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.     

Different prognostic value of white blood cell subtypes in patients with acute cerebral infarction

ObjectiveWe aimed to investigate the relationship of each white blood cells (WBC) subtype with neurologic severity and outcome in acute stroke.MethodsWe included 779 patients with first-ever acute cerebral infarction within 72 h after symptom onset. We investigated the association between counts for WBC subtypes in peripheral blood at admission and (1) initial stroke severity; (2) early change in stroke severity within one week; and (3) functional outcome at three months.ResultsHigher total WBC and neutrophil counts were associated with more severe stroke at admission (p < 0.001). In contrast, lower lymphocyte counts were associated with a lesser improvement during the first week after admission (p < 0.05) and with poor functional outcome at three months (OR = 0.706 per 1000 lymphocyte counts/mm³, p = 0.020).ConclusionsOur study merits further investigation on the role of each WBC subtype in ischemic injury and different prognostic value of WBC subtypes measured at admission in acute stroke.     

FADS gene polymorphisms in Koreans: association with ω6 polyunsaturated fatty acids in serum phospholipids, lipid peroxides, and coronary artery disease

ObjectiveWe investigated the association of polymorphisms in FADS genes with polyunsaturated fatty acids (PUFAs) in serum phospholipids, lipid peroxides, and coronary artery disease (CAD) in Koreans.MethodsIn this case–control study, CAD patients (n = 756, 40–79 years) and healthy controls (n = 890) were genotyped for rs174537 near FADS1 (FEN1 rs174537G > T), FADS2 (rs174575, rs2727270), and FADS3 (rs1000778). We calculated the odds ratios (ORs) for CAD risk and measured serum PUFA composition and lipid peroxide.ResultsAmong four SNPs, only rs174537G > T differed in allele frequencies between controls and CAD patients after adjustment for age, BMI, cigarette smoking, alcohol consumption, hypertension, diabetes mellitus, and hyperlipidemia (P = 0.017). The minor T allele was associated with a lower risk of CAD [OR 0.75 (95%CI 0.61–0.92), P = 0.006] after adjustment. rs174537T carriers had a significantly higher proportion of linoleic acid (LA, 18:2ω6), lower arachidonic acid (AA, 20:4ω6), and lower ratios of AA/dihomo-γ-linolenic acid (DGLA, 20:3ω6) and AA/LA than G/G subjects in both control and CAD groups. In the control group, 174537T carriers had significantly lower levels of total- and LDL-cholesterol, malondialdehyde, and ox-LDL. In CAD patients, rs174537T carriers showed a larger LDL particle size than G/G subjects. The proportion of AA in serum phospholipids positively correlated with LDL-cholesterol, ox-LDL, and malondialdehyde in controls and with 8-epi-prostaglandin F_2α in both control and CAD groups.ConclusionThe rs174537T is associated with a lower proportion of AA in serum phospholipids and reduced CAD risk, in association with reduced total- and LDL-cholesterol and lipid peroxides.     

High-density lipoprotein-cholesterol and risk of stroke and carotid atherosclerosis: a systematic review

Background and purposeEpidemiological studies have found no relationship between total cholesterol and stroke risk, but little attention has been paid to high-density lipoprotein-cholesterol (HDL-C).MethodsWe performed a systematic PubMed literature search for epidemiological studies that examined the association between HDL-C level and stroke or carotid intima-media thickness (IMT).ResultsWe identified 18 studies on the relationship between HDL-C and stroke risk and 37 on HDL-C and carotid IMT. Eight of ten prospective cohort studies (n = 238 739) and three of eight case–control studies (n = 3604 cases, 8220 controls) supported an association between elevated HDL-C level and decreased risk of stroke. Prospective cohort studies reporting on relative risk per unit increase in HDL-C showed an 11–15% decreased stroke risk per 10-mg/dl increase in HDL-C. Of 37 studies on carotid IMT, 31 reported cross-sectional, one longitudinal, and five both cross-sectional and longitudinal associations between HDL-C level and carotid IMT. Of 36 cross-sectional studies (n = 51 288), 20 showed an inverse association between HDL-C level and carotid IMT. Of six longitudinal studies (n = 20 065), three showed no association, one showed a weak association in a subgroup of white women and two showed a significant inverse relationship between HDL-C level and carotid IMT. Pooled estimates could not be calculated because of the variation in study designs and analysis.ConclusionsThe weight of evidence in the literature supports an inverse association between HDL-C level and stroke or carotid atherosclerosis, but more data are needed to firmly establish this protective effect.     

Endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives of diabetic patients are independent of the metabolic syndrome

Background and aimThe aim of the present study was to investigate endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives (offspring) of diabetic subjects and to explore the relationship with the metabolic syndrome and its components.Methods and resultsForty-five healthy normotensive normoglycemic subjects (aged 18–42 years), 29 first-degree relatives of diabetic subjects (FDR) and 16 with no parental history of type 2 diabetes mellitus were studied. Endothelial function was measured as flow-mediated dilation of the brachial artery (FMD) and arterial stiffness as carotid-femoral pulse wave velocity (PWV). Insulin resistance was calculated by homeostasis model assessment (HOMA). Plasma levels of inflammation markers (hsCRP, TNF-α, IL-1β, CD40L, VCAM, and ICAM) were evaluated.Normotensive normoglycemic FDR presented a 33% lower flow-mediated dilation than the control group (9.8 ± 5.2 vs. 16.2 ± 7.6%, p < 0.01). FMD was reduced in FDR, with or without insulin resistance, whereas arterial stiffness was significantly increased only in FDR with insulin resistance. To investigate the role of FDR status independently of altered components of the metabolic syndrome, subjects with no altered components of the metabolic syndrome were compared according to their FDR status: FDR subjects with no altered components of the metabolic syndrome presented a blunted endothelial function (lower FMD: 11.2 ± 1.6 vs. 16.8 ± 2.0%, p < 0.05) and stiffer large arteries (higher PWV: 9.6 ± 0.3 vs. 8.8 ± 0.3 m/s, p < 0.05) than controls.ConclusionNormoglycemic first-degree relatives of diabetic subjects have blunted endothelial function and increased stiffness of the large arteries. These alterations are already present at a very young age, before any alteration in glycemic control or blood pressure values can be detected, and are independent of the presence of the metabolic syndrome and its altered components.     

Influence of the CYP2J2 Gene Polymorphisms on Chronic Obstructive Pulmonary Disease Risk in the Chinese Han Population

IntroductionCytochrome P450 (CYP) 2J2 is a major enzyme that controls epoxyeicosatrienoic acids biosynthesis, which may play a role in chronic obstructive pulmonary disease (COPD) development. In this study, we aimed to assess the influence of CYP2J2 polymorphisms with COPD susceptibility.Material and methodsA case–control study enrolled 313 COPD cases and 508 controls was to investigate the association between CYP2J2 polymorphisms and COPD risk. Agena MassARRAY platform was used to genotype CYP2J2 polymorphisms. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the association between CYP2J2 polymorphisms and COPD risk.ResultsWe observed rs11207535 (homozygote: OR = 0.08, 95%CI = 0.01–0.96, p = 0.047; recessive: OR = 0.08, 95%CI = 0.01–0.94, p = 0.044), rs10889159 (homozygote: OR = 0.08, 95%CI = 0.01–0.92, p = 0.043; recessive: OR = 0.08, 95%CI = 0.01–0.90, p = 0.040) and rs1155002 (heterozygote: OR = 1.63, 95%CI = 1.13–2.36, p = 0.009; dominant: OR = 1.64, 95%CI = 1.15–2.35, p = 0.006; additive: OR = 1.45, 95%CI = 1.09–1.92, p = 0.011) were significantly associated with COPD risk. Allelic tests showed T allele of rs2280274 was related to a decreased risk of COPD and T allele of rs1155002 was associated with an increased COPD risk. Stratified analyses indicated the effects of CYP2J2 polymorphisms and COPD risk were dependent on gender and smoking status (p < 0.05). Additionally, two haplotypes (A_rs11207535C_rs10889159T_rs1155002 and A_rs11207535C_rs10889159C_rs1155002) significantly decreased COPD risk.ConclusionIt suggested CYP2J2 polymorphisms were associated with COPD susceptibility in the Chinese Han population.     

