The effect of WNT5B IVS3C>G on the susceptibility to type 2 diabetes in UK Caucasian subjects

Background and aimsThe wnt signaling pathway regulates adipogenesis and insulin secretion. The WNT5B gene has been reported to confer susceptibility to type 2 diabetes (T2D) in the Japanese population, and we therefore evaluated this in Caucasian subjects with respect to obesity status.Methods and resultsTwo thousand seven hundred and one Caucasian middle-aged men from the prospective Northwick Park Heart Study II (NPHSII) of whom 153 developed T2D over 15 years and 1268 Caucasian middle-aged patients with T2D (60% male) were genotyped using a TaqMan assay for the IVS3C > G variant (rs2270031) in the WNT5B gene. The frequency of the G allele was 0.026 (0.022–0.031) in controls and 0.031 (0.025–0.039) in patients with diabetes, p = 0.24. In the prospective analysis, G allele carriers with BMI below 26 kg/m² had significantly higher T2D hazard risk [3.46 (1.34–8.96), p = 0.01]. Comparing T2D cases with NPHSII controls, the G allele was associated with a significantly higher T2D odds ratio (OR) of 1.50 (1.06–2.12), p = 0.02 in subjects with BMI lower than 30 kg/m². Increasing BMI had a smaller effect on risk in G allele carriers. The effect on risk was not explained by genotype being associated with any classical T2D risk factor. When the combined effect of this SNP and the TCF7L2 IVS3C > T SNP (rs7903146) was evaluated, a 2.07 (1.40–3.07), p < 0.0001 fold higher OR was observed in carriers of both the rare alleles.ConclusionVariation in WNT5B predisposes to T2D in the absence of obesity. The increase in risk conferred by the presence of both WNT5B and TCF7L2 variants strengthens the role of wnt signaling in T2D.     

Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium

BackgroundCandidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ～50,000 SNPs across ～2100 candidate genes to identify genetic variants for ABI.Methods and resultsWe studied subjects of European ancestry from 8 studies (n = 21,547, 55% women, mean age 44–73 years) and African American ancestry from 5 studies (n = 7267, 60% women, mean age 41–73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI > 1.40) and PAD (defined as ABI < 0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p < 2 × 10^?6 to denote statistical significance.ResultsIn the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β = ?0.007, p = 6.02 × 10^?7) and rs290481 in TCF7L2 (β = ?0.008, p = 7.01 × 10^?7) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p = 4.99 × 10^?5) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n = 15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p = 0.75; rs290481, p = 0.19) and in the combined discovery and replication analysis the SNP–ABI associations were no longer significant (rs2171209, p = 1.14 × 10^?3; rs290481, p = 8.88 × 10^?5). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.ConclusionsGenetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.     

Obstructive sleep apnoea correlates with C-reactive protein in obese Asian Indians

BackgroundC-reactive protein (CRP), a marker of systemic inflammation, is an important predictor of future cardiovascular events. Whether the relationship of obstructive sleep apnoea (OSA) and CRP is independent of adiposity, needs to be investigated.ObjectiveTo investigate the association of CRP levels with OSA in the obese and their comparison with lean subjects without OSA in Asian Indians residing in India.Methods and resultsOne hundred and eight obese subjects (62 treatment naïve obese subjects with OSA [cases] and 46 obese subjects without OSA [obese controls]) and 26 lean control subjects without OSA were studied. The subjects were without any apparent inflammatory disease. Obese subjects were matched for body mass index (BMI) and percentage body fat (%BF). Assessment included anthropometry, lipid profile and high sensitivity CRP (hs-CRP) levels. Mean hs-CRP levels were significantly higher in cases [(3.6 ± 2.0) mg/l than in obese controls (1.4 ± 1.4) mg/l, p < 0.001)] and in lean controls [(0.93 ± 0.71) mg/l, p > 0.05].ConclusionsIn this sample of Asian Indians, subjects with OSA had significantly higher CRP levels. These levels were directly proportional to the increase in severity of OSA and it was independent of adiposity. These observations have important implications for future cardiovascular risk in Asian Indians with OSA.     

