Circulating lipopolysaccharide-binding protein and carotid intima-media thickness in obstructive sleep apnea.

Circulating lipopolysaccharide-binding protein (LBP), a metabolic endotoxemia marker, was identified as an independent predictor of atherosclerosis. Although increases in carotid intima-media thickness (CIMT) were repeatedly reported in obstructive sleep apnea (OSA), neither the role of OSA in metabolic endotoxemia nor of LBP in early atherosclerosis were explored in patients with OSA. At a tertiary university hospital we investigated the relationships between OSA, LBP and CIMT in 117 men who underwent full polysomnography and CIMT assessment by B-mode ultrasound. Circulating LBP concentrations and average CIMT increased from patients without OSA to those with mild-moderate and severe OSA (from 32.1+/-10.3 to 32.3+/-10.9 to 38.1+/-10.3 microg.ml(-1), p=0.015; from 0.52+/-0.09 to 0.58+/-0.06 to 0.62+/-0.10 mm, p=0.004, respectively). Oxygen desaturation index (ODI) was a predictor of serum LBP levels independent of age, waist-to-hip ratio (WHR), smoking, hypertension, HDL cholesterol, triglycerides and fasting glucose [p (ANOVA)=0.002, r(2)=0.154], with no independent effect of the ODI*WHR interaction term on LBP. Furthermore, serum LBP predicted CIMT independently of known risk factors of atherosclerosis including obesity (p<0.001, r(2)=0.321). Our results suggest that OSA severity contributes to metabolic endotoxemia in patients with OSA independently of obesity, and that LBP might represent a contributing factor promoting early atherosclerosis in such patients.

The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.

Familial hypercholesterolemia (FH) is most frequently caused by LDLR or APOB mutations. Therefore, the aim of our study was to examine the genetic background of Slovak patients suspected of FH. Patients with clinical suspicion of FH (235 unrelated probands and 124 family relatives) were recruited throughout Slovakia during the years 2011-2015. The order of DNA analyses in probands was as follows: 1. APOB mutation p.Arg3527Gln by real-time PCR method, 2. direct sequencing of the LDLR gene 3. MLPA analysis of the LDLR gene. We have identified 14 probands and 2 relatives with an APOB mutation p.Arg3527Gln, and 89 probands and 75 relatives with 54 different LDLR mutations. Nine of LDLR mutations were novel (i.e. p.Asp90Glu, c.314-2A>G, p.Asp136Tyr, p.Ser177Pro, p.Lys225_Glu228delinsCysLys, p.Gly478Glu, p.Gly675Trpfs*42, p.Leu680Pro, p.Thr832Argfs*3). This is the first study on molecular genetics of FH in Slovakia encompassing the analysis of whole LDLR gene. Genetic etiology of FH was confirmed in 103 probands (43.8 %). Out of them, 86.4 % of probands carried the LDLR gene mutation and remaining 13.6 % probands carried the p.Arg3527Gln APOB mutation.

Variation in CDKAL1 gene is associated with therapeutic response to sulphonylureas.

The aim of the present pilot pharmacogenetic study was to analyse quantitative effects of sulphonylurea treatment in addition to metformin on parameters of glycemic control with respect to CDKAL1 genotypes in patients with type 2 diabetes. Effect of 6-month sulphonylurea therapy on glycemic control according to CDKAL1 genotypes was evaluated in 101 patients with type 2 diabetes who failed to achieve glycemic control on metformin monotherapy. CDKAL1 rs7756992 polymorphism was determined by melting curve analysis of small amplicon following real-time PCR. After sulphonylurea treatment fasting plasma glucose (FPG) levels were significantly different (p=0.045) among three CDKAL1 genotype groups (AA: n=49; AG: n=36; GG: n=16). In a dominant genetic model, carriers of the G-allele (AG+GG, n=52) achieved significantly lower FPG levels in comparison with patients with the AA genotype (6.90±1.08 vs. 7.48±1.12 mmol/l, p=0.013). Consequently, adjusted ΔFPG was significantly higher in the AG+GG compared to the AA group (1.48±1.51 vs. 1.02±1.33 mmol/l, p=0.022). Similar trend was observed for HbA(1c) levels, but the difference between the genotype groups did not reach the level of statistical significance. Relatively small number of included patients is a limitation of the present study. In conclusion, our results suggest that the magnitude of FPG reduction after 6-month sulphonylurea treatment in patients with type 2 diabetes is related to the variation in CDKAL1.

