The K121Q polymorphism of ENPP1 and peripheral arterial disease

The K121Q variant of the ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) gene is associated with obesity, insulin resistance, and early myocardial infarction. Therefore, we hypothesized that the K121Q polymorphism might also be associated with an increased risk for peripheral arterial disease. Four hundred patients with peripheral arterial disease and 400 controls matched for sex and age (± 2 years) were genotyped cross-sectionally for the K121Q single nucleotide polymorphism of the ENPP1 gene. The frequency for the 121Q allele was 0.25 both in patients with peripheral arterial disease and in controls (P = 0.75). Subgroup analysis revealed association of the ENPP1 121QQ genotype with higher glycohemoglobin A1C levels (P = 0.001) and earlier onset of peripheral arterial disease (P = 0.003) in the cohort of nonsmokers. Whereas the K121Q genotype of the ENPP1 gene is not associated with presence of peripheral arterial disease in the whole Linz Peripheral Arterial Disease population, it is associated with type 2 diabetes mellitus and earlier onset of peripheral arterial disease in the subgroup of nonsmoking patients.     

Association of ENPP1 (PC-1) K121Q polymorphism with obesity-related parameters in subjects with metabolic syndrome

Background The metabolic syndrome (MS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), originally described as a plasma cell allo‐antigen and named plasma cell membrane glycoprotein (PC‐1), is an inhibitor of insulin‐induced activation of the insulin receptor. The single nucleotide polymorphism (SNP) K121Q in the ENPP1 gene has been studied in relation to obesity, insulin resistance and other features of MS in several populations with conflicting results. We therefore investigate the role of the K121Q SNP in the ENPP1 gene in MS in Caucasians from the province of Segovia in Central Spain (Castille). Design and methods We recruited 794 unrelated persons (46·5% males and 53·5% females), ages 35–74 years from a cross‐sectional population‐based epidemiological survey in the province of Segovia in Central Spain (Castille). Obesity‐related anthropometric measurements included BMI, waist circumference, blood pressure and lipid profile. MS was defined by International Diabetes Federation (IDF) guidelines. K121Q PC‐1 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). Results The 121Q allele was associated with an increased BMI and waist circumference among subjects fulfilling the criteria for MS. These differences remained statistically significant even after the adjustment for sex, age and degree of glucose tolerance (β = 1·347, P = 0·017 and β = 2·824, P = 0·046; for BMI and waist circumference, respectively). Moreover, among type 2 diabetic patients those carrying the 121Q allele had higher BMI and higher leptin levels than subjects carrying the K121K genotype. Conclusions Our results suggest that the ENPP1121Q allele might contribute to the genetic susceptibility to abdominal obesity among subjects with MS.     

Obesity risk associated with the K121Q polymorphism of the glycoprotein PC-1 gene

BACKGROUND: Obesity is considered to be a multifactorial trait resulting from the combined influence of genetic and environmental determinants. Insulin resistance plays an important role in the development of obesity. Plasma-cell membrane differentiation antigene-1 (PC-1) inhibits insulin receptor signalling when overexpressed and thus causes insulin resistance. PC-1 gene polymorphism might be associated with adipocyte metabolism disturbance and energy imbalance. The purpose of this study was to determine whether K121Q polymorphism in PC-1 gene is involved in obesity susceptibility in Chinese Han population. METHODS: The genotype of the polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism analysis for 338 unrelated subjects of Beijing, China. Their Body mass index (BMI), plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), free fatty acid (FFA) and insulin level were measured. Chi-square analyses were applied to test the significance differences in genotypic and allelic frequencies. Association studies were undertaken using the t-test and logistic regression analyses. RESULTS: The obese had significantly higher frequency of KQ/QQ genotype or Q allele than non-obese in females (26.7% vs. 10.9%, p = 0.014 and 13.3% vs. 5.5%, p = 0.021). Significant elevation of insulin amongst the Q121 carrier women in obesity individuals and higher FFA level of Q121 carrier men in non-obese controls (BMI < or = 23 kg/m2) were observed. Binary logistic regression analysis revealed that PC-1 genotype together with higher glucose, total cholesterol, triglyceride and serum HDL were independently associated with the presence of obesity. CONCLUSIONS: The observed genotype distributions revealed a significant association of PC-1 K121Q with obesity. PC-1 Q121 carriers are more likely to be insulin-resistant or get fatter in respect to KK subjects and carriers of the Q allele are at higher risk for the development of obesity in female.     

