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.

Intake and dietary sources of haem and non-haem iron among European adolescents and their association with iron status and different lifestyle and socio-economic factors.

BACKGROUND/OBJECTIVES: Adolescents are at risk of iron deficiency because of their high iron requirements. The aims of this study were: (1) to assess iron intake, its determinants and its most important food sources and; (2) to evaluate the relation of iron intake and status in European adolescents. SUBJECTS/METHODS: Two non-consecutive 24-h recalls were completed by a computerised tool. The socio-demographic and socio-economic data were collected by a self-reported questionnaire. Weight and height were measured. A distinction was made between haem and non-haem iron. RESULTS: The total iron intake was significantly higher among boys (13.8 mg/day; n=1077) than girls (11.0 mg/day; n=1253). About 97.3% of the boys and 87.8% of the girls met the estimated average requirement, and 72.4% of the boys and 13.7% of the girls met the recommendation for bio-available iron intake. The ratio of haem/non-haem iron intake was lower for girls than boys. Meat (19.2; 76%) and bread and rolls (12.6;3.9%) contributed most to total and haem iron intake. Bread and rolls (13.8%) and meat (10.8%) contributed most to non-haem iron intake. Age, sex and body mass index were associated with iron intake. Only red blood cell concentration was significantly negatively associated with total, haem and non-haem iron intake. CONCLUSION: Girls had lower iron intakes and ratio of haem/non-haem iron intake than boys. The main total iron and haem iron source was meat, while the main non-haem iron source was bread and rolls. Adolescent girls may be a group at risk for iron deficiency. Consequently, special attention and strategies are needed in order to improve iron intakes during adolescence.

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.

Intake and dietary sources of haem and non-haem iron in Flemish preschoolers.

BACKGROUND/OBJECTIVES: In the absence of biochemical data on iron status in preschoolers, data on the adequacy of iron intake may be used to assess the possible risk of iron deficiency in this population group. Therefore, this study aims to investigate iron intake and its food sources in Flemish preschoolers. SUBJECTS/METHODS: A total of 661 Flemish preschoolers 2.5-6.5 years old were recruited via a random cluster sampling design, using schools as primary sampling units. Three-day estimated diet records were used to assess dietary intakes. The contribution to iron intake (haem and non-haem) of 57 food groups was computed by summing the amount provided by the food group for all individuals divided by the total intake for all individuals. RESULTS: Mean total iron intake (s.d.) was 7.4 (±2.3) and 6.7 (±2.8) mg/day for boys and girls, respectively. In all 65% of the children <4 years old and 45% of those 4-6.5 years old presented adequate iron intakes. The food groups with the highest mean proportional contribution to total iron intake were bread, meat and meat products, breakfast cereals and sweet snacks (in that order). Children from small families whose mother had a low educational level had higher iron intakes. CONCLUSION: Iron intakes were similar for boys and girls and almost half of the Flemish preschoolers do not comply with the dietary iron recommendations.

Association between the FTO rs9939609 polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study.

We examined the association between the FTO rs9939609 polymorphism and serum leptin concentrations in adolescents. The FTO rs9939609 polymorphism was genotyped, and fasting serum leptin and insulin were measured in 655 European adolescents (365 females) aged 14.6 ± 1.2 years. We measured weight, height, triceps and subscapular skinfolds and waist circumference, and body fat percentage was calculated. Sex, pubertal status, center, physical activity (accelerometry), total or central adiposity and serum insulin concentrations were entered as confounders in the analyses. The minor A allele of the FTO rs9939609 was significantly associated with higher serum leptin concentrations independently of potential confounders including adiposity (+3.9 ng ml(-1) per risk allele (95% confidence interval: 2.0, 5.9); adjusted P < 0.001). These findings could link the FTO gene with serum leptin and consequently with the control of energy balance. Leptin could be a possible intermediary contributing to the association between the FTO rs9939609 polymorphism and adiposity.

Influence of maternal educational level on the association between the rs3809508 neuromedin B gene polymorphism and the risk of obesity in the HELENA study.