The differences in the involvements of loci of promoter region and Ile50Val in interleukin-4 receptor α chain gene between atopic dermatitis and Japanese cedar pollinosis

BackgroundAtopic dermatitis (AD) and Japanese cedar pollinosis (JCP) are common chronically allergic diseases associated with the activation of T-helper 2 cells. Recent studies have shown that polymorphisms in the genes for IL-4 receptor α chain (IL4RA) may contribute to susceptibility of AD and JCP, although the differences in the involvements of loci of IL4RA gene between AD and JCP are unclear. In this study, we investigated the role of polymorphisms in IL-4RA gene in conferring susceptibility to the development of AD and/or JCP using a family analysis and an association analysis in a Japanese population.MethodsFive polymorphisms in the IL-4RA gene, C-3223 T, T-1914C, T-890C, Ile50Val and Glu375Ala, have been genotyped using PCR-based methods in 75 trios families, including 15 AD families, 30 JCP families, and 30 families with combination of AD and JCP in the family analysis. Forty-five AD, 60 JCP and 125 control children constituted the association study.ResultsThe transmission disequilibrium test showed that the allele of Ile50 was significantly transmitted to children with JCP alone (p < 0.05). Haplotype analysis showed that the -3223 T/Ile50 haplotype was preferentially transmitted to both AD (p < 0.01) and JCP children (p < 0.01), while that the C-3223/Ile50 haplotype was preferentially transmitted to only JCP children (p < 0.01). The association study showed that -3223 T and haplotype of -3223 T/Ile50 were associated with aD children, but not with JCP. Ile50 was associated with both AD and JCP.ConclusionsOur data suggest that -3223 T and the -3223 T/Ile50 haplotype were risk factors for AD. Ile50 allele seems to be involved in both JCP and AD. Interactions of the IL-4RA loci may play a role both conferring susceptibility and modulating severity of AD.     

IL6, IL10 and TGFB1 gene polymorphisms in coeliac disease: differences between DQ2 positive and negative patients

Predisposition to coeliac disease (CD) might be partially due to an individual pattern of hyper-inflammatory biased immune response. One of these patterns of intense response may be linked to the haplotype carrying HLA-DQ2 alleles and TNF −308A allele. However, 10 % of CD patients do not express the DQ2 heterodimer and these do not usually carry the TNF −308A allele. A similar response might be achieved by genes codifying other cytokines.ObjectivesTo study biallelic polymorphisms in genes codifying for TNFα, IL10, IL6 and TGFβ1 in DQ2 negative CD patients and to compare the results with DQ2 positive patients and healthy controls, in order to establish whether any of these polymorphisms have a role in CD susceptibility.MethodsTNF −308 (G > A), IL-6 −174 (G > C) and TGFB1 codon 10 (+ 869, T > C) and codon 25 (+ 915, G > C) polymorphisms and IL-10 haplotype of polymorphisms in positions −1082 (G > A), −819 (C > T) and −592 (C > A) were typed by a SSP-PCR technique.ResultsThe distribution of allele frequencies for TNF −308 is different between DQ2 positive CD patients and controls and the same occurs for haplotype frequencies of the IL10 promoter (−1082, −819, −592): The frequencies of the TNF −308A allele (p = 0.027), TNF −308A carriers (p = 0.031) and of IL10GCC haplotype are increased (p = 0.013) in DQ2 positive CD patients. However, the IL6 −174 allele G is more frequent in DQ2 negative patients than in healthy controls (p = 0.018), DQ2 negative controls (p = 0,018), and DQ2 positive patients (p = 0.008).ConclusionsDQ2 negative CD patients show an increased frequency of genotypes associated to IL6 high production. These were mainly allele G homozygous for the IL6 gene (−174) polymorphism. The IL6 −174GG genotype (homozygous) may be an additional risk marker for CD in DQ2 negative patients, representing an alternative susceptibility factor for CD when TNF −308A is negative.     