Temporal profile and prognostic value of Lp-PLA2 mass and activity in the acute stroke setting

BackgroundLp-PLA2 is a novel biomarker in cardiovascular diseases due to its ability to predict first-ever and recurrent stroke. Little information is known regarding its influence on early outcome after stroke.ObjectivesWe aimed to investigate Lp-PLA2 in t-PA-treated stroke patients and to study its relationship with early outcome.MethodsLp-PLA2 mass and activity were measured in 135 healthy controls and also in stroke patients treated with t-PA at baseline (n = 99) and serially thereafter (n = 34) by means of the PLAC test at an automated Olympus analyzer and by a colorimetric activity method (diaDexus). NIHSS scores and TCD recordings were also obtained serially. Outcome was defined according to early neurological status, the presence of arterial recanalization and functional outcome at third month.ResultsLp-PLA2 mass was increased as compared to controls, whereas Lp-PLA2 activity was significantly decreased at baseline as compared with controls and with 1 and 24 h determinations. Lp-PLA2 mass and activity were not related with early (48 h) neurological status. Regarding recanalization, higher mass and activity were found among patients who did not achieve complete recanalization by the end of t-PA treatment (p = 0.029 for mass, p = 0.044 for activity). Lp-PLA2 mass and the existence of a proximal occlusion at baseline were the most powerful predictors for persistent occlusions (OR for proximal occlusion 6.8. p = 0.036, OR for Lp-PLA2 mass 7.2 per standard deviation increase, p = 0.008).ConclusionsSignificant changes in Lp-PLA2 concentrations occur early after stroke onset. Lp-PLA2 mass may add relevant information regarding early arterial recanalization in intravenous t-PA-treated stroke patients.     

Low ankle-brachial index predicts early risk of recurrent stroke in patients with acute cerebral ischemia

ObjectiveLow Ankle-Brachial Blood Pressure Index (ABI) identifies patients with symptomatic and asymptomatic peripheral arterial disease (PAD). We sought to investigate the association of low ABI with early risk of stroke recurrence in patients with acute cerebral ischemia (ACI) and without history of symptomatic PAD.MethodsConsecutive patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) and no previous history of PAD were prospectively evaluated with ABI measurements. Demographic characteristics, vascular risk factors and secondary prevention therapies were documented. An ABI ≤0.90 in either leg was considered as evidence of asymptomatic PAD, and an ABI >0.90 was considered as normal. Patients with elevated ABI (>1.30) were excluded. The outcome of interest was recurrent stroke during 30-day follow-up.ResultsA total of 176 patients with acute cerebral ischemia (mean age 64 ± 14 years, 59.1% men, 76.7% AIS) were evaluated. Asymptomatic PAD was detected in 14.8% (95%CI: 10.2–20.8%) of the studied population. The following factors were independently associated with low ABI on multivariate logistic regression models, after adjustment for potential confounders: coronary artery disease (p = 0.008), diabetes mellitus (p = 0.017) and increasing age (p = 0.042). The cumulative 30-day recurrence rate was higher in patients with low ABI (19.2%; 95%CI: 4.1–34.3) compared to the rest (3.3%; 95%CI: 0.4–6.2%; p = 0.001). Atherothrombotic stroke (ASCO grade I; p < 0.001), increasing age (p = 0.002) and low ABI (p = 0.004) were independent predictors of stroke recurrence on multivariate Cox regression models adjusting for confounders.ConclusionsLow ABI appears to be associated with a higher risk of early recurrent stroke in patients with ACI and no history of symptomatic PAD.     

KCNK17 genetic variants in ischemic stroke

BackgroundGenetic factors contribute to the development of ischemic stroke (IS). In order to identify susceptibility variants, we analyzed single nucleotide polymorphisms (SNPs) that had been previously linked to stroke in a genome-wide association study.MethodsWe analyzed 12 SNPs in a White population comprising IS patients and healthy controls. The analysis was adjusted for confounding variables and stratified by stroke etiology. Functional studies were then performed to elucidate the role of these variants in IS.ResultsIn a preliminary analysis of 268 controls and 531 IS cases, the rs10947803 SNP of KCNK17 (p = 0.012) and the rs7506045 of IMPA2 (p = 0.040) were associated with IS, although only the KCNK17 gene was an independent risk factor for IS. In a second phase, analysis of 271 new IS cases revealed that the A allele of rs10947803 was associated with stroke after correction for Bonferroni (OR = 1.48; 95% CI, 1.14–1.91, p = 0.003). Gene expression analysis revealed that KCNK17 mRNA levels were higher in the IS cases in the acute phase than in controls (14 ± 78% vs. 91 ± 41, p = 0.002) but not in the chronic phase (56 ± 57%; p = 0.230). Moreover, RNA levels depended on the alleles of the rs10947803 SNP in the control group (p = 0.021) and in the chronic phase (p = 0.033).ConclusionsThe A allele of the rs10947803 variant of KCNK17 was associated with increased risk of IS and increased levels of KCNK17 gene expression. The role of this potassium channel gene in IS opens diagnostic and therapeutic expectations and merits further investigation.     