OBJECTIVE: Neuromedin B (NMB) is a bombesin-like peptide, which inhibits food intake and modulates stress-related behaviour. An NMB gene polymorphism (P73T) has been earlier associated with obesity and abnormal eating behaviour in adults. METHODS: The association between four NMB polymorphisms and obesity-related phenotypes was investigated in the Healthy Lifestyle in Europe by Nutrition in Adolescence cross-sectional study (n=1144, 12-17-year-old European adolescents). This population was genotyped for the NMB rs1107179, rs17598561, rs3809508 and rs1051168 (P73T) polymorphisms. Obesity was defined according to Cole et al. (BMJ 2000; 320:1240-1243) criteria; eating behaviour was assessed by the Eating Behaviour and Weight Problems Inventory for Children (EWI-C) and the food choices and preferences questionnaires. Familial socioeconomic status (SES) was assessed through the parents' educational level. RESULTS: Only the genotype distribution of rs3809508 differed according to obesity status, as the TT genotype was more frequent in obese than in non-obese adolescents (8.6% vs 3.1%, P=0.05; adjusted odds ratio for obesity (95% confidence interval): 2.85 (1.11-7.31), P=0.03). Moreover, TT subjects had higher body mass index (22.8+/-4.4 kg m(-2) vs 21.3+/-3.7 kg m(-2), P=0.02), waist circumference (75.8+/-9.7 cm vs 72.2+/-9.3 cm, P=0.006), waist-to-hip ratio (0.84+/-0.14 vs 0.79+/-0.07, P<0.0001) and waist-to-height ratio (0.47+/-0.06 vs 0.44+/-0.55, P=0.002) than C allele carriers. The effects of this single nucleotide polymorphism on all anthropometric values were influenced by the maternal SES, in that a low maternal educational level aggravated the phenotype of adolescents carrying the TT genotype (interactions: P<0.02). No association with EWI-C scores was found, although sweet craving was a more frequent cause of between-meal food intake in TT subjects than in C allele carriers (24.3% vs 9.2%, P=0.01). CONCLUSION: In European adolescents, the TT genotype of the NMB rs3809508 polymorphism was associated with a higher risk of obesity. Moreover, the effects of this polymorphism on anthropometric values were influenced by the maternal educational level.

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.

Association between liver X receptor alpha gene polymorphisms and risk of metabolic syndrome in French populations.

CONTEXT: The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor alpha (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome. OBJECTIVE: In the search for susceptibility genes to metabolic syndrome, we hypothesized that common genetic variation in NR1H3 gene influences metabolic syndrome susceptibility. DESIGN: Two large French population-based studies (n=1130 and 1160) including overall 664 individuals with and 1626 individuals without metabolic syndrome were genotyped for three polymorphisms (rs12221497, rs11039155 and rs2279239) of NR1H3. RESULTS: We found that the -6A allele of rs11039155 was consistently associated with a 30% reduction in risk of metabolic syndrome in the two independent population samples (adjusted OR (95% CI)=0.68 (0.53-0.86), P=0.001 for the combined sample). Moreover, it was associated with an increase in plasma HDL-cholesterol concentrations (P=0.02 for the combined sample). Neither rs12221497 nor rs11039155, both polymorphisms located in the 5' region of NR1H3, had significant influence on NR1H3 and ATP-binding cassette transporter A1 (ABCA1) gene expression in primary human macrophages. CONCLUSIONS: These results suggest that NR1H3 plays an important role in the HDL-cholesterol metabolism and in the genetic susceptibility to metabolic syndrome.

A dominant negative human peroxisome proliferator-activated receptor (PPAR){alpha} is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms.

Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR)gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPARalpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPARalpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPARalpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPARalpha(mut) and the corresponding PPARgamma mutant were capable of inhibiting the expression of genes primarily regulated by PPARalpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.

The 5A6A polymorphism in the promoter of the stromelysin-1 (MMP3) gene as a risk factor for restenosis.