Association of the ENPP1 K121Q polymorphism with type 2 diabetes and obesity in the Moroccan population

AimThe ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme (ENPP1), which downregulates insulin signaling by inhibiting insulin-receptor tyrosine kinase activity, is encoded by the ENPP1 gene. A common functional ENPP1 K121Q polymorphism has been suggested to contribute to insulin resistance, obesity and type 2 diabetes (T2D) in various ethnic groups. For this reason, we assessed the association between the ENPP1 K121Q polymorphism in T2D and obesity phenotypes in the Moroccan population.MethodsUsing LightCycler^® technology, we genotyped the ENPP1 K121Q polymorphism in 503 subjects with T2D and 412 normoglycaemic individuals.ResultsThere was no evidence of an association between ENPP1 K121Q and T2D in either an additive (P = 0.99) or recessive mode of inheritance (P = 0.47). However, the Q121 variant was significantly more frequent in obese than in non-obese subjects after adjusting for age, gender and T2D status. We observed genetic heterogeneity between obese and non-obese T2D patients (P = 0.02). The K121Q polymorphism was associated with T2D in the presence of obesity in both additive (1.55 [95% CI 1.16–2.07]; P = 0.003) and recessive (2.31 [95% CI 1.34–3.97]; P = 0.002) modes of inheritance.ConclusionAlthough there was no evidence of an association between the ENPP1 K121Q variant and the general phenotype of T2D, we did find an association with adult obesity and T2D. The Q121 allele frequency in Morocco is 37.3%, placing it between European Caucasians (15%) and Black Africans (79%). This study is the first to report an association between K121Q and metabolic diseases in the Moroccan population.     

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes in northern Chinese

The K121Q polymorphism of the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been studied in relation to insulin resistance, type 2 diabetes, and obesity, and conflicting results were observed in various populations. The purpose of the present study was to investigate the prevalence of K121Q polymorphism of ENPP1 gene and to clarify whether this polymorphism is associated with type 2 diabetes susceptibility in northern Chinese population. We studied the association of the ENPP1 K121Q polymorphism with type 2 diabetes (T2D) in 639 unrelated patients and 885 control subjects with normal glucose tolerance of northern China. The patients were diagnosed in accordance with the guidelines of the American Diabetes Association (ADA). Genotypes were determined by the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. The distribution of KK, KQ, and QQ genotypes among patients was 79.5, 19.2, and 1.3%, similar to that of the control group (79.2, 20.1, and 0.7%). After readjusting for the confounding effects of age, gender, and BMI, no significant effect of genotypes on T2D was found for any of the genetic models tested (recessive model, dominant model, or additive model). All clinical characteristics tested were similar among the different genotypes, and no significant associations were observed both in T2D patients and in controls. When subgroup analyses of T2D patients and non-diabetic controls were stratified according to BMI and waist circumference, the variant was still not associated with T2D. The results showed that the ENPP1 K121Q polymorphism is not associated with genetic susceptibility of type 2 diabetes in the northern Chinese population.     

The association of the K121Q polymorphism of the plasma cell glycoprotein-1 gene with type 2 diabetes and hypertension depends on size at birth

Birth weight and length serve as indicators of the intrauterine environment, and a small body size at birth is a predictor of type 2 diabetes and hypertension. Insulin is one of the growth factors regulating fetal growth. The plasma cell glycoprotein 1 (PC-1) gene impairs insulin signaling at the insulin receptor level. Therefore, we investigated whether the K121Q polymorphism of the PC-1 gene association with insulin sensitivity, insulin levels, and the prevalence of diabetes and hypertension in adult life depends on size at birth in 489 subjects born in Helsinki during 1924-1933. We found that the effect of the PC-1 gene polymorphism on insulin levels and insulin sensitivity, measured as the homeostasis model assessment for insulin resistance, depended on birth length because fasting insulin levels and insulin resistance were highest in subjects carrying the 121Q allele who were small at birth (P for interaction = 0.04 and 0.05). Additionally, in those whose birth length was up to 49 cm, the K121Q polymorphism of the PC-1 gene was associated with a 2-fold higher incidence of type 2 diabetes. Moreover, subjects who were short at birth and who had the 121Q allele had the highest incidence (31.6%) of type 2 diabetes together with hypertension. We conclude that the interaction between the K121Q polymorphism of the PC-1 gene and birth length affects insulin sensitivity and increases susceptibility to type 2 diabetes and hypertension in adulthood.     

