scholarly journals Kringle IV Type 2, Not Low Lipoprotein(a), as a Cause of Diabetes: A Novel Genetic Approach Using SNPs Associated Selectively with Lipoprotein(a) Concentrations or with Kringle IV Type 2 Repeats

2017 ◽  
Vol 63 (12) ◽  
pp. 1866-1876 ◽  
Author(s):  
Andra Tolbus ◽  
Martin B Mortensen ◽  
Sune F Nielsen ◽  
Pia R Kamstrup ◽  
Stig E Bojesen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Odds Ratio ◽  
Plasma Concentrations ◽  
Nucleotide Polymorphisms ◽  
Genetic Approach ◽  
Lipoprotein A ◽  
Heart Study ◽  
Increased Risk ◽  
Per Se

Abstract BACKGROUND Low plasma lipoprotein(a) concentrations are associated with type 2 diabetes. Whether this is due to low lipoprotein(a) concentrations per se or to a large number of kringle IV type 2 (KIV-2) repeats remains unclear. We therefore aimed to identify genetic variants associated selectively with lipoprotein(a) concentrations or with the number of KIV-2 repeats, to investigate which of these traits confer risk of diabetes. METHODS We genotyped 8411 individuals from the Copenhagen City Heart Study for 778 single-nucleotide polymorphisms (SNPs) in the proximity of the LPA gene, and examined the association of these SNPs with plasma concentrations of lipoprotein(a) and with KIV-2 number of repeats. SNPs that were selectively associated with lipoprotein(a) concentrations but not with KIV-2 number of repeats, or vice versa, were included in a Mendelian randomization study. RESULTS We identified 3 SNPs (rs12209517, rs12194138, and rs641990) that were associated selectively with lipoprotein(a) concentrations and 3 SNPs (rs1084651, rs9458009, and rs9365166) that were associated selectively with KIV-2 number of repeats. For SNPs selectively associated with lipoprotein(a) concentrations, an allele score of 4–6 vs 0–2 had an odds ratio for type 2 diabetes of 1.03 (95% CI, 0.86–1.23). In contrast, for SNPs selectively associated with KIV-2 number of repeats, an allele score of 4–6 vs 0–2 had an odds ratio for type 2 diabetes of 1.42 (95% CI, 1.17–1.69). CONCLUSIONS Using a novel genetic approach, our results indicate that it is a high number of KIV-2 repeats that are associated causally with increased risk of type 2 diabetes, and not low lipoprotein(a) concentrations per se. This is a reassuring finding for lipoprotein(a)-lowering therapies that do not increase the KIV-2 number of repeats.

Analysis of the Potential Association of Drug-Metabolizing Enzymes CYP2C9*3 and CYP2C19*3 Gene Variations With Type 2 Diabetes: A Case-Control Study

2020 ◽  
Vol 21 (14) ◽  
pp. 1152-1160
Author(s):  
Imadeldin Elfaki ◽  
Rashid Mir ◽  
Faisel Mohammed Abu-Duhier ◽  
Chandan Kumar Jha ◽  
Adel Ibrahim Ahmad Al-Alawy ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Antiplatelet Drug ◽  
Drug Metabolizing Enzymes ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Specific Pcr ◽  
Increased Risk ◽  
Different Populations

Background:: Cytochrome P450s (CYPs) are drug-metabolizing enzymes catalyzing the metabolism of about 75% of drug in clinical use. CYP2C9 represents 20% CYP proteins in liver cells and is a crucial member of CYPs superfamily. CYP2C19 metabolizes very important drugs such as antiulcer drug omeprazole, the antiplatelet drug clopidogrel and anticonvulsant mephenytoin. Single nucleotide polymorphisms (SNPs) of CYP genes have been associated with unexpected drug reactions and diseases in different populations. Objective:: We examined the associations of CYP2C9*3 (rs1057910) and CYP2C19*3 (rs4986893) with T2D in Saudi population. Methods:: We used the allele-specific PCR (AS-PCR) and DNA sequencing in 111 cases and 104 controls for rs1057910, and in 119 cases and 110 controls for rs4986893. Results:: It is indicated that the genotype distribution of rs1057910 in cases and controls were not significantly different (P=0.0001). The genotypes of rs1057910 were not associated with type 2 diabetes (T2D) (P>0.05). Whereas the genotype distribution of rs4986893 in cases and controls was significantly different (P=0.049). The AA genotype of rs4986893 may be associated in increased risk to T2D with OR=17.25 (2.06-143.8), RR=6.14(0.96-39.20), P=0.008. Conclusion:: The CYP2C9*3 (rs1057910) may not be associated with T2D, while CYP2C19*3 (rs4986893) is probably associated with T2D. These findings need to be validated in follow-up studies with larger sample sizes and different populations.

