Low serum PON1 activity: An independent risk factor for coronary artery disease in North–West Indian type 2 diabetics

The paraoxonase (PON1) gene polymorphisms are known to affect the PON1 activity and coronary artery disease (CAD) risk. Studies done so far have given conflicting results. In the present study, we determined the role of PON1 genetic variants and PON1 activity in the development of CAD in North–West Indian Punjabis, a distinct ethnic group, having high incidence of both CAD and type 2 diabetes. 300 angiographically proven CAD with type 2 diabetics and 250 type 2 diabetics with no clinically evident CAD were enrolled. Serum PON1 activity and genotyping of coding (Q192R, L55M) and promoter (− 909G/C, − 162A/G, − 108C/T) region polymorphisms were carried out and haplotypes were determined using PHASE software.     

A case of primary selective hypoaldosteronism carrying three mutations in the aldosterone synthase (Cyp11b2) gene

An infant with a clinical phenotype of early onset hypoaldosteronism has been screened for mutation analysis of the Cyp11b2 gene encoding aldosterone synthase enzyme. We have described a novel nonsense mutation in exon 3 (c.508C>T) that gave rise to a shorter protein (Q170X) and two known concurrent missense mutations (c.594A>C in exon 3 and c.1157T>C in exon 7) that led to substitution of glutamic acid for aspartic acid at amino acid position 198 (E198D) and of valine for alanine at amino acid position 386 (V386A). The father, who carried E198D plus V386A mutations, showed a fractional sodium excretion of 1.25% that was unmodified by dietary salt restriction, suggesting a mild haploinsufficiency. We examined by in silico analysis the effect of the mutations on the secondary and tertiary structures of aldosterone synthase to explain the inefficient enzymatic activity. The Q170X mutation produced a truncated protein, which was consequently associated with a loss of catalytic activity. As predicted by JPred web system and Dock 6.3 software, the concurrent expression of E198D and V386A mutations induced a significant secondary structure rearrangement and a shift of the heme group and the 18-hydroxycorticosterone substrate from their optimal placement.     

Association of three polymorphisms of scavenger receptor class BI gene (exon8, exon1, intron5) with coronary stenosis in a coronary Tunisian population

Background

The potential role of scavenger receptor class BI (gene name SCARB1) in the regulation of lipoproteins metabolism and atherosclerosis has attracted considerable interest. We tested the relationship of SCARB1 polymorphisms with significant coronary stenosis (SCS) and lipid profile in a coronary Tunisian population.

Methods

Three SCARB1 polymorphisms (exon8 (C/T), exon1 (G/A), intron5 (C/T)) were studied in 316 Tunisian patients undergoing coronary angiography. SCS was defined as a luminal narrowing of ≥ 50% in at least one major coronary artery. Lipid profile was measured. Genotyping was performed using PCR–RFLP.

Results

Individuals with TT genotypes of exon8 were associated with higher concentrations of plasma HDL-C and ApoAI in the group without SCS. Carriers of T allele of exon8 were associated with 41% lower risk of SCS. This protective effect seemed to be particularly significant in women, nondiabetics and nonsmokers. Subjects homozygous for the variant allele of intron5 were significantly associated with an increased risk of SCS, particularly in smokers. AA genotype of exon1 was associated with an increased risk of SCS in diabetics and in patients with metabolic syndrome. The (CAT) haplotype was associated with increase in the risk of SCS compared to the wild haplotype and had a 4-fold greater risk of SCS than patients with haplotype (TGC) which seems to be the most protective against SCS.

Conclusion

Carriers of T allele of exon8 in SCARB1 seemed to increase HDL-C and ApoAI concentrations and reduce the risk of SCS. The intron5, exon1 and (CAT) haplotype seemed to have an atherogenic effect.     