ABCB1 haplotype is associated with major molecular response in chronic myeloid leukemia patients treated with standard-dose of imatinib

BackgroundImatinib mesylate (IM) is a selective tyrosine kinase inhibitor used for treating chronic myeloid leukemia (CML). IM has high efficacy, however some individuals develop a resistance due to impaired bioavailability. Polymorphisms in genes encoding membrane transporters such as ABCB1 have been associated with differences in protein expression and function that influence the response to several drugs.AimTo investigate the relationship of ABCB1 polymorphisms with markers of response to IM in patients with CML.MethodsOne hundred eighteen CML patients initially treated with a standard dose of IM (400 mg/day) for 18 months were selected at two health centers in Sao Paulo City, Brazil. The response criteria were based on the European LeukemiaNet recommendations. ABCB1 polymorphisms c.1236C > T (rs1128503), c.3435C > T (rs1045642) and c.2677G > T/A (rs2032582) were evaluated by PCR-RFLP.ResultsABCB1 polymorphisms were not related with a risk for CML in this sample population (p < 0.05). In the CML group, frequencies of ABCB1 SNPs were similar between responder and non-responder patients (p > 0.05). In the responder group, the frequency of ABCB11236CT/2677GT/3435CT haplotype was higher in patients with major molecular response (MMR) (51.7%) than in patients without MMR (8.3%, p = 0.010). Furthermore, carriers of this haplotype had increased the probability of reaching the MMR compared with the non-carriers (OR: 11.8; 95% CI: 1.43–97.3, p = 0.022).ConclusionsThe ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients.     

Illustrating the roles of C-reactive protein in the development of the metabolic syndrome in women--a cross-racial validation

Background and aimsThis study was designed to elucidate the role of C-reactive protein (CRP) as an inflammatory marker in the development of the metabolic syndrome (MS).Methods and resultsA total of 333 women without current medication attended an obesity-screening programme held in Yun-Lin, Taiwan. Anthropometric measurements were obtained; biochemical profiles, lipid profiles and high-sensitivity CRP (hsCRP) were measured. A structural equation model (SEM) was constructed to demonstrate that obesity might initiate the sequential pathway that leads to a pro-inflammatory state and other metabolic derangements. The results of SEM in the Taiwanese women showed that obesity was positively associated with elevated CRP (B = 0.69, p < 0.001). The pro-inflammatory state could result in insulin resistance (B = 0.57, p < 0.001), which in turn could lead to dyslipidaemia (B = 0.46, p < 0.01). The association between obesity and hypertension was positive and direct (B = 0.43, p < 0.01) without the intermediation of inflammation or insulin resistance. The implications could be reproduced when the same model was applied to the metabolic profiles of the Caucasian participants in the National Health and Nutrition Examination Survey 1999–2002.ConclusionOur study has demonstrated that obesity plays the central role in leading to hypertension and a pro-inflammatory state, insulin resistance and dyslipidaemia. The SEM has provided a comprehensive view to illustrate the complex interplay of the main components in the development of the MS, and this approach can be generalized to different populations.     

Effects of obesity, physical activity, and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance in the National Health and Nutrition Survey 1999–2002

Background and aimsThis study was designed to elucidate the effects of obesity, self-reported physical activity and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance.Methods and resultsData from 950 Caucasian subjects ranging in age from 19 to 49 years from the National Health and Nutrition Survey (NHANES), 1999–2002, were included to construct a population-based observational study. Cardiorespiratory fitness (VO₂ max) was predicted from a submaximal exercise stress test. Self-reported physical activity was measured by metabolic equivalent score transformed from a questionnaire. A structural equation model (SEM) was developed to examine the relationship between obesity, cardiorespiratory fitness, self-reported physical activity, and hypertension, inflammation, and insulin resistance. The model showed that obesity was positively linked to hypertension (B = 0.50, P < 0.001) and C-reactive protein (CRP; B = 0.15, p < 0.05), which in turn led to insulin resistance (B = 0.44, P < 0.05). Increased cardiorespiratory fitness was negatively associated with CRP (Γ = ?0.23, P < 0.01), but not correlated to hypertension after adjustment for potential confounding factors. No significant association was found between self-reported physical activity and hypertension, insulin resistance, and CRP.ConclusionObesity contributes to the development of hypertension, inflammation, and insulin resistance. Improved cardiorespiratory fitness might lead to clinical and biochemical improvement in insulin resistance by reducing the inflammatory state.     