Pharmacogenetics of oral antidiabetic treatment.

In the majority of patients with type 2 diabetes (T2D), oral antidiabetic drug (OAD) treatment is the first line treatment after lifestyle measures fail. Two major groups of OAD are used in clinical practice--insulin secretagogues and insulin sensitisers. Sulphonyluea (SU) derivatives are insulin secretagogues and stimulate insulin secretion by inhibiting ATP-sensitive potassium channels. Genes KCNJ11 and ABCC8 encode potassium channel proteins. KCNJ11 gene Glu23Lys polymorphism was associated with an increased risk of SU secondary failure, while Ser1369Ala polymorphism of ABCC8 gene had influence antidiabetic efficacy of SU drug gliclazide. In addition, the polymorphism of TCF7L2 gene, which has the strongest association with T2D, also influenced secondary SU drug failure. Insulin sensitisers include both metformin and glitazones. Some drug-genotype associations were observed for metformin in patients with T2D. Several genes influenced the effect of glitazone treatment. Rosiglitazone was more effective in diabetes control in carriers of Prol2Ala polymorphism of PPARG gene encoding the PPARg-receptor--the target of this drug. Rosiglitazone treatment had less effect on glycemic control and adiponectin increase in T2D patients with GG-genotypes of adiponectin (APM1) polymorphism. Pioglitazone treatment had smaller effect on glycemic control in patients with LPL Ser447X polymorphism. Identification of drug-genotype interactions in pharmacogenetic studies of the OAD treatment might have clinical implications in the near future resulting in selection of more specific "patient-tailored therapy" in T2D (Tab. 1, Ref. 58).

[Relationship of the CDKAL1 and KCNQ1 gene polymorphisms to the age at diagnosis of type 2 diabetes in the Slovakian population]. / Vzt'ah polymorfizmov génov CDKAL1 a KCNQ1 k veku diagnózy diabetu 2. typu v populácii slovenska.

BACKGROUND/AIMS: The association of CDKAL1 and KCNQ1 genes with type 2 diabetes mellitus (DM2T) was confirmed by several genome-wide association studies in both Caucasian and Asian populations. For both genes, it is supposed that the risk of DM2T development is related to impaired insulin secretion. Based on assumption that the presence of risk allele might predispose to an earlier onset of DM2T, the aim of the present study was to assess the frequency of risk alleles of CDKAL1 rs7756992 and KCNQ1 rs163184 polymorphisms and to analyze their association with the age at DM2T diagnosis in the Slovakian population. METHODS: CDKAL1 rs7756992 A/G and KCNQ1 rs163184 G/T polymorphisms were genotyped using asymmetric PCR with subsequent melting curve analysis in a group of 538 patients with DM2T. Anthropometric and laboratory parameters were determined by using standard methods. Since two genes were analysed, the required level for statistical significance was defined as p < 0.025. RESULTS: Risk homozygotes (CG) for KCNQ1 polymorphism had higher mean age of DM2T diagnosis by 2 years when compared to T-allele carriers (GT + TT) in a recessive model, but the difference did not reach the predefined level of statistical significance. No relationship of CDKAL1 polymorphism to the age at onset of DM2T diagnosis was observed. CONCLUSIONS: In the present study, no relationship of CDKAL1 and KCNQ1 polymorphisms to the earlier onset of type 2 diabetes was observed.

Effect of sulphonylurea treatment on glycaemic control is related to TCF7L2 genotype in patients with type 2 diabetes.