AIMS: Intracoronary ultrasound studies in humans show that chronic remodelling rather than neointimal hyperplasia is the mechanism of restenosis. Stent implantation limits this remodelling process and significantly reduces restenosis. MMP3 (Stromelysin-1), a member of the matrix metalloproteinase family may play a role in this remodelling. We used a functional polymorphism (with alleles designated 5A or 6A) in the promoter of the MMP3 gene to examine the possible role of MMP3 in restenosis. METHODS AND RESULTS: Genotypes were determined in a series of consecutive patients who underwent conventional balloon coronary angioplasty without stenting (n=287) or who also had successful implantation of a Palmaz-Schatz stent (stent) (n=198). For all patients restenosis was estimated at 6 months using quantitative computer-assisted angiography. The minimal luminal diameters before and after the procedures did not differ significantly between genotypes. At follow-up in the patients without stent, those with the 6A6A genotype had an increased degree of restenosis after coronary angioplasty compared to those with one or more 5A alleles, with a greater diameter stenosis (52+/-21% vs 45+/-19%, P=0.012), and a greater late loss (0.58+/-0.59 mm vs 0.38+/-0.59 mm, P=0.038). By contrast, in the stented patients MMP3 genotype was not associated with any angiographically determined measure of vessel dimensions. CONCLUSIONS: These data imply the involvement of MMP3 in chronic remodelling after conventional balloon angioplasty, and suggest that the 6A6A MMP3 genotype is a genetic susceptibility factor for restenosis after angioplasty without stenting.

The effect of the Gly16Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity.

The lipolytic effects of catecholamines are mediated through members of the beta(2)-adrenergic receptor (BAR-2) family. Previous studies have suggested that genetic variants in the BAR-2 gene may be associated with obesity in some populations. To our knowledge, no studies have directly examined the effects of this polymorphism on circulating nonesterified fatty acid (NEFA) levels. To explore this issue further, a cohort of 604 Caucasian individuals (aged 40-65 yr) was genotyped for a common polymorphism in the BAR-2 gene (Gly16Arg), and the relationships between genotype, body mass index (BMI), NEFA, and lipid levels were examined. Women bearing the Arg16 allele had higher BMI values (P < 0.01) than Gly16Gly women. Women carriers of the Arg16Arg genotype had lower fasting plasma NEFAs (P < 0.01) and greater suppression of NEFAs (P < 0.01) after an oral glucose load than women bearing the Gly16 allele. In multivariate analysis after adjustment for age, sex, and smoking status, the interaction between the BAR-2 genotype and BMI in determining fasting NEFA concentrations was statistically significant (P < 0.05). The availability of objective measures of total energy expenditure in this population permitted the further examination of interactions, particularly that between genotype and physical activity. In the population as a whole, after adjustment for confounding by age, smoking, and BMI, the effect of the Arg16Arg genotype on the suppression of NEFA levels was modified by physical activity level (P for interaction <0.05). These data suggest the existence in this population of a gene-physical activity interaction on NEFA levels.

Polymorphisms of the tissue factor pathway inhibitor gene and the risk of restenosis after coronary angioplasty.

Intracoronary stent implantation is associated with a significantly lower risk of restenosis compared with balloon angioplasty. However, restenosis still occurs in some cases. Experimental studies suggest that the tissue factor pathway is involved in this phenomenon. We investigated a possible relationship between three previously identified polymorphisms of the tissue factor pathway inhibitor (TFPI) gene and restenosis in 443 patients who underwent angioplasty, with or without stent implantation. The effect of the intron 7-33T<--C polymorphism and that of the combined intron 7 and promoter genotype on plasma TFPI levels was also investigated in 58 healthy subjects. DNA analysis was performed by polymerase chain reaction amplification of genomic DNA extracted from white blood cells, followed by digestion with the restriction enzymes Hind III, Nde I and Mae III for the detection of promoter, intron 7 and exon IX polymorphisms, respectively. The minimal luminal diameter, percent stenosis, acute gain, late loss and loss index did not differ according to the genotype before, immediately after or 6 months after angioplasty, regardless of stent implantation. Interestingly, subjects with the intron 7 CC genotype had significantly higher total TFPI levels than those with the TT genotype before and after an enoxaparin injection. Moreover, subjects with the -287TT/Int7TT combined genotype had the lowest plasma TFPI levels. Despite significant variations in plasma TFPI levels, we found no evidence that three polymorphisms of the TFPI gene influence the risk of restenosis. These results do not exclude the possibility that other polymorphisms in the TFPI gene may influence this risk.

Polymorphisms in the insulin response element of APOC-III gene promoter influence the correlation between insulin and triglycerides or triglyceride-rich lipoproteins in humans.

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.

The human G-protein beta3 subunit C825T polymorphism is associated with coronary artery vasoconstriction.

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.

Impact of sulfonylurea receptor 1 genetic variability on non-insulin-dependent diabetes mellitus prevalence and treatment: a population study.

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.

An uncoupling protein 3 gene polymorphism associated with a lower risk of developing Type II diabetes and with atherogenic lipid profile in a French cohort.

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.