<Emphasis Type="Italic">ENPP1</Emphasis> K121Q polymorphism and obesity,hyperglycaemia and type 2 diabetes in the prospective DESIR Study

AIMS/HYPOTHESIS: We assessed the predictive value of ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1) SNPs with regard to the risk of developing obesity and/or type 2 diabetes in a large French general population. METHODS: We genotyped the ENPP1 SNPs K121Q (rs1044498), IVS20delT-11 (rs1799774) and A/G+1044TGA (rs7754561) in 5,153 middle-aged participants of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. RESULTS: At baseline, the K121Q polymorphism was not associated either with BMI (p = 0.98) or with class I obesity (odds ratio [OR] 0.99, p = 0.81), but showed a borderline association with class II obesity (OR 1.65, p = 0.02). The K121Q variant was not associated with any trait during the 9-year follow-up. Pooled analyses both at baseline and at follow-up failed to show any association with hyperglycaemia (OR 1.08, p = 0.28) or type 2 diabetes (OR 1.15, p = 0.38). However, we did show an association of the Q121 allele with the risk of hyperglycaemia (OR 1.45, p = 0.001; n = 265) and type 2 diabetes (OR 1.65, p = 0.01; n = 103) in participants reporting a family history of type 2 diabetes. These results did not remain significant after a Bonferroni correction. The IVS20delT-11 and A/G+1044TGA polymorphisms and the three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA [QdelTG]) were not associated with any trait, either at baseline or at follow-up. CONCLUSIONS/INTERPRETATION: In a general French population we did not find an association of the QdelTG risk haplotype with adult obesity and type 2 diabetes. We detected nominal evidence of association between the K121Q polymorphism and both severe adult obesity at baseline and the risk of hyperglycaemia or type 2 diabetes in participants with a family history of type 2 diabetes in pooled analyses both at baseline and follow-up.     

The PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic and is associated with type 2 diabetes

The human glycoprotein PC-1 codon Q121 allele has been correlated with insulin resistance, but not with type 2 diabetes or obesity. We investigated the prevalence of PC-1 Q121 in the Dominican Republic population (755 subjects studied) and whether this variant is associated with insulin resistance, obesity, or type 2 diabetes. The prevalence of PC-1 Q121 was high compared with that in other populations. The proportions of genotypes detected were: KK, 21.6%; KQ, 48.3%; and QQ, 30.1%. This compares to approximately 74%, 24%, and 2% in other populations. Among nonobese, nondiabetic subjects, the insulin response of KQ (P = 0.027) and QQ (P = 0.031) subjects was greater during the oral glucose tolerance test than that of KK subjects, whereas plasma glucose profiles were comparable. The Q allele was more prevalent in obese type 2 diabetics than in controls (P = 0.026; odds ratio = 1.56). Multiple regression analysis, after adjusting for age, gender, and body mass index, showed the QQ genotype to be associated with type 2 diabetes (P = 0.043; odds ratio = 2.74), but not obesity (P = 0.068). These results indicate that the PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic, contributing to both insulin resistance and type 2 diabetes.     

Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohort

Genetic susceptibility modulates the impact of obesity on the risk for type 2 diabetes. One candidate gene predisposing to type 2 diabetes is ENPP1/PC1. A common polymorphism in this protein, K121Q, is associated with insulin resistance and increased susceptibility to type 2 diabetes in Caucasian, Afro-Caribbean, and South Asian populations. The goal of this study was to evaluate differences in the prevalence of the ENPP1 121Q variant in the Caucasian, African-American, and Hispanic populations in Dallas county and to establish a population-based estimate of gene variant prevalence for future investigations. We also evaluated the association between the ENPP1 121Q variant and diabetes. The Dallas Heart Study (DHS) is a multiethnic probability-based sample of the Dallas county population in which African-Americans were systematically oversampled so that the final sample was 50% African-Americans. We performed ENPP1/PC1 genotyping in 1038 non-Hispanic Whites (544 women, 494 men), 1815 African-Americans (1052 women and 763 men), and 597 Hispanics (347 women, 250 men). The frequency of ENPP1/PC1 K121Q was higher in both African-Americans (78.5%) and Hispanics (21.9%) than in the non-Hispanic White group (13.2%). The former two groups also have a higher prevalence of type 2 diabetes (African-Americans, 14.1%, and Hispanics, 11.7%) compared to non-Hispanic Whites (6.8%). Logistic regression analysis revealed significant interactions between the ENPP1 genotype, age, and body mass index within each ethnic group. After adjustment for these variables and their interactions, ENPP1 Q allele predicted diabetes when a recessive model was tested. Ethnic differences in ENPP1 121Q allele frequency may contribute to the increased susceptibility to type 2 diabetes observed in US minority groups.     