Abstract MP037: Plasma Organochlorine Concentration and Risk of Diabetes: the Nurses' Health Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Hongyu Wu ◽  
Kimberly A Bertrand ◽  
Anna L Choi ◽  
Frank B Hu ◽  
Francine Laden ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Polychlorinated Biphenyl ◽  
Plasma Concentrations ◽  
Diabetes Risk ◽  
Health Study ◽  
Blood Draw ◽  
Incident Type ◽  
Increased Risk ◽  
Incident Type 2 Diabetes

Background: Animal experiments have suggested that exposure to persistent organic pollutants (POPs) may lead to increased risk of type 2 diabetes. Although recent human studies supported this hypothesis, evidence from prospective investigations is sparse. Objective: To examine the associations of plasma POP concentrations with risk of incident type 2 diabetes in a prospective setting among US women. Methods: Study population was comprised of participants from two independent nested case-control studies in the Nurses’ Health Study, in which major polychlorinated biphenyl (PCB 118, 138, 153, and 180), p-p'- dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyltrichloroethane (DDT), and hexachlorobenzene (HCB) were measured. A non-parametric approach was used to derive standardized scores for plasma concentrations of lipid-adjusted POPs within each study to minimize between-study variation of the POP measurements. Risk of incident type 2 diabetes during the follow-up period (1990-2008) across the tertiles of the scores was examined. Results: Of 1,120 participants, we identified 48 incident type 2 diabetes cases. After adjusting for covariates assessed at blood draw in 1990, including smoking status, body mass index, and total fish intake, plasma HCB concentration was positively associated with type 2 diabetes risk: odds ratio (OR) (95% confidence interval [CI]) was 2.77 (1.17, 6.55, P for trend =0.022) comparing the highest vs. lowest tertile. Other POPs were not significantly associated with diabetes: the ORs (95% CI) were 1.10 (0.51, 2.34, P for trend =0.81) for p-p'-DDE, 0.93 (0.44, 1.95, P for trend =0.86) for DDT, and 0.88 (0.39, 1.97, P for trend =0.76) for sum of the 4 major PCBs, comparing the extreme tertiles. Conclusion: The significant association of plasma HCB concentration with diabetes risk supports a role of POP exposure in the etiology of type 2 diabetes. More prospective data are warranted to confirm these findings.

scholarly journals Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Habiba Alsafar ◽  
Ahmed Hassoun ◽  
Shaikha Almazrouei ◽  
Wala Kamal ◽  
Mustafa Almaini ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Angiotensin Converting Enzyme ◽  
Odds Ratio ◽  
Association Studies ◽  
Converting Enzyme ◽  
Obesity Status ◽  
Increased Risk

The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped forACEI/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of theACEI/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status,ACEDD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34,p=0.086] or hypertension [odd ratio (OR) = 1.02,p=0.93]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotypeACEDD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80,p=0.02] but was found to be protective against the hypertension in the obese group ((OR) = 0.54,p=0.01). However, there was no effect of obesity status on the association ofACEgenotypes with T2DM. The risk of hypertension associated withACEDD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed thatACEI/D polymorphism is not associated with T2DM risk in Emirati population.

scholarly journals The E23K Variant of KCNJ11 Encoding the Pancreatic β-Cell Adenosine 5′-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes

2006 ◽  
Vol 91 (6) ◽  
pp. 2334-2339 ◽  
Author(s):  
Giorgio Sesti ◽  
Emanuela Laratta ◽  
Marina Cardellini ◽  
Francesco Andreozzi ◽  
Silvia Del Guerra ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Outcome Measure ◽  
Combined Therapy ◽  
Diabetic Patients ◽  
Main Outcome Measure ◽  
Increased Risk ◽  
Secondary Failure

