The G-308A promoter variant of the tumor necrosis factor-alpha gene is associated with hypertension in adolescents harboring the metabolic syndrome

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been associated with obesity, obesity-related hypertension, and metabolic syndrome. We investigated the possible contribution of the G-308A TNF-alpha mutant to explain variables of the metabolic syndrome. METHODS: Data and blood samples were used from the 175 adolescents that satisfied the criterion of having systolic or diastolic blood pressures (BP) more than the 80th or less than the 20th percentiles, out of a cross-sectional, population-based study of 934 high school students. Genotyping for the polymorphism was performed by polymerase chain reaction-based restriction fragment length polymorphism analysis. RESULTS: In univariate analysis, we found that there was no difference between A allele carriers and noncarriers in most of the clinical characteristics of the metabolic syndrome such as body mass index (BMI), waist-to-hip ratio, plasma leptin levels, total cholesterol, HDL- and LDL-cholesterol, triglycerides, plasma fasting glucose, insulin, and homocysteine levels. However, we found a significantly (P = .015) higher age- and sex-adjusted systolic BP (Z score) in the A allele carriers, and A allele carriers also showed an elevated homeostasis model assessment of insulin resistance (HOMA) index with respect to noncarriers. Logistic regression analysis indicates that A allele carriers had a 2.8-fold higher probability of being hypertensive independent of BMI, waist-to-hip ratio, and HOMA index. CONCLUSIONS: In this report we found a positive association between the G-308A TNF-alpha variant and systolic arterial BP Z score and HOMA index in adolescents harboring features of metabolic syndrome. Therefore, the A allele may predispose to hypertension and insulin resistance in youth.     

Tumor necrosis factor-alpha--308 G/A polymorphism in obese Caucasians

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is expressed primarily in adipocytes, and elevated levels of this cytokine have been linked to obesity and insulin resistance. Recently, the A allele of a polymorphism in the 5'-flanking region of the TNF-alpha gene (G-308A) has been reported to be more frequent in obese than in lean subjects and has also been associated with increased expression of this cytokine in fat tissue and influences fat mass and insulin resistance. We, therefore, examined the relationship between this variant and obesity in a German Caucasian population. SUBJECTS AND METHODS: We genotyped 176 index subjects recruited within the framework of the BErG (Berlin Ern?hrung Geschwister)- Study for the TNF-alpha-G-308A polymorphism. Subjects were characterized for weight, height, waist and hip circumference, body mass index (BMI), body composition, glucose tolerance, leptin and angiotensinogen levels. RESULTS: The frequency of the -308A allele (0.18) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (GG, n=118; GA, n=53; AA, n=5). There was a significant difference in allele frequencies of the polymorphism by BMI quartiles (I,<27.3 kg/m2; II, 27.3-31.9 kg/m2; III, 31.9-36.5 kg/m2; IV,>36.5 kg/m2, in each quartile n=44) with -308A allele carriers having a higher BMI than G allele carriers (P=0.013). Despite previous smaller studies that have related insulin resistance to the G-308A polymorphism, we found no relationship between glucose and insulin response during an oral glucose tolerance test (OGTT) and the polymorphism. Furthermore, none of the plasma parameters were related to the polymorphism. CONCLUSION: Our findings support the hypothesis that the G-308A polymophism of the TNF-alpha gene is associated with BMI. The G-308A polymorphism may, therefore, represent a genetic marker for increased susceptibility for obesity in Caucasians.     

An insulin receptor gene polymorphism is associated with diastolic blood pressure in Chinese subjects with components of the metabolic syndrome