Proinflammatory cytokines and cardiac abnormalities in uncomplicated obesity: relationship with abdominal fat deposition

Background and aimObesity can be considered a state of chronic, low-grade inflammation. Particularly, visceral adipose tissue (VAT) seems to be an active compartment in pro-inflammatory molecule secretion. The possible existence of a correlation between circulating cytokines, their soluble receptors, abdominal fat accumulation and echocardiographic abnormalities in uncomplicated obesity was investigated.Methods and resultsEchocardiographic parameters, C-reactive protein (CRP), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6-R), tumor necrosis factor-α (TNF-α) and soluble TNF receptor I (TNFR-I) were assessed in 27 normotensive obese women (age 33.3 ± 8.3 years; BMI 43.5 ± 4.8 kg/m²) and 15 normal-weight controls (age 36.8 ± 8.2 years; BMI 22.6 ± 1.7 kg/m²). VAT was assessed by CT. The obese patients had higher serum IL-6 (p < 0.01), sIL-6-R (p < 0.0001), sIL-6-R/IL-6 complex (p < 0.05), TNF-α (p < 0.02), sTNF-α-RI (p < 0.03) and CRP (p < 0.0001) levels than normal women. Moreover, end-diastolic septum thickness (SW), end-diastolic posterior wall thickness (PW), absolute and indexed left ventricular mass, deceleration time (DT), myocardial performance index (MPI) and isovolumetric relaxation time (IVRT) were correlated with sIL-6-R, sIL-6-R/IL-6 complex and CRP levels. Interestingly, sIL-6-R, sIL-6-R/IL-6 complex, CRP, SW, PW, DT and MPI were higher in patients with a VAT area >130 cm² than those with <130 cm².ConclusionIn normotensive obese women several pro-inflammatory molecules correlate with both echocardiographic abnormalities and the amount of intra-abdominal fat; these results may support a role for visceral fat in predisposing to cardiac dysfunction, possibly through a low-grade state of inflammation.     

Akt2 Gene common allelic variants in insulin resistance and the metabolic syndrome

Background and aimSeveral lines of evidence indicate that glucose homeostasis may be under the control of Akt2 and it can therefore be seen as a candidate gene for human insulin resistance (IR) and related phenotypes. The aim of our study was the identification of Akt2 common allelic variants that might modulate susceptibility to IR and related metabolic abnormalities.Methods and resultsThe Akt2 gene (exons, 5′ and 3′ regulatory regions) was re-sequenced in samples of 50 blood donors from the Gargano region. Two single nucleotide polymorphisms (SNPs) in 5′ (rs11669332 and rs969531) and two in 3′ (rs2304186 and C1658T) regulatory regions were exploited in an association study using 661 healthy unrelated Caucasian individuals from the same region.Individuals being homozygous for the T allele of rs11669332 (an Akt2 promoter) showed lower systolic blood pressure (p = 0.04), total/HDL cholesterol ratio (p = 0.02) and the metabolic syndrome score (p = 0.04), while carriers of the A allele of rs969531 (in 5′-UTR) showed higher systolic blood pressure (p = 0.027). The association between phenotypic traits and possible haplotypes was tested as well. However, no haplotype affecting the risk of metabolic abnormalities was found.ConclusionsTwo variants in 5′ regulatory region of Akt2 gene are associated and may modulate susceptibility to IR and related metabolic abnormalities.     

CRP and CD14 polymorphisms correlate with coronary plaque volume in patients with coronary artery disease--IVUS substudy of the ENCORE trials

BackgroundSeveral proinflammatory single-nucleotide polymorphisms (SNPs) have been linked to the progression of atherosclerosis and coronary artery disease (CAD). Plaque size and its destabilization by inflammatory processes are major determinants of ischemia and acute coronary syndromes. Intravascular ultrasound (IVUS) allows for quantification of plaque size in vivo. We therefore investigated the relation of plaque size with mutations of proinflammatory genes in patients with CAD.MethodsIn 196 patients with stable CAD enrolled in the ENCORE trials coronary plaque and vessel volume was assessed by IVUS. 173 patients were successfully genotyped for polymorphisms of proinflammatory genes CD14 C(?260)T and CRP C(+1444)T using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach.ResultsBaseline characteristics were comparable for all genotype groups. Higher ratios of plaque volume/vessel volume were observed in patients with the CRP 1444TT (n = 11) and CD14 260TT (n = 33) genotypes (p = 0.016 and p = 0.026, respectively).ConclusionIn patients with stable coronary artery disease the CRP 1444TT and CD14 260TT variants are associated with larger coronary plaque volume independently of concomitant cardiovascular risk factors.     