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.     

Association of a single nucleotide polymorphism of the NPR3 gene promoter with early onset ischemic stroke in an Italian cohort

BackgroundNPR3, located on human chromosome 5 (5p14–p13), encodes the natriuretic peptide receptor type C (NPR-C) that is mainly known as the natriuretic peptide clearance receptor. Involvement of NPR3 in susceptibility to cardiovascular diseases, i.e. hypertension, has been previously shown. With regard to stroke predisposition, evidence for a potential role of genetic variation within or nearby NPR3 has been suggested by a previous genome wide association study.MethodsWe investigated the contribution to early-onset ischemic stroke susceptibility of the NPR3 ? 55 C > A transition by genotyping this variant in an Italian cohort of 368 cases and 335 controls.ResultsIn a multivariable logistic regression analysis adjusting for age, gender, hypertension, hypercholesterolemia, smoking habit and diabetes, a significant association of the ? 55 AA genotype with stroke was observed (OR = 3.2, 95% CI 1.2–8.3, p = 0.016). Remarkably, the polymorphism remained associated with stroke after adjusting for hypertensive status.ConclusionOur observation obtained in an Italian cohort of early onset ischemic strokes suggests that a NPR3 promoter gene variant could have a role on cerebrovascular disease susceptibility.     

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.     

IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy

ObjectiveThe IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to type 1 diabetes (T1D), type 2 diabetes (T2D) and diabetic nephropathy (DN). Its protein functionally binds to 5’-UTR of the imprinting IGF2 gene. The present study aims to evaluate the IGF2BP2-IGF2 genetic effects in diabetes and DN.Materials and MethodsThree cohorts including T1D with and without DN (n = 1139) of European descents from the GoKinD study, Swedish T1D with and without DN (n = 303) and Czech control subjects without diabetes, T1D, T2D with and without DN (n = 1418) were enrolled in TaqMan genotyping experiments for IGF2BP2 rs4402960 and IGF2 rs10770125. Igf2bp2 gene expression in kidney tissues of db/db and control mice at the ages of 5 and 26 weeks was examined with real time RT-PCR and Western blot.ResultsAn association of IGF2BP2 rs4402960 with T2D in the Czech population was replicated. This IGF2BP2 polymorphism (P = 0.037, OR = 0.69 95% CI 0.49–0.98) was found to be associated with DN in male not in female patients with T1D selected from the GoKinD study. In the analyses of combined the GoKinD, Czech and Swedish populations, the association between IGF2BP2 polymorphism and DN in male patients with T1D was still significant (P = 0.030, OR = 0.73, 95% CI 0.54–0.97). IGF2 rs10770125 was also associated with DN in male T1D patients of the GoKinD population (P = 0.038, OR = 0.67 95% CI 0.46–0.98). There might be a genetic interaction between IGF2BP2 and IGF2 (P = 0.05). The Igf2bp2 gene expression levels were increased in the kidneys of db/db mice compared to controls at the age of 5 weeks but not at 26 weeks.ConclusionsThe present study has replicated the association of IGF2BP2 rs4402960 with T2D in the Czech population and provided data suggesting that IGF2BP2 may have genetic interaction with IGF2 with a protective effect against DN in male patients with T1D.     