The aim of the present study was to analyse effects of sulphonylurea treatment on parameters of glycaemic control in relation to transcription factor 7-like 2 (TCF7L2) genotypes. In 87 patients with type 2 diabetes who failed to achieve glycaemic control on metformin monotherapy, effects of 6-month sulphonylurea in addition to metformin on reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels were evaluated. Reduction in HbA1c and FPG in response to 6-month sulphonylurea treatment was significantly higher in patients with CC genotype compared to those with the CT+TT genotype (1.16 ± 0.07 vs. 0.86 ± 0.07%, p = 0.003; 1.57 ± 0.12 vs. 1.14 ± 0.14 mmol/l, p = 0.031, respectively). In the multivariate analysis, baseline HbA1c and the TCF7L2 genotype were the only significant predictors of HbA1c reduction. In conclusion, the magnitude of HbA1c and FPG reductions after 6-month sulphonylurea treatment in addition to metformin is related to the TCF7L2 gene polymorphism.

Relationship of five type 2 diabetes candidate gene polymorphisms to the age at diagnosis of diabetes in the Slovakian population.

OBJECTIVES: To examine the relationship between polymorphisms of five candidate genes for type 2 diabetes mellitus (T2DM) and the age at diagnosis of T2DM. METHODS: 538 Slovakian patients with T2DM were included and their age at diagnosis of T2DM retrieved from their medical records. Polymorphisms of genes encoding peroxisome proliferator activated receptor gamma (PPARG), PPARG-coactivator-1 (PGC1), insulin-receptor substrate 1 (IRS1), the subunit Kir 6.2 of the ATP-dependent potassium-channel (KCNJ11) and transcription factor 7-like 2 (TCF7L2) were detected by PCR-RFLP methods. RESULTS: No significant relationship between the risk alleles of the examined gene polymorphisms to the lower mean age at diagnosis of T2DM was observed. The carriers of the TT-genotype of TCF7L2 rs7903146 polymorphism had significantly increased odds ratio for diagnosis of diabetes before the age of 40 years [OR 3.02 (1.34, 6.81), p = 0.008], in comparison with the CC/CT genotype carriers. CONCLUSION: No significant association of PPARG, PGC1, IRS1, KCNJ11 and TCF7L2 gene polymorphisms and the age at diagnosis of T2DM was observed in the present study. Homozygotes for the risk allele of TCF7L2 had more frequently early onset of T2DM, before age of 40 years (Tab. 4, Ref. 15).

Relationship among urinary albumin excretion rate, lipoprotein lipase PvuII polymorphism and plasma fibrinogen in type 2 diabetic patients.

Plasma fibrinogen level represents a strong cardiovascular risk factor and is regulated by an interplay of genetic and environmental factors. Hyperfibrinogenemia frequently occurs in cluster with dyslipidemia within the frame of insulin resistance syndrome (IRS) and type 2 diabetes mellitus. Genetic variants with a pleiotropic effect have been proposed to cause IRS features including hyperfibrinogenemia. We studied the influence of polymorphisms in lipoprotein lipase (LPL) gene, beta-fibrinogen gene (FIBB) and environmental factors on plasma fibrinogen levels in type 2 diabetes patients. 131 type 2 diabetes patients (mean age 62+/-10 years, 33% male) were genotyped for polymorphisms in LPL gene (intron 6 PvuII, intron 8 HindIII) and FIBB gene (-148C/T, -455G/A) by PCR-RFLP method. Fibrinogen was measured by thrombin coagulation method, albuminuria by immunoturbidimetric assay. Polymorphism LPL PvuII showed a gene-dose effect on fibrinogen levels, with the highest fibrinogen in P-P- homozygotes (p = 0.05, analysis of variance). P-carriers (P-P- and P+P- combined) had significantly higher fibrinogen levels compared with P+P+ homozygotes (3.74+/-1.40 g/l vs 3.06+/-1.20 g/l, p=0.03). Other studied polymorphisms were not significantly related to fibrinogen levels. Age- and sex-adjusted fibrinogenemia correlated significantly with albuminuria (r = 0.48, p=0.001), serum uric acid (r = 0.42, p=0.006) and serum creatinine (r = 0.32, p=0.04). Multiple stepwise linear regression identified interaction term of LPL PvuII and albuminuria as an independent predictor of fibrinogen level, explaining 18% of fibrinogen variance. Albuminuria thus appears to be the best predictor of fibrinogen plasma levels in type 2 diabetic patients. Relationship between albuminuria and fibrinogenemia may be modified by the genotype LPL PvuII, which also shows a weak association with plasma fibrinogen level in type 2 diabetes patients.

