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NLRP3 Inflammasome Polymorphism and Macrovascular Complications in Type 2 Diabetes Patients.

ABSTRACT: BACKGROUND:It is generally accepted that poor glycemic control, arterial hypertension and/or hyperlipidemia, and the associated oxidative stress may contribute to the development of macro- and microvascular complications in type 2 diabetes (T2D). Such metabolic damage signals may activate inflammasome and trigger chronic inflammation. We investigated common polymorphisms in inflammasome coding genes and the risk for macro- and microvascular complications in T2D. METHODS:In total 181 clinically well-characterised T2D patients were genotyped for NLRP3 rs35829419 and CARD8 rs2043211. Risk for diabetic complications was assessed using logistic regression. RESULTS:Patients with median duration of T2D 11 (6-17) years had relatively well controlled blood glucose and lipid levels and blood pressure on the prescribed treatment regimen. Duration of T2D and plasma cholesterol levels were the most important clinical risk factors for macrovascular complications (P = 0.007 and P = 0.031). NLRP3 rs35829419 was associated with increased risk for macrovascular complications (P = 0.004), with myocardial infarction in particular (P = 0.052). No association was observed between CARD8 polymorphism and any of T2D complications. CONCLUSIONS:Our preliminary data suggest the role of NLRP3 polymorphism in diabetic macrovascular complications, especially in myocardial infarction.

SUBMITTER: Klen J

PROVIDER: S-EPMC4530261 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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NLRP3 Inflammasome Polymorphism and Macrovascular Complications in Type 2 Diabetes Patients.

Klen Jasna J Goričar Katja K Janež Andrej A Dolžan Vita V

Journal of diabetes research 20150727

<h4>Background</h4>It is generally accepted that poor glycemic control, arterial hypertension and/or hyperlipidemia, and the associated oxidative stress may contribute to the development of macro- and microvascular complications in type 2 diabetes (T2D). Such metabolic damage signals may activate inflammasome and trigger chronic inflammation. We investigated common polymorphisms in inflammasome coding genes and the risk for macro- and microvascular complications in T2D.<h4>Methods</h4>In total 1 ...[more]

PMID: 26273672

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Project description:BackgroundType 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies.MethodsThis cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina's Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control.FindingsThe analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4).InterpretationWe have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina's Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

Project description:IntroductionType 2 diabetes is associated with vascular complications that deteriorate the quality of life and decrease the life expectancy of individuals. We previously reported the efficacy of sitagliptin for glucose control in patients with type 2 diabetes in the Sitagliptin Registration Type 2 Diabetes-Juntendo Collaborating Project (SPIRITS-J). Through the results of the SPIRITS-J study, we expected that optimal comprehensive management of type 2 diabetes according to current clinical practice guidelines in addition to achieving individualized glycemic goals would reduce macrovascular complications and all-cause mortality in Japan. The aim of this study was to evaluate this hypothesis.MethodsWe investigated the clinical outcomes prospectively in the extended SPIRITS-J study and compared these to previous Japanese cohort studies in the era before widespread use of guidelines. The primary clinical outcome was a composite of myocardial infarction (MI), stroke, and all-cause mortality.ResultsMean duration of follow-up was 3.5 ± 1.3 years. The crude incidence of the primary outcome per 1000 person-years was 13.9 (non-fatal MI 1.44, non-fatal stroke 4.22, all-cause mortality 8.79 per 1000 person-years, respectively). It is noteworthy that the incidence of MI in the SPIRITS-J study was very much lower than that in a previous Japanese cohort study. In multivariate analysis, both the history of coronary artery disease and low-density lipoprotein cholesterol (LDL-C) were independently associated with incidence of primary clinical outcome.ConclusionThe extended SPIRITS-J study demonstrated that optimal comprehensive management in patients with type 2 diabetes according to the recent practice guidelines has succeeded in preventing macrovascular complications in Japan. This study suggests that more intensive LDL-C-lowering therapy is important for further prevention of macrovascular complications even in Japanese patients with type 2 diabetes (UMIN 000004121).