Annexin A5 prevents post-interventional accelerated atherosclerosis development in a dose-dependent fashion in mice

BackgroundActivated cells in atherosclerotic lesions expose phosphatidylserine (PS) on their surface. Annexin A5 (AnxA5) binds to PS and is used for imaging atherosclerotic lesions. Recently, AnxA5 was shown to inhibit vascular inflammatory processes after vein grafting. Here, we report a therapeutic role for AnxA5 in post-interventional vascular remodeling in a mouse model mimicking percutaneous coronary intervention (PCI).Methods and resultsAssociations between the rs4833229 (OR = 1.29 (CI 95%), p_allelic = 0.011) and rs6830321 (OR = 1.35 (CI 95%), p_allelic = 0.003) SNPs in the AnxA5 gene and increased restenosis-risk in patients undergoing PCI were found in the GENDER study. To evaluate AnxA5 effects on post-interventional vascular remodeling and accelerated atherosclerosis development in vivo, hypercholesterolemic ApoE^?/? mice underwent femoral arterial cuff placement to induce intimal thickening. Dose-dependent effects were investigated after 3 days (effects on inflammation and leukocyte recruitment) or 14 days (effects on remodeling) after cuff placement. Systemically administered AnxA5 in doses of 0.1, 0.3 and 1.0 mg/kg compared to vehicle reduced early leukocyte and macrophage adherence up to 48.3% (p = 0.001) and diminished atherosclerosis development by 71.2% (p = 0.012) with a reduction in macrophage/foam cell presence. Moreover, it reduced the expression of the endoplasmic reticulum stress marker GRP78/BiP, indicating lower inflammatory activity of the cells present.ConclusionsAnxA5 SNPs could serve as markers for restenosis after PCI and AnxA5 therapeutically prevents vascular remodeling in a dose-dependent fashion, together indicating clinical potential for AnxA5 against post-interventional remodeling.     

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.     

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.     

Gene-nutrient interactions and gender may modulate the association between ApoA1 and ApoB gene polymorphisms and metabolic syndrome risk

ObjectiveDyslipidemia is a key feature of the metabolic syndrome (MetS), which is determined by both genetic and dietary factors.MethodsWe determined the relationships between ApoA1 and ApoB polymorphisms and MetS risk, and whether dietary fat modulates this in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754).ResultsApoB rs512535 and ApoA1 rs670 major G allele homozygotes had increased MetS risk (OR 1.65 [CI 1.24, 2.20], P = 0.0006; OR 1.42 [CI 1.08, 1.87], P = 0.013), which may be, partly, explained by their increased abdominal obesity and impaired insulin sensitivity (P < 0.05) but not dyslipidemia. Interestingly these associations derived primarily from the male GG homozygotes (ApoB rs512535 OR 1.92 [CI 1.31, 2.81], P = 0.0008; ApoA1 rs670 OR 1.50 [CI 1.05, 2.12], P = 0.024). MetS risk was exacerbated among the habitual high-fat consumers (>35% energy) (ApoB rs512535 OR 2.00 [CI 1.14, 3.51], P = 0.015; OR 1.58 [CI 1.11, 2.25], P = 0.012 for ApoA1 rs670). In addition a high monounsaturated fat (MUFA) intake (>14% energy) increased MetS risk (OR 1.89 [CI 1.08, 3.30], P = 0.026 and OR 1.57 [CI 1.10, 2.40], P = 0.014 for ApoB rs512535 and ApoA1 rs670, respectively). MetS risk was abolished among the habitual low-fat consumers (<35% energy). Saturated and polyunsaturated fat intake did not modulate MetS risk.ConclusionApoB rs512535 and ApoA1 rs670 may influence MetS risk. Apparent modulation of these associations by gender and dietary fat composition suggests novel gene-gender-diet interactions.     

Proinflammatory HLA-DRB1*01-haplotype predisposes to ST-elevation myocardial infarction

BackgroundMajor histocompatibility complex (MHC) gene region harbours haplotypes that associate with coronary artery disease (CAD). Their role in ST-elevation infarction (STEMI) or on the inflammatory level is not known.MethodsFour candidate MHC markers were analyzed by real-time quantitative PCR and constructed into haplotypes from patients with STEMI (n = 162), matched controls with no CAD (n = 319) and general population sample (n = 149). High sensitivity C-reactive protein (hsCRP) was assessed in a follow-up visit from patients (n = 86) and at inclusion from other study subjects.ResultsThe haplotype with one copy of HLA-DRB1*01, C4A, C4B but no HLA-B*35 doubled the risk of STEMI (OR = 2.15, 95%CI = 1.11–4.15, p = 0.020 for patients vs. controls, and OR = 2.26, 95%CI = 0.97–5.24, p = 0.052 for patients vs. population sample). The association between patients and controls persisted in multivariate analyses. The frequency of the haplotype was 5.86% (n = 19/324) in patients, 2.82% (n = 18/638) in controls and 2.68% (n = 8/298) in population sample. None of the individual MHC markers alone showed significant association with STEMI.In multivariate analyses, the haplotype carriers had higher hsCRP levels in patients (median 3.37 mg/L in carriers vs. 1.14 mg/L in non-carriers, p = 0.019) and in controls (median 2.90 mg/L vs. 1.21 mg/L, p = 0.009, respectively).ConclusionThe MHC haplotype associates with STEMI and elevated baseline hsCRP levels. The results are in concordance with previous data on non-STEMI patients, implying that a HLA-DRB1*01 – related haplotype increases the risk of CAD, possibly though increased inflammation.     