Effect of gene polymorphisms on lipoprotein levels in patients with dyslipidemia of metabolic syndrome.

Dyslipidemia in the metabolic syndrome (MS) is considered to be one of the most important risk factors for atherosclerosis. It is characterized by hypertriglyceridemia, low concentration of plasma HDL-cholesterol, predominance of small dense LDL particles and an increased concentration of plasma apolipoprotein B (apoB). The pathogenesis of this type of dyslipidemia is partially explained, but its genetic background is still unknown. To evaluate the influence of cholesterol ester transfer protein (CETP) TaqIB polymorphism, lipoprotein lipase (LPL) PvuII and HindIII polymorphisms, hepatic lipase (LIPC) G-250A polymorphism and apolipoprotein C-III (APOC3) SstI gene polymorphism on lipid levels in dyslipidemia of the metabolic syndrome, 150 patients with dyslipidemia of metabolic syndrome were included. 96 % of patients had type 2 diabetes. The patients did not take any lipid lowering treatment. The exclusion criterion was the presence of any disease that could affect lipid levels, such as thyroid disorder, liver disease, proteinuria or renal failure. Gene polymorphisms were determined using the polymerase chain reaction and restriction fragment length polymorphisms. The genotype subgroups of patients divided according to examined polymorphisms did not differ in plasma lipid levels with the exception of apoB. The apoB level was significantly higher in patients with S1S1 genotype of APOC3 SstI polymorphism when compared with S1S2 group (1.10+/-0.26 vs. 0.98+/-0.21 g/l, p=0.02). Similarly, patients with H-H- genotype of LPL HindIII polymorphism had significantly higher mean apoB, compared with H+H- and H+H+ group (1.35+/-0.30 vs. 1.10+/-0.26 g/l, p=0.02). In the multiple stepwise linear regression analysis, apoB level seemed to be influenced by APOC3 SstI genotype, which explained 6 % of its variance. The present study has shown that the S1 allele of APOC3 SstI polymorphism and the H- allele of LPL HindIII polymorphism might have a small effect on apoB levels in the Central European Caucasian population with dyslipidemia of metabolic syndrome.

[Relation of polymorphism of genes controlling endothelial function and blood pressure and the occurrence of vascular complications in type 2 diabetes]. / Vzt'ah polymorfizmov génov ovplyvnujúcich funkciu endotelu a krvný tlak k výskytu vaskulárnych komplikácií pri diabete 2. typu.

Genetic polymorphisms of factors regulating the function of endothelium and blood pressure are recently intensively studied also in type 2 diabetes because endothelial dysfunction and arterial hypertension are risk factors of atherosclerosis. The following review deals with relations of polymorphisms in the renin-angiotensin-aldosterone (RAAS) system, polymorphisms of NO-synthase (NOS) as well as the gene for atrial natriuretic peptide (hANP). So far most information was assembled on the influence of polymorphisms of RAAS genes, in particular the gene coding the angiotensin converting enzyme (ACE), on complications of type 2 diabetes. A relationship with the development of coronary disease was described in ACE genes, the receptor for angiotensin II--type 1 (AT1R), angiotensinogen and in several NOS polymorphisms. Also the relationship of polymorphisms of genes ACE, AT1R, NOS and hANP was described in relation to the development of hypertension which is an important risk factor for macrovascular and microvascular complications of diabetes. In some investigations the relationship of polymorphisms of ACE and AT1R genes and the development of diabetic nephropathy was described where a significant acceleration of the process of atherogenesis occurs. As type 2 diabetes mellitus and atherosclerosis are polygenically determinal diseases, it will be in particular necessary to investigate in future the concurrent influence of several gene polymorphisms and their interactions with the diabetic milieu intérieur on the development of macrovascular and microvascular complications of diabetes.