The role of GSTM1, GSTT1, GSTP1, and OGG1 polymorphisms in type 2 diabetes mellitus risk: a case-control study in a Turkish population

The aim of the present study was to investigate the role of some polymorphisms in GSTs (GSTM1, GSTT1 and GSTP1) which are very important protective mechanisms against oxidative stress and in OGG1 gene which is important in DNA repair, against the risk of type 2 diabetes mellitus (T2DM). 127 T2DM and 127 control subjects were included in the study. DNA was extracted from whole blood. Analyses of GSTM1 and GSTT1 gene polymorphisms were performed by allele specific PCR and those of GSTP1 Ile105Val and OGG1 Ser326Cys by PCR-RFLP. Our data showed that GSTM1 null genotype frequency had a 2-6 times statistically significant increase in a patient group (OR=3.841, 95% CI=2.280-6.469, p<0.001) but no significance with GSTT1 null/positive and GSTP1 Ile105Val genotypes was observed. When T2DM patients with OGG1 Ser326Cys polymorphism were compared with patients with a wild genotype, a 2-3 times statistically significant increase has been observed (OR 1.858, 95% CI=1.099-3.141, p=0.021). The combined effect of GSTM1 null and OGG1 variant genotype frequencies has shown to be statistically significant. Similarly, the risk of T2DM was statistically increased with GSTM1 null (OR=3.841, 95% CI=2.28-6.469), GSTT1 null+GSTP1 (H+M) (OR=4.118, 95% CI=1.327-12.778) and GSTM1 null+OGG1 (H+M) (OR=3.322, 95% CI=1.898-5.816) and GSTT1 null+OGG1 (H+M) (OR=2.179, 95% CI=1.083-4.386) as compared to the control group. According to our study results, it has been observed that the combined evaluation of GSTM1-GSTT1-GSTP1 and OGG1 Ser326Cys gene polymorphisms can be used as candidate genes in the etiology of T2DM, especially in the development of T2DM.     

Association of heat shock protein70-2 (HSP70-2) gene polymorphism with coronary artery disease in an Iranian population

Background

Coronary artery disease (CAD) is an inflammatory process and a major cause of mortality and morbidity. The (heat shock protein70-2) HSP70-2 gene is reported to be associated with coronary artery disease possibly by affecting the regulation of pro-inflammatory cytokines such as TNF-α. The association between CAD and the HSP70-2 gene + 1267A>G polymorphism has been studied in some populations but there are no data about this association in the Iranian population.

Aim

We have investigated the association between the HSP70-2 gene + 1267A>G polymorphism and angiographically defined CAD within an Iranian population.

Methods

We determined the presence of the HSP70-2 gene + 1267A>G polymorphism in 628 patients with CAD and 307 healthy individuals using PCR-RFLP. Of the patients, 433 (68%) had > 50% stenosis (CAD +) and the remaining 195 patients had < 50% stenosis (CAD −), based on coronary angiography. Angiogram positive patients were subdivided into three groups: those with single (n = 113), double (n = 134), and triple vessels (n = 186) disease.

Results

A significant higher frequency of AG + GG genotypes (G allele carriers) was observed in angiogram positive and angiogram negative groups compared to controls in a dominant analysis model of the HSP70-2 gene + 1267A>G position (51.2 vs. 43.2, P = 0.002, OR = 1.37) (51.0 vs. 43.2, P = 0.01, OR = 1.37). The allele frequency of the HSP70-2 G was also significantly higher in angiogram positive and angiogram negative groups compared to the control group (51.2 vs. 43.2, P = 0.002, OR = 1.37) (51.0 vs. 43.2, P = 0.01, OR = 1.37).

Conclusion

These results suggest that HSP70-2 + 1267 polymorphism may influence the risk of CAD in Iranian population, however further studies are needed to clarify the role of other HSP70-2 gene polymorphisms in the pathogenesis of the CAD.     

Association of ghrelin Leu72Met polymorphism with type 2 diabetes mellitus in Chinese population

Background

Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to implicate the development of the type 2 diabetes mellitus (T2DM). The Leu72Met (+ 408 C > A) polymorphism of the preproghrelin, has been linked to obesity, insulin resistance and diabetes.

Objective

To investigate the distribution of ghrelin gene Leu72Met polymorphism and its association with the type 2 diabetes mellitus in Chinese population.