Orlistat and sibutramine beyond weight loss

Background and aimTo investigate, through a meta-analysis of clinical trials, the effect of two weight-reducing drugs, such as orlistat and sibutramine, on serum lipid profiles in overweight and obese subjects, independently of weight loss.MethodsA systematic search strategy, incorporating the terms orlistat, sibutramine, fat, cholesterol, lipid profile, cardiovascular risk, was developed to identify randomized trials in MEDLINE from inception to the end of May 2005. Trial selection was limited by language of publication (English) and duration (6–12 months).ResultsFifteen and ten randomized, double-blind, placebo-controlled trials on orlistat and sibutramine respectively, were eligible for inclusion. In the 15 trials with orlistat, mean weight loss showed a significant correlation with mean reduction of total cholesterol (r = 0.48; p < 0.05), which maintained statistical significance after adjustment for mean weight loss (B = −2.81 ± 1.28; p < 0.05). Conversely, in the ten trials with sibutramine, treatment was not associated with a significant decrease in cholesterol levels after adjustment for weight loss (B = 3.25 ± 4.13; p not significant).ConclusionOrlistat or sibutramine, when individually compared to placebo, are effective in promoting significant weight loss. In addition, orlistat determines a significant reduction of total cholesterol, independent of weight loss itself. These observations indicate that orlistat is a useful adjunctive tool for improving cardiovascular risk factor profiles in overweight and obese patients.     

Association of genetic variability in selected regions in visfatin (NAMPT) gene with anthropometric parameters and dietary composition in obese and non-obese Central-European population

AimsVisfatin (NAMPT/PBEF) is a recently identified adipocytokine which harbors strong insulin-mimetic activity and was reported to be associated with obesity. However, nothing is known about whether visfatin is related to specific nutritional behavior which may result in obesity development. This is the first study focusing on genetic variability of the visfatin gene and its association with circulating visfatin, anthropometric parameters and dietary composition.Materials and MethodsWe analyzed a total of 11 exons and adjacent non-coding regions of the NAMPT gene in 20 extremely obese Czech individuals (mean BMI 52.2 ± 5.0 SD) using direct sequencing and a frequency of rs2302559 was established in the validation cohort of another 605 individuals with completed 7-day food records and complex anthropometric measurements. Serum levels of visfatin, leptin and leptin-receptor were measured in all sequenced individuals and in part of the validation cohort.ResultsThree common polymorphisms were identified, two in non-coding regions (rs78411774 A/C, rs71564769 A/C) and one synonymous SNP in exon 7 (rs2302559 A/G). The rs2302559 showed significant correlation with visfatin serum level throughout the entire study cohort (p < 0.001); there was a significant tendency toward higher visfatin levels in G allele carriers with GG homozygotes having the highest visfatin serum levels. Furthermore, a negative correlation was observed between visfatin and leptin serum level (p = 0.01). No association between investigated SNPs and anthropometric parameters or native dietary composition was observed.ConclusionThis is the first study to demonstrate that the rs2302559 polymorphism in the PBEF gene is related to circulating levels of visfatin. As the SNP is synonymous, we hypothesize it might be linked to another SNP in the PBEF gene which controls visfatin serum levels.     

Serum IGF-I and C-reactive protein in healthy black and white young men: The CARDIA male hormone study

ObjectiveAnimal and human studies suggest that C-reactive protein (CRP) may be inversely associated with serum insulin-like growth factor-I (IGF-I) concentrations. However, most human studies have not controlled adequately for confounding factors, particularly nutritional intake. This population-based study examined whether CRP is inversely associated with IGF-I and IGFBP-3 concentrations.MethodsIn cross-sectional analysis, multivariable linear regression with adjustment for age, BMI, smoking status, alcohol intake, and nutritional factors was used to relate log CRP, the independent variable, to IGF-I and IGFBP-3 in a sample of black (n = 364) and white men (n = 486) separately by race.ResultsOnly black men had positive findings: log CRP was significantly associated with IGF-I (β = ?13.1 ng/ml, p = 0.02) and the difference in mean IGF-I concentrations between the highest and lowest quartiles of CRP was 26 ng/ml. There was a statistically significant interaction between log CRP and smoking status (p = 0.02); the regression coefficient for IGF-I predicted from log CRP was significant in smokers (β = ?39.8 ng/ml, p = 0.0001), but not in non-smokers. The difference in mean IGF-I concentrations between highest and lowest quartiles of CRP was 100 ng/ml for black smokers. There were no associations for IGFBP-3.ConclusionsIn our study, CRP levels are inversely associated with IGF-I concentrations in black male smokers; however, the causal nature of the association is unclear and should be studied further.     