Insulin resistance has been described as a possible underlying link for the clustering of Type 2 diabetes mellitus, hypertension, obesity, and dyslipidemia, known as the metabolic syndrome. Mutations within the insulin receptor have been associated with hypertension in some white and Oriental populations. We examined the relationship between the insulin receptor NsiI restriction fragment-length polymorphism (RFLP) and biochemical and anthropometric parameters associated with these disorders in 933 Chinese subjects. Of the 933 subjects, 117 were control subjects and 816 had one or more components of the metabolic syndrome: 59.7% hypertension, 64.6% glucose intolerance, 55.3% dyslipidemia, and 53.3% obesity. The prevalences of the N1 allele and N1N1 genotype were 74.4% and 55.8%, respectively, in the whole population. No differences were observed in the genotype and allele frequency distributions between the control group and the cohorts with glucose intolerance, hypertension, or dyslipidemia alone or in combination. Using one-way ANOVA, there was a weak relationship between the insulin receptor genotypes and diastolic blood pressure (DBP), P = .069. The DBP was significantly higher in subjects carrying the N1N1 genotype in both the total population (80 +/- 13 v 76 +/- 12 mm Hg, P = .038) and subjects with glucose intolerance (80 +/- 12 v 76 +/- 10 mm Hg, P = .048). Using stepwise multiple regression, the insulin receptor NsiI polymorphism was found to be an independent predictor of DBP in this Chinese population, P = .018. Age, gender, and body mass index (BMI) were also included in the analysis and were all significantly associated with diastolic DBP. To conclude, the insulin receptor gene NsiI RFLP is associated with DBP in these Chinese subjects.     

Variation of the fatty acid binding protein 2 gene is not associated with obesity and insulin resistance in Japanese subjects.

An alanine to threonine substitution at codon 54 of the fatty acid binding protein 2 (FABP2) gene has been associated with insulin resistance in Pima Indians and with obesity in aboriginal Canadians. We investigated whether this polymorphism contributes to obesity and insulin resistance in 258 Japanese subjects. Thirty-six subjects (13.9%) were homozygous for the Thr54 allele, 106 (41.1%) were heterozygous for the Ala54/Thr54 allele, and 116 (45.0%) were homozygous for the Ala54 allele. The frequency of the Thr54 allele was 0.34 and did not differ significantly between men and women. The incidence of non-insulin-dependent diabetes mellitus (NIDDM) was not different among the three genotypes. The variation at codon 54 of the FABP2 gene was not associated with obesity, hypertension, dyslipidemia, hyperuricemia, or hyperinsulinemia. These results suggest that the polymorphism at codon 54 of the FABP2 gene is not a major contributing factor to obesity and insulin resistance in Japanese subjects.     

瘦素受体基因Gln223 Arg多态性与代谢综合征患者胰岛素抵抗的相关性

目的 研究瘦素受体基因Gln223Arg多态性与代谢综合征(MS)患者胰岛素抵抗的相关性.方法 代谢综合征组167例,对照组216名,以聚合酶链反应-限制性片段长度多态性(PCR-RFLP)法分析其瘦素受体基因型,并进行临床生化检测.结果 携带A等位基因者发生MS的风险是G等位基因的3.302倍(P<0.01).携带A等位基因的MS患者发生胰岛素抵抗的风险是G等位基因的3.446倍(P<0.01).结论 瘦素受体基因Gln223Arg多态性A等位基因携带者发生MS的风险增加,更容易发生胰岛素抵抗.     

Tumor necrosis factor alpha gene G-308A polymorphism, insulin resistance, and fasting plasma glucose in young, older, and diabetic Japanese men

In obese subjects, the levels of tumor necrosis factor alpha (TNF-alpha) expression and protein synthesis in adipocytes are increased. A recent study of Caucasians suggested that the TNF-alpha gene promoter region polymorphism at position -308 influences insulin resistance and percent body fat and increases serum leptin levels, although conflicting data are also reported. The present study was performed to investigate the relationship between this polymorphism and the body mass index (BMI), blood pressure, glucose and lipid profiles, and serum leptin in 122 healthy young men aged 21 to 29, 177 older men aged 45 to 65, and 71 type 2 diabetic male patients aged 42 to 78. The BMI, blood pressure, and fasting plasma glucose (FPG), serum lipids, uric acid, insulin, and leptin concentrations were measured. The TNF-alpha G-308A polymorphism was assessed by the polymerase chain reaction restriction fragment length polymorphism method. In the young group, 4 subjects (3.3%) were heterozygous for the TNF2 (G-308A-positive) allele, but there were no significant differences between the TNF1 (wild-type) and TNF2 groups in any measured anthropometric or metabolic parameter. In the older group, the frequency of the TNF2 group was 2.8%, and FPG was significantly higher in the TNF2 versus the TNF1 group (108 +/- 7 v 99 +/- 9 mg/dL, P= .042 by Mann-Whitney Utest). Plasma triglycerides and the insulin resistance index tended to be higher and high-density lipoprotein (HDL) cholesterol tended to be lower in the TNF2 group (P = .06, .20, and .07, respectively), although these differences were not statistically significant. In type 2 diabetic subjects, the frequency of the TNF2 group was also 2.8%, and there were no significant differences between the TNF1 and TNF2 groups in any parameter. HDL cholesterol tended to be lower (P = .10) in the TNF2 group, although it was not statistically significant. In conclusion, no major difference was associated with TNF1 and TNF2 polymorphisms in terms of obesity, blood pressure, lipids, or glucose in young, older, or diabetic Japanese men, although FPG was significantly higher in older men, possibly through increased insulin resistance.     