Correlates of endothelial function and the peak systolic blood pressure response to a graded maximal exercise test

PurposeAn elevated systolic blood pressure (SBP) response to a graded maximal exercise stress test (GEST) may be a predictor of endothelial dysfunction and hypertension. We examined relationships among the GEST peak SBP response and indicators of endothelial function.MethodsMen (n = 48, 43.7 ± 1.4 yr) with high BP (145.1 ± 1.5/85.5 ± 1.1 mm Hg) completed a GEST. Peak SBP was the highest SBP achieved during the GEST. Blood samples were taken for fasting glucose and insulin, nitric oxide (NO), and DNA. Endothelial nitric oxide synthase (NOS3, rs2070744) ?786 T > C genotyping was determined by PCR. NOS3 genotypes were combined using a dominant model [TT (n = 24); TC/CC (n = 24)]. Brachial artery reactivity (BAR) was determined via ultrasound before, 1 min, and 3 min post occlusion and calculated as % change. Analysis of variance (ANOVA) tested changes in the peak SBP GEST response by NOS3 genotype. Multiple variable regression analyses examined relationships among the GEST peak SBP response and measures of endothelial function.Results%BAR change at 1 min (r² = 0.093, p = 0.020), glucose (r² = 0.062, p = 0.014), NOS3 ?786 T > C (r² = 0.040, p = 0.024), NO (r² = 0.037, p = 0.064), and age (r² = 0.009, p = 0.014) explained 24.1% of the GEST peak SBP response (p = 0.043). The GEST peak SBP change from baseline was 11.1 ± 5.0 mm Hg higher among those with the NOS3 C allele (92.4 mm Hg + 3.8) than the NOS3 TT genotype (81.3 mm Hg + 3.2) (p = 0.03).ConclusionIndicators of endothelial function appear to explain a clinically significant portion of the GEST peak SBP response. Further investigation is needed to unravel the mechanisms by which endothelial function influences the GEST peak SBP response.     

Cardiovascular risk factors and subclinical atherosclerosis among Nunavik Inuit

ObjectiveTo evaluate subclinical atherosclerosis in Nunavik Inuit and its correlation to traditional cardiovascular disease risk factor.MethodThe intima–media thickness (IMT) of 12 segments of the carotid arteries (IMT_{12_seg}) free of plaque were assessed in randomly selected 40 years old and older Inuit from. Clinical assessment was performed which included fasting plasma glucose, fasting insulin, systemic blood pressure, body mass index, smoking, circulating blood lipids and oral glucose tolerance test. In addition, documented presence of ischemic heart disease (IHD), stroke, diabetes mellitus, hypertension and dyslipidemia were determined from medical files.ResultsThe average age of the 287 participants was 51.2 ± 0.6 years (56.8% women). Mean IMT_{12_seg} was 0.80 ± 0.17 mm (range: 0.55–1.47 mm). Compared with disease free Inuit, individuals with history of stroke showed greater carotid internal IMT (0.68 ± 0.01 mm vs. 0.96 ± 0.15 mm respectively; p < 0.005) but no difference was observed for IHD. Hypertensive and dyslipidemic Inuit had higher IMT_{12_seg} compared to risk factor free individuals but no difference was observed in diabetics. None of the clinical assessments were associated with IMT_{12_seg}. In a multivariate backward elimination model, only age, gender, and medically documented history of hypertension were found to be predictors of IMT_{12_seg} (adjusted r-square of 0.54; p < 0.0001).ConclusionCompared with disease free Nunavik Inuit, subclinical signs of atherosclerosis determined by IMT was higher in individual diagnosed with stroke. Independent predictors of IMT_{12_seg} in our group were age, gender and history of hypertension. No other traditional risk factors imparted IMT.