Thioredoxin interacting protein genetic variation is associated with diabetes and hypertension in the Brazilian general population

ObjectiveTo investigate the relationship between TXNIP polymorphisms, diabetes and hypertension phenotypes in the Brazilian general population.MethodsFive hundred seventy-six individuals randomly selected from the general urban population according to the MONICA-WHO project guidelines were phenotyped for cardiovascular risk factors. A second, independent, sample composed of 487 family-trios from a different site was also selected. Nine TXNIP polymorphisms were studied. The potential association between TXNIP variability and glucose-phenotypes in children was also explored. TXNIP expression was quantified by real-time PCR in 53 samples from human smooth muscle cells primary culture.ResultsTXNIP rs7211 and rs7212 polymorphisms were significantly associated with glucose and blood pressure related phenotypes. In multivariate logistic regression models the studied markers remained associated with diabetes even after adjustment for covariates. TXNIP rs7211 T/rs7212 G haplotype (present in approximately 17% of individuals) was significantly associated to diabetes in both samples. In children, the TXNIP rs7211 T/rs7212 G haplotype was associated with fasting insulin concentrations. Finally, cells harboring TXNIP rs7212 G allele presented higher TXNIP expression levels compared with carriers of TXNIP rs7212 CC genotype (p = 0.02).ConclusionCarriers of TXNIP genetic variants presented higher TXNIP expression, early signs of glucose homeostasis derangement and increased susceptibility to chronic metabolic conditions such as diabetes and hypertension. Our data suggest that genetic variation in the TXNIP gene may act as a “common ground” modulator of both traits: diabetes and hypertension.     

Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15

ObjectiveIndividual propensity to chronic, low-grade inflammation—a determinant of atherosclerosis-is in part under the control of genetic factors. To identify genes involved in this modulation, we performed a 10 cM genome screen for linkage with plasma C-reactive protein in 38 extended families including 317 non-diabetic and 177 type 2 diabetic family members (2547 relative pairs).Methods and resultsIn a variance component analysis, heritability of CRP values was significant (h² = 0.39, p < 0.0001). This effect was independent of BMI and was present in both diabetic (h² = 0.42, p = 0.003) and non-diabetic (h² = 0.34, p = 0.0015) relatives. The strongest evidence of linkage with CRP was on chromosome 5p15, where the LOD score reached genome-wide significance (LOD = 3.41, genome-wide p = 0.013). Both diabetic and non-diabetic family members contributed to linkage at this location. Smaller linkage peaks were detected on chromosomes 5q35 (LOD = 1.35) and 17p11 (LOD = 1.33). When the analysis was restricted to diabetic family members, another peak of moderate intensity (LOD = 2.17) was evident at 3p21.ConclusionsA major gene influencing CRP levels appears to be located on chromosome 5p15, with an effect that is independent of diabetes. Another gene on 3p21 may control CRP variation but only in the presence of a diabetic or insulin-resistant environment.     

The relationship of gamma-glutamyltransferase to C-reactive protein and arterial stiffness

Background and aimsThe relationships between γ-glutamyltransferase (GGT), C-reactive protein (CRP), and arterial stiffness have not been fully investigated. The aim of this study was to clarify whether serum GGT is related to CRP and arterial stiffness estimated using brachial-ankle pulse wave velocity (baPWV).Methods and resultsThe subjects were 3412 males and 854 females. GGT, CRP, baPWV, and conventional risk factors were evaluated. On multiple regression analysis, after adjustment for the conventional risk factors, log GGT was significantly associated with log CRP in male and female subjects (male subjects: beta = 0.168, p < 0.0001; female subjects: beta = 0.098, p < 0.05). After adjustment for the conventional risk factors, log GGT was significantly associated with PWV in male subjects (beta = 0.060, p < 0.0001), but in female subjects, no significant relationships were found after adjustment (beta = 0.007, p = 0.82).ConclusionThese results suggest that GGT is independently associated with an increased level of CRP in both males and females. In addition, in males, GGT is related to an increased level of arterial stiffness.     