The metabolic syndrome: Insulin resistance

Insulin resistance is the most accepted unifying theory explaining the pathophysiology of the metabolic syndrome. However, epidemiologic studies indicate that a substantial proportion of patients with the metabolic syndrome do not have evidence of insulin resistance, and the correlation between insulin resistance and individual components of the syndrome is weak to moderate. Insulin resistance may play an important role in the development of hyperglycemia and dyslipidemia, which can further aggravate insulin resistance. The implication of insulin resistance in hypertension appears to be less strong than its role in causing hyperglycemia and dyslipidemia. Obesity may be another pathogenic factor in the metabolic syndrome that may help initiate or worsen insulin resistance. However, like insulin resistance, obesity is not universal in the metabolic syndrome, and many obese subjects do not have metabolic abnormalities. This review provides an update on the relationship between insulin resistance and main components of the metabolic syndrome: hyperglycemia, dyslipidemia, hypertension, and obesity.     

Apolipoproteins and carotid artery atherosclerosis in an elderly multiethnic population: the Northern Manhattan stroke study

There is accumulating evidence for a role of tumor necrosis factor-alpha (TNF-alpha) in insulin resistance induced by obesity. The purpose of this study was to investigate whether the TNF alpha/G-308A polymorphism was associated with responses to oral glucose and fat tolerance tests in a case--control study comparing male offspring with a paternal history of premature myocardial infarction (cases, n=335) to age-matched controls (n=340) recruited from 14 European university populations. Genotype frequencies did not significantly differ between cases and controls. Among cases, those carrying the A allele exhibited a higher area under the curve for insulin (64.5 vs 55.9 mU h/l, P=0.009), a higher increment between baseline concentration and peak of insulin (63.1 vs 52.8 mU/l, P=0.005) and a greater decrease between peak and insulin at 120 min (49.1 vs 36.8 mU/l, P=0.003) than those with the GG genotype. No such effect was observed in control subjects. No association was observed with response to a fat tolerance test either in cases or in controls. The present results suggest that the TNF alpha/G-308A polymorphism might interact with other susceptibility factors to coronary heart disease to predispose to insulin resistance, and that the ability of TNF-alpha to induce insulin resistance may extend beyond obesity.     

Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese

The metabolic syndrome is characterized by a clustering of cardiovascular risk factors including type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity. Elevated plasma insulin and urinary norepinephrine (noradrenaline) and reduced urinary epinephrine (adrenaline) excretion are associated with obesity in Caucasian populations. We examined the interrelationships between obesity, plasma insulin, and urinary catecholamine excretion in Chinese subjects with various components of the metabolic syndrome. A total of 577 Chinese subjects (aged 38 +/- 10 years; 68% with type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria and 32% healthy subjects) were studied, all of whom had a plasma creatinine less than 150 micromol/L. The blood pressure, height, weight, waist and hip circumference, and fasting plasma glucose, insulin, lipid, and creatinine levels were measured. A 24-hour urine sample was collected for measurement of albumin and catecholamine excretion. The body mass index (BMI) and waist circumference were used as measures of general and central obesity, respectively. The insulin resistance index was estimated by the calculated product of fasting plasma insulin and glucose concentrations. Patients with an increasing number of components of the metabolic syndrome (type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria) were more obese, hyperglycemic, dyslipidemic, and albuminuric and had higher blood pressure, plasma insulin, insulin resistance indices, and 24-hour urinary norepinephrine excretion but lower urinary epinephrine output (all P < .005). Increasing quintiles of BMI in the whole population or waist circumference in both sexes were associated with increasing trends for adverse lipid profiles, plasma insulin, insulin resistance indices, and urinary norepinephrine excretion but a decreasing trend for urinary epinephrine output (all P < .001). There were close associations between age, obesity, blood pressure, fasting plasma glucose, lipid, insulin, insulin resistance indices, and urinary catecholamine excretion. Using stepwise multiple regression analysis (all P < .001), 34% of the variability of the BMI and 45% of that of the waist circumference were independently related to gender (waist higher in males and BMI higher in females), increased plasma insulin, triglyceride, and urinary norepinephrine excretion, and decreased high-density lipoprotein (HDL) cholesterol and urinary epinephrine output. In Chinese subjects with different manifestations of the metabolic syndrome, hyperinsulinemia, insulin resistance, elevated norepinephrine, and reduced epinephrine excretion were closely associated with general and central obesity. Based on these findings, we postulate that complex interactions between the insulin and sympathoadrenal systems may lead to the development of obesity and the metabolic syndrome.     