ENPP1 K121Q polymorphism and type 2 diabetes mellitus in the Chinese population: a meta-analysis including 11,855 subjects

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) K121Q gene polymorphism has been suggested to be associated with the increased risk of developing type 2 diabetes mellitus (T2D), but relevant research results are still contradictory. To explore the relationship between ENPP1 K121Q gene polymorphism and T2D in the Chinese population, a meta-analysis was performed. Fourteen independent studies involving 11 855 subjects were retrieved from electronic databases. The pooled odds ratio (ORs) for the distribution of Q allele frequency of the ENPP1 K121Q gene and its corresponding 95% confidence interval (95% CI) were assessed using a random-effects model. Under an allelic model of inheritance, the distribution of Q allele frequency was 0.107 for the T2D group and 0.093 for the control group. The pooled OR for the distribution of Q allele frequency of ENPP1 K121Q gene was 1.29 (95% CI, 1.09-1.53; P(heterogeneity) = .006; I(2) = 55.6%). There was a significant association between ENPP1 K121Q gene polymorphism and T2D in the Chinese population (P = .003). Under a dominant model of inheritance, the KQ + QQ/KK value was 0.259 for the T2D group and 0.220 for the control group. The pooled OR for the KQ + QQ/KK value was 1.51 (95% CI, 1.20-1.91; P(heterogeneity) < .0001; I(2) = 71.8%). The association between ENPP1 K121Q gene polymorphism and T2D in the Chinese population followed a dominant model of inheritance (P = .0005). In the Chinese population, the ENPP1 K121Q gene polymorphism was implied to be involved with T2D susceptibility. People with the Q allele of the ENPP1 K121Q gene might be predisposed to T2D.     

The ENPP1 K121Q polymorphism determines individual susceptibility to the insulin-sensitising effect of lifestyle intervention

Aims/hypothesis  

The K121Q (rs1044498) single nucleotide polymorphism (SNP) in the ENPP1 gene has shown association with insulin resistance and type 2 diabetes in various ethnic populations. We hypothesised that K121Q may predict the success of lifestyle intervention in terms of improvement of insulin sensitivity.     

Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection and hepatitis C virus core antigen levels in subjects in a hyperendemic area of Japan

Background  The clinical course of chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and obesity. The K121Q polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)-1 gene and the rs7566605 genotype located near insulin-induced gene 2 have been shown to be associated with insulin resistance and obesity. This study examined whether the K121Q polymorphism in ENPP1 or the rs7566605 genotype is associated with the clinical course of HCV infection. Methods  The relationships between the clinical characteristics of 469 anti-HCV antibody-seropositive subjects (353 were positive for HCV core antigen or RNA, whereas 116 were negative for HCV RNA) and the polymorphisms were analyzed. Results  No significant differences in body mass index, plasma glucose level, serum insulin level, and other biochemical markers were observed between subgroups of subjects with different genotypes at the K121Q polymorphism or rs7566605. The frequency of the homozygous wild-type genotype at K121Q in HCV carriers, however, was significantly higher than that in subjects who were negative for HCV RNA (84.5% vs. 75.9%; P < 0.05). Moreover, in HCV carriers, HCV core antigen levels in subjects homozygous for the wild-type genotype at K121Q were significantly higher than in heterozygous carriers of K121Q (5358 fmol/l vs. 4002 fmol/l; P = 0.04). In contrast, the rs7566605 genotype was not associated with hepatitis C viremia or with the HCV core antigen level. Conclusions  The K121Q variant of ENPP1 may be associated with hepatitis C viremia and core antigen levels in HCV carriers.     

Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults

OBJECTIVE: To test for association of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) K121Q polymorphism with body mass index (BMI) and diabetes in a large sample of Caucasians and African-Americans by selectively genotyping individuals at the extremes of the phenotypic distribution. SUBJECTS: Subsets comprising the extremes of the BMI distribution (10th-20th and above the 90th BMI percentile for Caucasians and between the 10th-30th and above the 80th percentile for African-Americans) from a group of 10,260 Caucasian and 2268 African-American adults participating in New York Cancer Project were studied. METHODS: Subjects were genotyped for the ENPP1 K121Q polymorphism by pyrosequencing and tested for association with BMI and diabetes by regression analysis. RESULTS: Regression analysis with BMI as the dependent variable demonstrated a significant association (P = 0.02) of genotype at K121Q with BMI, with no significant race-by-genotype interaction (P = 0.30). Compared with Q/Q or Q/K individuals, the K/K individuals had a BMI approximately 1.3 kg/m2 higher, without effects of age, gender or race. By logistic regression analysis, the K121Q alleles had no significant effect on diabetes status (P = 0.37) in obese subjects. CONCLUSION: In both Caucasians and African-Americans, the K121 polymorphism in ENPP1 was associated with increased BMI, but not with diabetes.     

Possible role for ENPP1 polymorphism in obesity but not for INSIG2 and PLIN variants

Previous studies have suggested that ENPP1, INSIG2, and PLIN may be linked with a higher risk for obesity or with increased phenotypic measures of obesity. We selected polymorphisms in these candidate genes based on their prior associations with obesity risk or obesity parameters. K121Q (rs1044498) in ENPP1, rs7566605 in INSIG2, and rs894160 in PLIN were genotyped by Taqman assays in a Belgian sample of 1,078 obese subjects (body mass index (BMI) > 30 kg/m²) and 323 lean controls (18.5 < BMI < 25 kg/m²). BMI, waist circumference, and waist-to-hip ratio (WHR) were assessed by standard methods while a computerized tomography-scan was used to measure visceral (VFA), subcutaneous (SFA), and total (TFA) abdominal fat areas. Presence of the rare allele was not significantly different between cases and controls for the three variants that were tested, while only WHR was associated with ENPP1 in obese subjects. Our data thus indicate that K121Q, rs7566605, and rs894160 are not major contributing factors for obesity. Armand Peeters and Sigri Beckers contributed equally to this work.     

Effect of ENPP1/PC-1-K121Q and PPARgamma-Pro12Ala polymorphisms on the genetic susceptibility to T2D in the Tunisian population

Diabetes mellitus is the most common chronic metabolic disease. The raising diabetes epidemic is unfolding as an interaction between several environmental factors and a genetic predisposition. The aim of the current study was to evaluate the role of the PPARγ-Pro12Ala and ENPP1-K121Q polymorphisms on type 2 diabetes (T2D) risk in a case–control study in the Tunisian population. To assess for any association of ENPP1-K121Q and PPARγ-Pro12Ala polymorphisms with T2D risk, we analysed the genotypic and allelic distributions of each variant in the studied cohort. Our results support that the genetic variation at ENPP1-K121Q predisposes to T2D in the Tunisian population after adjustment on gender, age and BMI status (OR = 1.55, 95%CI [1.11–2.16], p = 0.007).Conversely, the PPARγ-Pro12Ala variant seems not to have a significant effect on T2D risk in our Tunisian cohort. However, the minor A-allele would convey protection against overweight in the Tunisian population. In fact, the over weighted subjects showed a significantly lower frequency of A-allele than lean controls (OR = 0.49, 95%CI [0.25–0.97], p = 0.02). In conclusion, our findings support the hypothesis that ENPP1-121Q is involved in the genetic susceptibility of T2D in the Tunisian population, while the PPARγ-12Ala allele may confer protection against overweight.     

PC-1 (ENPP1) K121Q polymorphism in overweight and obese type 2 diabetic coronary heart disease patients

AIM: The aim of the present study was to investigate the prevalence of the PC-1 121Q allele and to test its association to cardiovascular risk factors in type 2 diabetes mellitus (DM) patients. METHODS: A total of 103 unrelated Caucasians from Serbia, including 71 DM patients without CHD (aged 59.4 +/- 8.9 years, with a mean body mass index (BMI) of 33.3 +/- 4.8 kg/m2) and 32 DM patients who suffered from coronary heart disease (DM+CHD) (aged 59.3 +/- 8.0 years, with a mean BMI of 30.37 +/- 3.71 kg/m2), were genotyped for PC-1 K121Q using a mutagenic separated PCR assay. RESULTS: The prevalence of the PC-1 121Q allele was significantly higher in DM+CHD, compared to DM (P < 0.001) and control (P < 0.001) groups, since it was found in 10 (14%) DM patients, 13 (41%) DM+CHD patients and 10 (17%) control subjects.When the association of PC-1 121Q allele and the risk of suffering from CHD were assessed within the DM group in a binary logistic regression model adjusting for age and sex, PC-1 121Q allele carriers had a 76% lower risk (OR 0.24; 95% CI: 0.08-0.67, P = 0.006) for developing CHD compared to subjects who exhibited PC-1 wild-type. CONCLUSION: The prevalence of the PC-1 121Q allele was significantly higher in type 2 diabetic patients who suffered from CHD, compared to type 2 diabetic patients without CHD. However, after a binary logistic regression model analysis, adjusting for age and sex., PC-1 121Q allele carriers had a 76% lower risk (OR 0.24; 95% CI: 0.08-0.67, P = 0.006) for developing CHD compared to subjects who exhibited PC-1 wild-type. Since these data were cross-sectional, the potential patient selection and survival bias, as well as community underdiagnosis of DM and CHD, could most likely substantially underestimate the genetic influence.     