Methods

We conducted a case–control study on 877 patients with T2DM and 864 controls, which were genotyped by the polymerase chain reaction (PCR) technique, denaturing high performance liquid chromatography (DHPLC) and DNA sequence analysis. Laboratory analyses were carried out in the hospital laboratory.

Results

No significant difference in the Leu72Met genotype distributions and allele frequency was observed between type 2 diabetes mellitus and controls (both P > 0.05). The polymorphism was not associated with T2DM. However, among the T2DM group, the patients carrying Leu72Leu genotype had significantly increased levels of FPG and serum creatinine compared with variant genotypes (Leu72Met and Met72Met) (P < 0.05). In the control group, the subjects with variant genotypes had significantly increased levels of FINS, HOMA-IR compared with Leu72Leu genotype (P < 0.05).

Conclusion

The Leu72Met polymorphism of the preproghrelin gene was not associated with T2DM in Chinese population. However, it may have some roles in the etiology of insulin resistance.     

Genetic association of ADIPOQ gene variants with type 2 diabetes,obesity and serum adiponectin levels in south Indian population

Objective

To investigate the genetic association of eight variants of the adiponectin gene with type 2 diabetes mellitus (T2DM), obesity and serum adiponectin level in the south Indian population.

Methods

The study comprised of 1100 normal glucose tolerant (NGT) and 1100 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. The variants were screened by polymerase chain reaction-restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotype frequencies.

Results

Of the 8 variants, four SNPs namely, + 276 G/T (rs1501299), − 4522 C/T (rs822393), − 11365 C/G (rs266729), and + 712 G/A (rs3774261) were significantly associated with T2DM in our study population. The −3971 A/G (rs822396) and − 11391 G/A (rs17300539) SNPs' association with T2DM diabetes was mediated through obesity (where the association with type 2 diabetes was lost after adjusting for BMI). There was an independent association of + 276 G/T (rs1501299) and − 3971 A/G (rs822396) SNPs with generalized obesity and + 349 A/G (rs2241767) with central obesity. Four SNPs, −3971 A/G (rs822396), + 276 G/T (rs1501299), − 4522 C/T (rs822393) and Y111H T/C (rs17366743) were significantly associated with hypoadiponectinemia. The haplotypes GCCATGAAT and AGCGTGGGT conferred lower risk of T2DM in this south Indian population.

Conclusion

The adiponectin gene variants and haplotype contribute to the genetic risk towards the development of type 2 diabetes, obesity and hypoadiponectinemia in the south Indian population.     

Two genetic variants in FABP1 and susceptibility to non-alcohol fatty liver disease in a Chinese population

Liver fatty acid-binding protein (FABP1) serves as a key regulator of hepatic lipid metabolism, and polymorphisms within the FABP1 gene have been associated with several metabolic traits. To investigate the association between FABP1 polymorphisms and the risk of non-alcohol fatty liver disease (NAFLD) in a Chinese population, the genotypes and haplotypes of FABP1 (rs2241883 T/C and rs1545224G/A) were determined in 553 patients with NAFLD and 553 healthy controls. The results showed that individuals with at least one copy of the rs2241883 C allele (TC or CC genotype) had an elevated risk for developing NAFLD (odds ratio [OR]=1.32, 95% CI: 1.01-1.71), and individuals with at least one copy of the rs1545224 A allele (GA or AA genotype) also had a significantly increased risk for NAFLD (OR=1.52, 95% CI: 1.14-2.02). Cumulative effect analysis of the two SNPs revealed that individuals with two risk genotypes were at significantly higher risk of NAFLD than those without risk genotype, and a significant trend of increased risk with increasing numbers of risk genotype was observed. Stratification analysis showed that the rs2241883 C allele carriers had higher level of LDL-C and the rs1545224 A allele carriers had higher level of FPG than those without this allele. In addition, haplotype analysis revealed that the one composed of the rs1545224 A and rs2241883 C variants was significantly associated with an increased risk for NAFLD (OR=1.34; 95% CI=1.05-1.40) compared to the GT haplotype. Taken together, the present study suggests that genetic variations within FABP1 influence susceptibility to NAFLD independently or jointly.     