高尿酸血症患者G-308A TNF-α基因型分布与心血管疾病危险因素相关性研究

目的高尿酸血症(HUA)是代谢综合征(MS)的组成成分,肿瘤坏死因子-α(TNF-α)启动子区-308G/A(G-308ATNF-α)与MS各组分之间的的关系仍存在争议。该研究旨在探讨中国山东沿海地区高尿酸血症患者G-308ATNF-α基因型分布与其心血管危险因素的关系。方法在5003名流行病学调查人群中筛选162名高尿酸血症患者、77名健康者。采用PCR-RFLP法检测G-308ATNF-α基因型分布。采用尿酸氧化酶法测定血尿酸。采用稳态模型评估(HOMA-IR)法检测胰岛素抵抗指数。结果(1)239名研究对象G-308ATNF-α基因型分布符合Hardy-Weinberg平衡;(2)在HUA伴脂代谢紊乱和高血压患者中AA+GA基因型频率明显高于单纯高尿酸血症组和健康组对照组(P0.05);(3)AA+GA组腰围与臀围比值、收缩压、舒张压、血尿酸、甘油三酯高于GG型组(P0.05～0.01)。结论高尿酸血症个体中TNF-α308A携带者的基因型与高尿酸血症伴脂代谢紊乱和高血压有关。提示TNF-α308A携带可能与高尿酸血症伴发心血管危险因素有关。     

Impact of interleukin 6 -174G>C polymorphism on obesity-related metabolic disorders in people with excess in body weight

Low-grade inflammation has been related to obesity, insulin resistance, and related metabolic disorders. In this context, the -174G>C gene polymorphism of the proinflammatory interleukin 6 (IL-6) cytokine has also been associated with these diseases. Based on this, the aim of the current study was to evaluate the role of IL-6 -174G>C polymorphism in the risk of developing metabolic alterations in people with excessive body weight. One hundred six Caucasian volunteers (body mass index, 33.2 +/- 5.3 kg/m(2)) were recruited to assess the potential relationship between carrying the -174G>C polymorphism and the risk of developing obesity-related metabolic disorders, such as hypertension, atherogenic dyslipidemia, and insulin resistance evaluated by the homeostasis model assessment of insulin resistance index. Subjects carrying the C allele showed higher plasma insulin concentrations and systolic blood pressure than homozygotes for the G allele. A multiple regression analysis showed that the presence of the C allele induced an increase in the homeostasis model assessment of insulin resistance index as compared with GG subjects (adjusted R(2) = .26, P < .001). Analyzing the mentioned obesity-related diseases, an enhanced prevalence of presenting high risk of developing these complications was found for the GC and CC genotypes relative to GG, with an adjusted odds ratio of 5.2 (P = .003). This association remained significant after controlling for multiple comparisons by the 10,000-permutation test (P = .004838). These data demonstrate that the occurrence of C allele of IL-6 -174 G>C gene polymorphism in people with excessive body weight is accompanying a higher risk of developing obesity-related metabolic disorders, especially insulin resistance.     