Abstract Context: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking. Objective: The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure. Design: Secondary sulfonylurea failure was defined as fasting plasma glucose greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia. Setting: The study was conducted in an ambulatory care facility. Patients: A total of 525 Caucasian type 2 diabetic patients were enrolled in the study. Intervention: Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment. Main Outcome Measure: Secondary failure was the main outcome measure. Results: Of the diabetic patients enrolled in the study, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58 and 66.8% among patients treated with oral therapy or secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 1.01–2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (odds ratio, 1.69; 95% confidence interval, 1.02–2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). After 24-h exposure to high (16.7 mmol/liter) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant. Conclusions: These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.

scholarly journals In vivo reporter assays uncover changes in enhancer activity caused by type 2 diabetes associated SNPs

2020 ◽  
Author(s):  
Ada Admin ◽  
Ana Eufrásio ◽  
Chiara Perrod ◽  
Marta Duque ◽  
Fábio J.Ferreira ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Nucleotide Mutation ◽  
Reporter Assays ◽  
Coding Snp

Many single nucleotide polymorphisms (SNPs) associated to type 2 diabetes overlap with putative endocrine pancreatic enhancers, suggesting that these SNPs modulate enhancer activity and consequently, gene expression. We performed <i>in vivo</i> mosaic transgenesis assays in zebrafish to quantitatively test the enhancer activity of type 2 diabetes-associated <i>loci</i>. Six out of ten tested sequences are endocrine pancreatic enhancers. The risk variant of two sequences decreased enhancer activity, while in another two incremented it. One of the latter (rs13266634) locates in a <i>SLC30A8 </i>exon, encoding a tryptophan-to-arginine substitution that decreases <i>SLC30A8 </i>function, being the canonical explanation for type 2 diabetes risk association. However, other type 2 diabetes associated SNPs that truncate SLC30A8, confer protection to this disease, contradicting this explanation. Here, we clarify this incongruence showing that rs13266634 boosts the activity of an overlapping enhancer, suggesting a SLC30A8 gain-of-function as the cause for the increased risk for the disease. We further dissected the functionality of this enhancer finding a single nucleotide mutation sufficient to impair its activity. Overall, this work assesses <i>in vivo</i> the importance of disease-associated SNPs in the activity of endocrine pancreatic enhancers, including a poorly explored case where a coding SNP modulates the activity of an enhancer.

scholarly journals Associations between Aquaglyceroporin Gene Polymorphisms and Risk of Type 2 Diabetes Mellitus

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Yijun Wang ◽  
Gang Chen ◽  
Qingyun Tu ◽  
Junxia Wu ◽  
Yu Qin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Diseases ◽  
Proteinase K ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Polymerase Chain ◽  
And Gender

Objectives. AQP7 and AQP9 represent glycerol channel in adipose tissue and liver and have been associated with metabolic diseases. We aimed to investigate the associations between genetic variants in AQP7 and AQP9 genes and the risk of type 2 diabetes (T2DM) in Chinese population. Methods. Blood samples were drawn from 400 T2DM patients and 400 age- and gender-matched controls. Genomic DNA was extracted by proteinase K digestion and phenol–chloroform extraction. Genotyping of 5 single nucleotide polymorphisms (SNPs) in AQP7 (rs2989924, rs3758269, and rs62542743) and AQP9 (rs57139208, rs16939881) was performed by the polymerase chain reaction assay with TaqMan probes. Results. The subjects with rs2989924 GA+AA genotypes had 1.47-fold increased risk of T2DM (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.06-2.04), compared to those with GG genotype, and this association remained significant after adjustment for covariates (OR 1.66, 95% CI 1.07-2.57). When compared with rs3758269 CC genotype, the subjects with CT+TT genotypes had 45% decreased T2DM risk after multivariate adjustment (OR 0.55, 95% CI 0.35-0.85). The associations were evident in elder and overweight subjects and those with central obesity. No association was observed between AQP9 SNPs and T2DM risk. Conclusions. AQP7 SNP rs2989924 and rs3758269 were associated with T2DM risk in Chinese Han population.