Association of P213S polymorphism of the L-selectin gene with type 2 diabetes and insulin resistance in Chinese population

Aims

L-selectin belongs to selectin family of adhesion molecule and participates in the generation and development of type 2 diabetes (T2D). In this study, we evaluated the relationship between the P213S polymorphism of L-selectin gene and T2D and insulin resistance in the Chinese population.

Methods

We genotyped P213S polymorphism in 801 patients with T2D and 834 healthy controls in the Chinese population using polymerase chain reaction–ligase detection reaction (PCR–LDR) technique. Plasma glucose, insulin, lipid, blood urea nitrogen, creatinine and uric acid levels were measured by biochemical technique.

Results

The frequency of 213PP genotype and P allele of the L-selectin gene in patients with T2D was significantly higher than that in controls (P = 0.007; P = 0.019, respectively). The relative risk of allele P suffered from T2D was 1.191 times higher than that of allele S. Moreover, the levels of FPG and HOMA-IR of PP and PS genotype carriers were significantly higher than those of SS genotype carriers in the T2D group (P < 0.05).

Conclusion

These findings indicated that the P213S polymorphism of L‐selectin gene may contribute to susceptibility to T2D and insulin resistance in the Chinese population, and P allele appears to be a risk factor for T2D.     

The effects of age and gender on the relationship between HMGCR promoter-911 SNP (rs33761740) and serum lipids in patients with coronary heart disease

Background

Hydroxymethylglutaryl-Coenzyme A Reductase (HMGCR) catalyzes the rate-limiting step of cholesterol biosynthesis. This enzyme is the target of the widely available cholesterol lowering statins. In this population-based case–control study, the frequencies of -911 C>A polymorphism (rs3761740) of the HMGCR gene in patients with coronary heart disease (CHD) and healthy subjects were investigated and the correlations between the different genotypes and hypercholesterolemia with cardiovascular risk factors were analyzed.

Methods

The HMGCR genotypes were determined in 365 patients with CHD and 365 controls by PCR–RFLP assay. Anthropometric measurements were measured in all participants.

Results

There was no significant difference in the genotype frequencies of the HMGCR polymorphism between the male subjects of both patient and control groups, however, the HMGCR-CC genotype was found to be more frequent in female patients with CHD than female controls (p = 0.002). The HMGCR-CC genotype showed higher total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels than the CA + AA genotypes in male CHD patients (p = 0.018). Due to this significant sex interaction, a multivariate analysis was conducted on the patient group. In the multivariate logistic regression analysis, the HMGCR-CC genotype was significantly associated with age < 55 (OR = 2.837, p = 0.001) and TC ≥ 5.18 mmol/L (OR = 1.970, p = 0.027) in male subjects. However, this association was not observed in female patients (p > 0.05). This analysis confirmed that the HMGCR-CC genotype was associated with elevated TC levels in male CHD patients with age < 55 years.

Conclusion

These results suggest that age and sex modify the contribution of the HMGCR-911 polymorphism to fasting serum TC, LDL-C levels and risk of CHD.     

Association analysis of common variants in FOXO3 with type 2 diabetes in a South Indian Dravidian population

Recent studies have identified common variants in forkhead box O3 gene (FOXO3) to be strongly associated with longevity in different populations. But studies have not been carried out to analyse the role of common variants in FOXO3 with type 2 diabetes. Since type 2 diabetes is an age related disorder and FOXO proteins play an important role in the regulation of metabolism, we studied the role of common variants in FOXO3 for association with type 2 diabetes. The study was carried out in 994 type 2 diabetic samples and 984 normoglycemic control samples from a South Indian Dravidian population. In our analysis, we found that there was no association between any of the selected SNPs in FOXO3 with type 2 diabetes. Analysis of these SNPs with diabetes related biochemical and clinical parameters also did not reveal any significant association. Haplotype association of SNPs in FOXO3 with type 2 diabetes was observed, but the frequency of the haplotypes was considerably lower and they do not remain significant after correction for multiple testing. In conclusion, we did not observe any association of SNPs in FOXO3 with type 2 diabetes and related parameters suggesting an entirely different mechanism by which these SNPs influence longevity. However additional studies in other populations are required to completely rule out the association of common variants in FOXO3 with type 2 diabetes.     