Tumor necrosis factor-beta gene NcoI polymorphism decreases insulin resistance in Japanese men

Given that the NcoI polymorphism of the tumor necrosis factor-beta (TNF-beta) gene has been shown to be associated with tumor necrosis factor-alpha (TNF-alpha) secretory capacity, we know that this TNF-beta gene polymorphism may influence insulin resistance. In Caucasians, 2 polymorphisms of the TNF-alpha promoter region (positions -308 and -238) have been reported to be associated with insulin resistance. Thus, we investigated how genetic variation in the TNF-beta and TNF-alpha genes was associated with insulin resistance in 211 Japanese men. The frequency of the TNF-beta gene polymorphism was 0.41, and insulin resistance, estimated by homeostasis model assessment (HOMA), was significantly lower in variant homozygotes versus wild-type allele. The frequencies of the -308 and -238 polymorphisms were 0.01 and 0.02, respectively, and these polymorphisms were not associated with insulin resistance. Our results suggest that the TNF-beta gene polymorphism decreases insulin resistance, and that the -308 and -238 polymorphisms of the TNF-alpha promoter region are not a major contributing factor to insulin resistance in Japanese men.     

G-308A polymorphism of the tumor necrosis factor alpha gene promoter and salivary cortisol secretion

The objective of the current study was to examine the potential impact of the G-->A substitution at position -308 of the tumor necrosis factor alpha (TNF-alpha) gene promoter on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones including salivary cortisol in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of the 5' untranslated region of the TNF-alpha gene followed by digestion with the restriction enzyme NcoI. The frequencies were 0.77 for allele G and 0.23 for allele A. Tests for differences in salivary cortisol levels between the TNF-alpha genotypes revealed that there were significantly higher cortisol levels in the morning, before as well as 30 and 60 min after stimulation by a standardized lunch in homozygotes for the rare allele in comparison with the other genotypes. In addition, homozygotes for the rare allele had a tendency toward higher mean values of body mass index, waist to hip ratio, and abdominal sagittal diameter compared with the other genotype groups. The results also indicated a weak trend toward elevated insulin and glucose levels among men with the A/A genotype. In conclusion, a G-->A polymorphism in the 5' untranslated region of the TNF-alpha gene is associated with elevated morning cortisol levels as well as elevated postprandial cortisol secretion. This increase in cortisol secretion might be the endocrine mechanism underlying the previously observed associations between the NcoI TNF-alpha polymorphism and obesity as well as insulin resistance. However, to what extent this polymorphism is associated with these conditions is uncertain from the present data.     

Association of the C825T polymorphism of the G-protein beta3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese

A C825T polymorphism of the gene encoding the G-protein beta3 subunit (GNB3) is associated with increased intracellular signal transduction. We know that this C825T polymorphism may influence hypertension and obesity. In whites, the C825T polymorphism has been reported to induce hypertension, obesity, and diabetic nephropathy. Thus, we investigated how genetic variation in the GNB3 gene is associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, and diabetic therapies in 427 Japanese subjects with type 2 diabetes mellitus and in 368 Japanese subjects who underwent general health examinations. The frequency of the GNB3 gene polymorphism was 0.48 and 0.47 in subjects with diabetes and in those who had general health examinations, respectively. The amount of hyperlipidemia of the CT allele was significantly lower than the amount in the CC allele in the Japanese subjects with diabetes. Our results suggest that the C825T polymorphism influences lipid metabolism and is not associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, or diabetic therapies.     

Large-scale studies of the Leu72Met polymorphism of the ghrelin gene in relation to the metabolic syndrome and associated quantitative traits.

AIM: Recently, low-frequency polymorphisms in the coding region of the ghrelin gene were suggested to be involved in the aetiology of obesity and to modulate glucose-induced insulin secretion in different ethnic study groups. The objective of the present large study was to investigate whether the Leu72Met polymorphism of the ghrelin gene associates with features of the metabolic syndrome (MS) in the Danish population. METHODS: The variant was examined, using PCR-RFLP, in the DanMONICA cohort, a population-based sample of 2413 subjects. The metabolic syndrome was defined using the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria. RESULTS: The allelic frequency of the Met72 allele was 8.6%[6.3-10.9%] in the MS group and 7.8%[7.0-8.6%] among subjects classified as not having the MS (NS). Similarly, there were no significant differences across the three groups of genotypes with respect to any of the examined variables, including BMI, waist circumference, fasting serum lipids, plasma glucose, serum insulin and HOMA estimates of insulin resistance and insulin secretion. CONCLUSION: In conclusion, the Leu72Met polymorphism of the ghrelin gene is not associated with the metabolic syndrome or related quantitative traits in the Danish population.     