Project description:IntroductionThis retrospective cohort study investigated the relation between different measures of glycemic exposure and micro- and macrovascular complications among patients with type 2 diabetes.MethodsThe analysis included patients receiving oral antihyperglycemic agents between 1 January 2006 and 31 December 2014 from the General Practitioner Database from the PHARMO Database Network. All recorded HbA1c levels during follow-up were used to express glycemic exposure in four ways: index HbA1c, time-dependent HbA1c, exponential moving average (EMA) and glycemic burden. Association between glycemic exposure and micro-/macrovascular complications was analyzed by estimating hazard ratios and 95% confidence intervals using an adjusted (time-dependent) Cox proportional hazards model.ResultsThe analysis included 32,725 patients (median age, 65 years; 47% female). Median follow-up was 5.4 years; median number of HbA1c measurements per patient was 18.0. From all measures, HbA1c at index showed the weakest relation between all micro-/macrovascular complications, with coronary artery disease (CAD) having the highest HR (95% CI): 1.18 (1.04-1.34) for HbA1c ≥64 mmol/mol (8%). The time-dependent HbA1c model showed a significant association only for microvascular complications, with retinopathy having the highest HR (95% CI): 1.55 (1.40-1.73) for HbA1c ≥64 mmol/mol (8%). EMA-defined exposure showed similar findings, although the effect of retinopathy was more pronounced [HR (95% CI): 1.81 (1.63-2.02) for HbA1c ≥64 mmol/mol (8%)] and was also predictive for CAD [HR (95% CI): 1.29 (1.10-1.50) for HbA1c ≥64 mmol/mol (8%)]. A statistically significant relation with glycemic burden was found for all selected micro-/macrovascular complications, with retinopathy having the highest HR (95%): 2.60 (2.19-3.07) for glycemic burden years >3.ConclusionThis study shows that greater and more prolonged exposure to hyperglycemia increases the risk of micro- and macrovascular complications.FundingJanssen Pharmaceutica NV.

Project description:BackgroundVascular complications are the major morbid consequences of type 2 diabetes mellitus (T2DM). The transcription factor 7-like 2 (TCF7L2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and inwardly-rectifying potassium channel, subfamily J, member 11 gene (KCNJ11) are common T2DM susceptibility genes in various populations. However, the associations between polymorphisms in these genes and diabetic complications are controversial. This study aimed to investigate the effects of combined gene-polymorphisms within TCF7L2, KCNQ1, and KCNJ11 on vascular complications in Thai subjects with T2DM.MethodsWe conducted a case-control study comprising 960 T2DM patients and 740 non-diabetes controls. Single nucleotide polymorphisms in TCF7L2, KCNQ1, and KCNJ11 were genotyped and evaluated for their association with diabetic vascular complications.ResultsThe gene variants TCF7L2 rs290487-T, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-C were associated with increased risk of T2DM. TCF7L2 rs7903146-C, TCF7L2 rs290487-C, KCNQ1 rs2237892-T, and KCNQ1 rs2237897-T revealed an association with hypertension. The specific combination of risk-alleles that have effects on T2DM and hypertension, TCF7L2 rs7903146-C, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-T, as genetic risk score (GRS), pronounced significant association with coronary artery disease (CAD), cumulative nephropathy and CAD, and cumulative microvascular and macrovascular complications (respective odds ratios [ORs] with 95% confidence interval [95% CI], comparing between GRS 2-3 and GRS 5-6, were 7.31 [2.03 to 26.35], 3.92 [1.75 to 8.76], and 2.33 [1.13 to 4.79]).ConclusionThis study demonstrated, for the first time, the effect conferred by specific combined genetic variants in TCF7L2 and KCNQ1 on diabetic vascular complications, predominantly with nephropathy and CAD. Such a specific pattern of gene variant combination may implicate in the progression of T2DM and life-threatening vascular complications.

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NLRP3 Inflammasome Polymorphism and Macrovascular Complications in Type 2 Diabetes Patients.

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NLRP3 Inflammasome Polymorphism and Macrovascular Complications in Type 2 Diabetes Patients.

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