Fenofibrate exhibits a high potential to suppress the formation of squamous cell carcinoma in an oral-specific 4-nitroquinoline 1-oxide/arecoline mouse model

The excessive use of areca nut and/or tobacco may induce the production of free radicals and reactive oxygen species, which affect the lipid contents of the cell membrane and are possibly involved in tumorigenic processes in the oral cavity. The aim of this study was to investigate the therapeutic efficacy of fenofibrate (0.1% or 0.3%, w/w), a ligand of the peroxisome proliferator-activated receptor alpha (PPARα), in a 4-nitroquinoline 1-oxide (4-NQO)/arecoline-induced oral cancer mouse model. The carcinogen, 4-NQO/arecoline, was administrated to C57BL/6JNarl mice for 8 weeks followed by fenofibrate treatment for 12 or 20 weeks. After 28 weeks, changes in serum lipids, the multiplicity of tumor lesions, and tumor sizes were determined together with changes in the immunohistochemical expressions of PPARα, acetyl-coenzyme A carboxylase (ACC), the epidermal growth factor receptor (EGFR), and cyclooxygenase-2 (COX2). The results showed that when compared to the 4-NQO/arecoline only group, 0.3% fenofibrate treatment increased serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels. 0.3% fenofibrate treatment suppressed the incidence rate of tongue lesions, reduced the multiplicity of squamous cell carcinoma (SCC), decreased the tumor size, and increased the immunoreactivity of EGFR and COX2 in oral dysplasia but decreased EGFR and COX2 expressions in SCC. These findings indicated that fenofibrate reduced the tumor incidence rate and suppressed the tumor progression into SCC and that these molecular events might be linked to the EGFR and COX2 regulatory pathways. We suggest that fenofibrate provides a new strategy for preventing oral tumor progression.     

Chitinase 3-like 1 gene-329G/A polymorphism, plasma concentration and risk of coronary heart disease in a Chinese population

Background

The chitinase-like 1 protein, YKL-40, is involved in inflammation and tissue remodeling. Patients with coronary heart disease (CHD) and acute myocardial infarction have elevated levels of serum YKL-40. The goal of the present study was to investigate whether the chitinase-like 1 gene-329G/A variant (rs10399931) confers susceptibility to CHD, and whether it is associated with the clinical phenotype and severity of disease.

Methods

We performed a case-control study of 410 unrelated CHD patients (coronary stenosis ≥ 50% or documented myocardial infarction) and 442 controls from China. A ligase detection reaction was used to determine a single-nucleotide polymorphism in rs10399931. The genotypic and allelic associations of this single-nucleotide polymorphism with CHD, phenotypes and severity were also evaluated. Plasma levels of YKL-40 were measured using ELISA assays.

Results

Three genotypes, CC, CT, and TT, existed in rs10399931 and there were no significant differences found in either the genotypic or allelic frequencies between the CHD cases and controls. Patients with CHD had higher YKL-40 levels compared to controls and those with acute myocardial infarction had the highest levels of YKL-40 compared to patients with either stable or unstable angina pectoris (all p < 0.01). Rs10399931 affected neither the main anthropometric or metabolic characteristics, nor did there exists any association between rs10399931 and the severity of coronary lesions assessed by Gensini scores (all p > 0.05).

Conclusions

Our results do not support that rs10399931 is associated with clinical phenotypes of CHD and the extent of coronary lesions; however, YKL-40 levels are higher in CHD patients and associated with its clinical phenotypes.     