Relationship of the tumor necrosis factor-alpha -308 A/G promoter polymorphism with insulin sensitivity and abdominal fat distribution in Japanese patients with type 2 diabetes mellitus

We investigated the relationship of the A/G variant of the tumor necrosis factor-alpha (TNF-alpha) gene promoter at position -308 with insulin resistance and abdominal fat distribution in type 2 diabetic patients in the Japanese population. The TNF-alpha polymorphism was evaluated by polymerase chain reaction-restriction fragment length polymorphism in 142 healthy volunteers and 132 type 2 diabetic patients. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) index in healthy subjects and hyperinsulinemic euglycemic clamp in type 2 diabetic patients. Abdominal fat distribution was evaluated by computed tomography (CT) scanning in diabetic patients. The TNF-alpha polymorphism was detected in three healthy volunteers and three type 2 diabetic patients, all of them being heterozygotes. There was no significant difference in allele frequencies of the -308 polymorphism between healthy subjects (0.0106) and type 2 diabetic patients (0.0114). HOMA index was no significant difference between healthy subjects with and without polymorphism (1.09 +/- 0.03 vs. 1.02 +/- 0.05). Glucose infusion rate (GIR), an index of insulin sensitivity, was not significantly different between diabetic patients with and without TNF-alpha polymorphism (40.4 +/- 4.1 vs. 45.0 +/- 1.8 micromol/kg per min). Moreover, no remarkable effect of TNF-alpha polymorphism on abdominal fat distribution was observed in diabetic patients. These results suggest that A/G heterozygotes of the TNF-alpha gene promoter at position -308 play no major role in the pathogenesis of insulin resistance or abdominal fat distribution in Japanese type 2 diabetic patients.     

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects

Aims/hypothesis Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor α subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes.Subjects and methods The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites.Results No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10–1.25], p=1×10⁻⁶). In case–control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m²; odds ratio 1.63 [95% CI 1.09–2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait.Conclusions/interpretation In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.     

The -238 and -308 G-->A polymorphisms of the tumor necrosis factor alpha gene promoter are not associated with features of the insulin resistance syndrome or altered birth weight in Danish Caucasians

Recently, two G-->A polymorphisms at positions -308 and -238, in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, have been identified. These variants have, in different ethnic groups, been linked to estimates of insulin resistance and obesity. The objective of the present study was to investigate whether these genetic variants of TNF-alpha were associated with features of the insulin resistance syndrome or alterations in birth weight in two Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. All study participants underwent an iv glucose tolerance test with the addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the polymorphisms by applying PCR restriction fragment length polymorphism. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome (body mass index, waist to hip ratio, fat mass, fasting serum lipids or fasting serum insulin or C-peptide). Birth weight and the ponderal index were also not associated with the polymorphisms. In conclusion, although the study was carried out on sufficiently large study samples, the study does not support a major role of the -308 or -238 substitutions of the TNF-alpha gene in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects.     

Polymorphisms in candidate genes for type 2 diabetes mellitus in a Mexican population with metabolic syndrome findings

The metabolic or insulin resistance syndrome, characterized by hypertension, dyslipidemia, glucose intolerance and hyperinsulinemia, may have genetic determinants. The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. We examined eight polymorphisms in these genes in 163 individuals from Yucatan, Mexico; this population has a high prevalence of obesity, type 2 diabetes mellitus and dyslipidemia. Subjects were evaluated for body mass index (BMI) and blood pressure. Blood samples were collected to determine glucose, insulin, triglycerides and cholesterol levels, as well as for DNA isolation. Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. Among the eight polymorphisms analyzed, the PstI polymorphism in INS was significantly associated with hypertriglyceridemia and with the presence of at least one abnormality related to the metabolic syndrome (P=0.007 and 0.004, respectively). The MaeIII polymorphism in INS was associated with fasting hyperinsulinemia (P=0.045). In multilocus analyses including both INS polymorphisms, significant associations were seen with hypertriglyceridemia (P=0.006), hypercholesterolemia (P=0.031) and with presence of at least one metabolic abnormality (P=0.009). None of the polymorphisms in INSR or IRS1 was associated with any of these traits. These findings suggest that the insulin gene may be an important determinant of metabolic syndrome, and particularly of dyslipidemia, in this population.