The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance.

PC-1 is a membrane glycoprotein that impairs insulin receptor function. Its K121Q polymorphism is a genetic determinant of insulin resistance. We investigated whether the PC-1 gene modulates insulin sensitivity independently of weight status (i.e. both in nonobese and obese individuals). Nondiabetic subjects [164 males, 267 females; age, 37 +/- 0.6 yr, mean +/- SEM; body mass index (BMI), 32.7 +/- 0.5 kg/m(2)], who were subdivided into 220 nonobese (BMI < or = 29.9) and 211 obese, were studied. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P < 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. Insulin sensitivity, measured by euglycemic clamp in a representative subgroup of 131 of 431 randomly selected subjects, progressively decreased (P < 0.001) from nonobese K121K [n = 61; glucose disposal (M) = 34.9 +/- 1.1 micromol/kg/min] to nonobese Q (n = 21; M = 29.9 +/- 2.0), obese K121K (n = 31, M = 18.5 +/- 1.2), and obese Q (n = 18, M = 15.5 +/- 1.2) carriers. The K121Q polymorphism was correlated with insulin sensitivity independently (P < 0.05) of BMI, gender, age, and waist circumference. In conclusion, the Q121 PC-1 variant and obesity have independent and additive effects in causing insulin resistance.     

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

Aims/hypothesis The 825C>T polymorphism in the gene encoding the G protein β3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with divergent results. Only a few association studies have investigated whether this polymorphism is related to type 2 diabetes or the metabolic syndrome. We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome. Materials and methods The GNB3 825C>T polymorphism was genotyped in 7,518 white Danish subjects using mass spectrometry analysis of PCR products. Case–control studies were undertaken for obesity, hypertension, type 2 diabetes and the metabolic syndrome, and a meta-analysis including data from the present study and previous studies of hypertension was performed. Quantitative trait studies of metabolic variables were carried out in 4,387 glucose-tolerant subjects. Results We observed minor differences in 825C>T genotype distributions for type 2 diabetes (CC/CT/TT 49/41/10% (control) vs 46/46/9% (cases), respectively, p=0.007); however, after correction for multiple testing, these were not statistically significant. No association was found with hypertension, obesity or the metabolic syndrome. Curiously, the T allele was associated with nominally lower systolic and diastolic blood pressure levels—a finding in contrast with most previous studies–but not with other metabolic variables. Meta-analysis demonstrated a high degree of heterogeneity between study populations of different ethnic origin. Although there was a tendency towards an increased risk of hypertension among 825T allele carriers, this was not statistically significant. Conclusions/interpretation The present study suggests no major involvement of the GNB3 825C>T polymorphism in components of the metabolic syndrome.     

Lack of association between the Pro<Subscript>12</Subscript>Ala polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in the Qatari consanguineous population

Peroxisome proliferators-activated receptor γ (PPARγ) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR γ2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro₁₂Ala polymorphism of PPAR γ2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case–control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro₁₂Ala polymorphism in PPAR γ2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro₁₂Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P < 0.001). In this study, no association is seen between the Pro₁₂Ala polymorphism in PPAR γ2 gene and the type2 diabetes in Qatar.     

膜糖蛋白PC-1基因K121Q多态性与2型糖尿病相关性

运用PCR-RFLP方法分析膜糖蛋白PC-1基因K121Q多态性，观察Q、K等位基因和KQ、KK基因型在正常对照组和2型糖尿病组中的分布，同时测定多种生化及临床指标。结果显示，Q等位基因与2型糖尿病有相关性，且与2型糖尿病伴肥胖、高血压、高脂血症有关。