Pro-inflammatory cytokine gene polymorphisms and threat for coronary heart disease in a North Indian Agrawal population

The association of IFN-γ (+ 874 A/T; rs2430561), TNF-α (− 308 G/A; rs1800629) and TNF-β (+ 252 A/G; rs909253) with Coronary Heart Disease (CHD) has not been rigorously tested in Indian population. In the present study we sought to examine the role of these cytokines in the causation of CHD and their association with conventional CHD risk factors. A total of 138 case and 187 unrelated healthy controls aged 35 to 80 years, matched on ethnicity and geography were collected from North Indian Agrawal population. Single nucleotide polymorphisms at the promoter TNF-α − 308 G/A and the intronic IFN-γ + 874 A/T were analyzed by allele-specific PCR, and the intronic TNF-β + 252 A/G was analyzed by RFLP. Of the three selected polymorphisms, genotypic distribution of IFN-γ + 874 A/T and TNF-β + 252 A/G polymorphisms was significantly different between patients and controls in the present study. OR revealed statistically significant risk for CHD with respect to IFN-γ + 874 T allele, whereas OR for TNF-β + 252 A/G showed three fold risk in homozygous condition though not significant. No such trend could be observed for TNF-α − 308 G/A polymorphism. Multivariate logistic regression after adjusting for all the confounders showed significant risk for CHD with the genotypes and genotypic combinations of all the three markers (albeit not significant with TNF-α). Increased risk for CHD was likely to be associated with interaction of IFN-γ with diastolic hypertension, TNF-α with diabetes and BMI, and TNF-β with serum triglyceride and very low density lipoprotein (VLDL) levels. The results suggest that these selected cytokine polymorphisms could possibly serve as potential bio-markers for CHD in conjunction with specific conventional risk factors.     

BsmI polymorphisms in vitamin D receptor gene are associated with diabetic nephropathy in type 2 diabetes in the Han Chinese population

We investigated the relationship between BsmI/ApaI polymorphisms in vitamin D receptor gene and diabetic nephropathy in a Han Chinese population. PCR-restriction fragment length polymorphism was used to test the genotype and allele frequency of BsmI and ApaI polymorphisms in 304 patients with type 2 diabetes mellitus (DM group) and 100 control individuals (ND group). The DM group was further divided into DN0 (no diabetic nephropathy), DN1 (diabetes with small amount of albuminuria), DN2 (diabetes with large amount of albuminuria), L/NDN (late-onset DN after 5 years/no DN over the whole follow-up period of 5 years) and EDN (early-onset diabetic nephropathy occurring within first year) subgroup. We found that (1) genotype and allele frequency of BsmI polymorphism had significant difference between DM and ND group; BB+Bb genotype and B allele frequency were significantly higher in DN2 group than in ND and DN0 group; the ApaI polymorphism and allele frequency did not show any difference between DM and ND group; (2) BsmI BB+Bb genotype and B allele frequency were significantly higher in EDN group than in L/NDN group; (3) among patients with nephropathy, albumin excretion rate (AER) in 24-hour urine was significantly higher in those with BB+Bb phenotype than in those with bb phenotype (P<0.01), (4) unconditional logistic regression analysis showed that BsmI BB+Bb genotype was not only correlated with type 2 diabetic nephropathy, but also correlated with early-onset type 2 diabetic nephropathy. We conclude that the allele B (BB or Bb genotype) in vitamin D receptor gene is correlated with large amount albuminuria in the Han Chinese population with type 2 diabetes, and is probably a risk factor for early-onset diabetic nephropathy.     

Association of RAGE gene polymorphism with circulating AGEs level and paraoxonase activity in relation to macro-vascular complications in Indian type 2 diabetes mellitus patients

Background and aims

Sustained interaction of advanced glycation end products (AGEs) with their receptor RAGE and subsequent signaling plays an important role in the development of diabetic complications. Genetic variation of RAGE gene may be associated with the development of vascular complications in type 2 diabetes mellitus (T2DM).

Objectives

The present study aimed to explore the possible association of RAGE gene polymorphisms namely − 374T/A, − 429T/C and G82S with serum level of AGEs, paraoxonase (PON1) activity and macro-vascular complications (MVC) in Indian type 2 diabetes mellitus patients (T2DM).

Methods

A total of 265 diabetic patients, including DM without any complications (n = 135), DM-MVC (n = 130) and 171 healthy individuals were enrolled. Genotyping of RAGE variants were assessed by polymerase chain reaction-restriction fragment length polymorphism. Serum AGEs were estimated by ELISA and fluorometrically. and PON1 activity was assessed spectrophotometrically.