Lack of replication of common EXT2 gene variants with susceptibility to type 2 diabetes in Lebanese Arabs

ObjectiveRecent genome-wide association studies and replication analyses have reported the association of variants of the exostosin-2 (EXT2) gene and risk of type 2 diabetes mellitus (T2DM) in some populations, but not in others. This study investigated the associations of EXT2 variants rs1113132, rs3740878 and rs11037909 with T2DM in a Lebanese Arab population.MethodsThis case-control study involved 995 T2DM patients and 1076 control subjects. Genotyping was done by the allelic exclusion method.ResultsWhile minor allele frequencies (MAFs) of rs11037909 (P = 0.028) and rs3740878 (P = 0.048), but not rs1113132 (P = 0.841), were higher in patients, this was lost after correcting for multiple testing. Apart from EXT2 rs1113132, which was marginally associated with T2DM in the additive model (P = 0.054), but not after adjustment for covariates, none of the tested EXT2 SNPs were associated with T2DM in any of the genetic models tested. However, variable associations of EXT2 variants with T2DM were noted according to BMI status. While the three tested EXT2 variants were not associated with T2DM in obese subjects, rs1113132 and rs11037909, but not rs3740878, were associated with T2DM in non-obese subjects. Meta-analysis revealed a significant association of rs11037909 and a marginal association of rs3740878 with T2DM in the fixed model. Using a common (GTA) haplotype as reference, three-locus (rs1113132/rs11037909/rs3740878) haplotype analysis demonstrated no association between any of the EXT2 haplotypes with T2DM, not even before correcting for multiple testing.ConclusionThis study demonstrated no association of rs1113132, rs3740878 and rs11037909 EXT2 variants with T2DM.     

Single polymorphism nucleotide rs1333049 on chromosome 9p21 is associated with carotid plaques but not with common carotid intima-media thickness in older adults. A combined analysis of the Three-City and the EVA studies

ObjectivesTo address the relationship of rs1333049, the 9p21 variant showing the strongest association with coronary heart disease (CHD), with carotid plaques and plaque-free common carotid artery intima-media thickness (CCA-IMT) in older adults from 2 French population-based cohorts.MethodsWe genotyped for rs1333049, 4097 CHD-free participants including 3191 aged 65–86 years from the Three-City (3C) Study and 906 aged 59–71 years from the Vascular Aging Study (EVA). Plaque-free mean CCA-IMT and the presence of carotid plaques were assessed.ResultsIn multivariate analysis, each C allele copy of rs1333049 was associated with baseline carotid plaques (odds ratio (OR) = 1.24; 95% confidence interval (CI) = 1.13–1.36; p < 0.001) but not with baseline CCA-IMT (p = 0.19). Among the EVA participants, the C allele was associated with 4-year plaques progression (p = 0.04) but not with CCA-IMT progression.ConclusionThe chromosome 9p21 locus might influence CHD risk through carotid plaques development.     

A study in three European IBD cohorts confirms that the ATG16L1 c.898A > G (p.Thr300Ala) variant is a susceptibility factor for Crohn’s disease

Background and aimsA recent study reported that a nonsynonymous SNP rs2241880 (c.898A > G, p.Thr300Ala) within ATG16L1 confers susceptibility to Crohn's disease (CD). We analyzed ATG16L1 c.898A > G in three independent European inflammatory bowel disease (IBD) cohorts from Germany, Hungary and the Netherlands.MethodsIn total, we included 910 European IBD patients and compared the ATG16L1 c.898A > G genotype frequency with 707 ethnically matched healthy controls. We included patients from 3 populations originating from Germany (CD n = 310; ulcerative colitis [UC] n = 179), Hungary (CD n = 147; UC n = 117), and the Netherlands (CD n = 157). Subtyping analysis was performed in respect to CARD15 alterations and clinical characteristics.ResultsWe found a highly significant association of c.898A > G to CD. The association was significant (p = 0.0005) for the total CD cohort but also for the individual populations from Germany (p = 0.02) and Netherlands (p = 0.02) whereas in the Hungarian CD patients a clear trend was observed (p = 0.19; OR 1.227, 95% CI 0.910; 1.654). No association was found between c.898A > G and UC. No statistical interactions were observed between ATG16L1 c.898A > G and CARD15 variants. Furthermore no association to a CD subphenotype was detected.ConclusionsWe confirm that ATG16L1 variant c898A > G confers a risk variant for CD but is not associated with a distinct CD phenotype.