Results

Of the three examined SNPs, association of − 429T/C polymorphism with MVC in T2DM was observed (OR = 3.001, p = 0.001) in the dominant model. Allele ‘A’ of − 374T/A polymorphism seems to confer better cardiac outcome in T2DM. Patients carrying C allele (− 429T/C) and S allele (G82S) had significantly higher AGEs levels. − 429T/C polymorphism was also found to be associated with low PON1 activity. Interaction analysis revealed that the risk of development of MVC was higher in T2DM patients carrying both a CC genotype of − 429T/C polymorphism and a higher level of AGEs (OR = 1.343, p = 0.040).

Conclusion

RAGE gene polymorphism has a significant effect on AGEs level and PON1 activity in diabetic subjects compared to healthy individuals. Diabetic patients with a CC genotype of − 429T/C are prone to develop MVC, more so if AGEs levels are high and PON1 activity is low.     

Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids

Considering that the vitamin D receptor as well as the 1-α-hydroxylase enzyme that converts 25-hydroxyvitamin D (25(OH)D) to its active form 1,25-dihydroxyvitamin D have been found in tissues throughout the body, it is likely that vitamin D is important for more than the calcium balance. Accordingly, low serum levels of 25(OH)D have been associated with mortality, cardiovascular disease, type 2 diabetes, hypertension and obesity. Low serum levels of 25(OH)D have also been associated with an unfavourable lipid profile, which could possible explain the relation with cardiovascular disease and mortality. However, the relation between vitamin D and lipids have so far received little attention and is therefore the main focus of the present review. A PubMed search identified 22 cross-sectional studies where serum levels of 25(OH)D and lipids were related and that included a minimum of 500 subjects, and 10 placebo-controlled double-blind intervention studies with vitamin D where more than 50 subjects were included. In all the cross-sectional studies serum 25(OH)D was positively associated with high-density lipoprotein cholesterol (HDL-C) resulting in a favourable low-density lipoprotein cholesterol (LDL-C) (or total cholesterol) to HDL-C ratio. There was also a uniform agreement between studies on a negative relation between serum 25(OH)D and triglycerides (TG). On the other hand, the intervention studies gave divergent results, with some showing a positive and some a negative effect of vitamin D supplementation. However, none of the intervention studies were specifically designed for evaluating the relation between vitamin D and lipids, none had hyperlipemia as an inclusion criterion, and none were sufficiently powered. In only one study was a significant effect seen with an 8% (0.28 mmol/L) increase in serum LDL-C and a 16% (0.22 mmol/L) decrease in serum TG in those given vitamin D as compared to the placebo group. Accordingly, the effect of vitamin D supplementation on serum lipids is at present uncertain. Considering the numerous other promising vitamins and minerals that when properly tested have been disappointing, one should wait for the results of forthcoming vitamin D intervention studies before drawing conclusions on potential beneficial effects of vitamin D.     

In vitro effect of gliclazide on DNA damage and repair in patients with type 2 diabetes mellitus (T2DM)

Type 2 diabetes mellitus is associated with elevated level of oxidative stress, which is one of the most important factors responsible for the development of chronic complications of this disease. Moreover, it was shown that diabetic patients had increased level of oxidative DNA damage and decreased effectiveness of DNA repair. These changes may be associated with increased risk of cancer in T2DM patients, since DNA damage and DNA repair play a pivotal role in malignant transformation. It was found that gliclazide, an oral hypoglycemic drug with antioxidant properties, diminished DNA damage induced by free radicals. Therefore, the aim of the present study was to evaluate the in vitro impact of gliclazide on: (i) endogenous basal and oxidative DNA damage, (ii) DNA damage induced by hydrogen peroxide and (iii) the efficacy of DNA repair of such damage. DNA damage and DNA repair in peripheral blood lymphocytes of 30 T2DM patients and 30 non-diabetic individuals were evaluated by alkaline single cell electrophoresis (comet) assay. The extent of oxidative DNA damage was assessed by DNA repair enzymes: endonuclease III and formamidopyrimidine-DNA glycosylase. The endogenous basal and oxidative DNA damages were higher in lymphocytes of T2DM patients compared to non-diabetic subjects and gliclazide decreased the level of such damage. The drug significantly decreased the level of DNA damage induced by hydrogen peroxide in both groups. Gliclazide increased the effectiveness of DNA repair in lymphocytes of T2DM patients (93.4% (with gliclazide) vs 79.9% (without gliclazide); P< or =0.001) and non-diabetic subjects (95.1% (with gliclazide) vs 90.5% (without gliclazide); P< or =0.001). These results suggest that gliclazide may protect against the oxidative stress-related chronic diabetes complications, including cancer, by decreasing the level of DNA damage induced by reactive oxygen species.     

Genetic predisposition to obesity and risk of subclinical atherosclerosis

Obesity has been associated with increased common carotid artery (CCA) intima–media thickness (IMT), a measure of subclinical atherosclerosis. We assessed the association between genetic predisposition to obesity and CCA IMT. The study included 428 young Chinese adults with CCA IMT measured using a high-resolution B-mode tomographic ultrasound system. We created a genetic risk score (GRS) by summing the risk alleles of 6 obesity-associated genetic variants confirmed in our previous analyses. The GRS was significantly associated with greater CCA IMT (p < 0.001) after adjustment for age and gender. Per 2 alleles of the GRS was related to 0.023 mm increment in IMT. The association was attenuated by one half with additional adjustment for obesity status, but remained significant (p = 0.009). In addition, we found that blood pressure significantly modified the association between the GRS and CCA IMT (p for interaction = 0.001). The associations between the GRS and CCA IMT were stronger in participants with systolic blood pressure (SBP) ≥ 120 mm Hg and/or diastolic blood pressure (DBP) ≥ 80 mm Hg (per 2 allele increment of the GRS relating to 0.028 mm greater CCA IMT, p for trend < 0.001) than those with SBP < 120 mm Hg and DBP < 80 mm Hg (per 2 allele increment of the GRS relating to 0.001 smaller CCA IMT, p for trend = 0.930). Our data provides suggestive evidence supporting the potential causal relation between obesity and development of subclinical atherosclerosis. Elevated blood pressure might amplify the adverse effect of obesity on cardiovascular risk.     

Association of adiponectin (AdipoQ) and sulphonylurea receptor (ABCC8) gene polymorphisms with Type 2 Diabetes in North Indian population of Punjab

In Type 2 Diabetes (T2D), adiponectin (AdipoQ) and sulphonylurea receptor genes (ABCC8) are important targets for candidate gene association studies. The single nucleotide polymorphisms (SNPs) in these genes have been associated with features of the metabolic syndrome across various populations. The present case–control study undertaken in the population of Punjab, evaluates the association of + 45T>G polymorphism in AdipoQ gene; and Exon16-3C>T as well as Exon18C>T polymorphisms in ABCC8 gene with T2D. These SNPs were genotyped in 200 T2D cases and 200 non-diabetic healthy controls using the PCR-RFLP method. The frequency of the minor G-allele for AdipoQ+ 45(T>G) polymorphism was significantly higher in T2D cases (29.0%) than in controls (21.5%) [P = 0.02, OR = 1.49 (1.07–2.04)]. The genetic model analysis revealed that the G-allele cumulatively provides nearly 1.59–1.78 fold increased risk to T2D under the additive (P = 0.009; OR = 1.59, 1.12–2.25 at 95% CI), dominant (TG/GG vs. TT) (P = 0.034, OR = 1.64, 1.04–2.56 at 95% CI) and codominant model (TG vs. TT/GG) (P = 0.014; OR = 1.78, 1.12–2.82 at 95% CI) after adjusting for confounding factors. However, no difference in the distribution of genotype and allele frequencies was observed for both the ABCC8 polymorphisms. The distribution of obesity profiles (BMI, WC and WHR) was also significantly different between cases and controls (P < 0.05). Higher BMI and central obesity were observed to increase the risk of T2D. G-allele of + 45(T>G) polymorphism in the adiponectin gene appears to be associated with increased risk of T2D, but the polymorphisms in sulphonylurea receptor gene do not seem to be associated with T2D in the population of Punjab.