Evaluation of the Associations of GC and CYP2R1 Genes and Gene-Obesity Interactions with Type 2 Diabetes Risk in a Chinese Rural Population

2020 ◽  
Vol 76 (3) ◽  
pp. 175-182
Author(s):  
Yanting Zhao ◽  
Gaoshuai Wang ◽  
Yuqian Li ◽  
Xiaotian Liu ◽  
Li Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Interaction Analysis ◽  
Allele Carrier ◽  
Gene Variants ◽  
Nucleotide Polymorphisms ◽  
Additive Interaction ◽  
Asian Populations ◽  
Increased Risk ◽  
Gc Gene

Introduction: Group-specific component (GC) and cytochrome P450 family 2 subfamily R member 1 (CYP2R1) gene polymorphisms and obesity have been associated with an increased risk for development of type 2 diabetes mellitus (T2DM) in Asian populations. Objective: This study assessed the associations of interactions between GC gene variants and CYP2R1 gene variants and between genes and obesity with T2DM risk. Methods: A study that included 2,271 subjects was performed. Eight single nucleotide polymorphisms in the GC and CYP2R1 genes were genotyped. Interaction analysis was performed using rs7041 in the GC gene and rs1993116 in the CYP2R1 gene. The effects of multiplicative and additive gene-gene and gene-environment interactions on T2DM risk were assessed. Results: The T2DM risk was significantly associated with being overweight/obese, abdominal obesity, rs7041, and rs1993116. A significant additive interaction between rs1993116 and rs7041 was associated with T2DM. In addition, there was a significant multiplicative interaction between rs7041 and body mass index (BMI) associated with elevated blood glucose levels, and at a higher BMI (>28.47), the G allele carrier showed a stronger effect than the TT genotype. Conclusions: The interactions between GC rs7041-CYP2R1 rs1993116 and GC rs7041-BMI may explain the mechanisms by which these factors increase the risk of T2DM development.

Early-Onset Subgroup of Type 2 Diabetes and Risk of Dementia, Alzheimer’s disease and Stroke: A Cohort Study

2021 ◽  
pp. 1-6
Author(s):  
K. Wang ◽  
H. Liu
Keyword(s):  
Type 2 Diabetes ◽  
Early Onset ◽  
Glycemic Status ◽  
Community Based ◽  
Diabetes Onset ◽  
Onset Diabetes ◽  
Heart Study ◽  
Increased Risk ◽  
Onset Of Diabetes

BACKGROUND: This study aimed to assess the relation of early-onset type 2 diabetes (age<55years) versus later in life to the risk of dementia, Alzheimer Disease (AD) dementia and stroke. Methods: This study was based on the Framingham Heart Study Offspring cohort (FHS-OS) which is a community-based prospective cohort. Glycemic status was ascertained at serial examinations over six decades among participants who initially did not have diabetes. Surveillance for incident events including dementia and stroke has been continued for approximately 30 years. Results: At baseline, there were 142 (5%) subjects with onset of diabetes prior to age 55 years, 172 (6%) subjects with 55-64 years, 349 (11%) subjects over 65 years and 2389 (78%) subjects without diabetes. The risk of dementia, AD and stroke increased with decreasing age of diabetes onset (P<0.05, for trend). Compared with never developing diabetes, early-onset diabetes conferred a higher risk of all dementia, AD dementia and stroke [HR 2.86(1.16-5.51) for dementia; HR 2.42(1.63-4.33) for AD; HR 2.85(1.37-3.98) for stroke]. Whereas later-onset diabetes was only associated with greater risk for stroke, neither dementia nor AD. Conclusion: Early-onset diabetes was stronger associated with an increased risk of all dementia, AD dementia and stroke than later-onset.

Pharmacogenetics of sulfonylurea-induced hypoglycemia in Type 2 diabetes patients: the SUCLINGEN study

2021 ◽  
Author(s):  
Navin Kumar Loganadan ◽  
Hasniza Zaman Huri ◽  
Shireene Ratna Vethakkan ◽  
Zanariah Hussein
Keyword(s):  
Type 2 Diabetes ◽  
Odds Ratio ◽  
Gene Polymorphisms ◽  
Prospective Observational Study ◽  
Severe Hypoglycemia ◽  
Prior History ◽  
Increased Risk ◽  
History Of

Aim: This study investigated the incidence of sulfonylurea-induced hypoglycemia and its predictors in Type 2 diabetes (T2D) patients. Patients & methods: In this prospective, observational study, T2D patients on maximal sulfonylurea-metformin therapy >1 year were enrolled. Hypoglycemia was defined as having symptoms or a blood glucose level <3.9 mmol/l. Results: Of the 401 patients, 120 (29.9%) developed sulfonylurea-induced hypoglycemia during the 12-month follow-up. The ABCC8 rs757110, KCNJ11 rs5219, CDKAL1 rs7756992 and KCNQ1 rs2237892 gene polymorphisms were not associated with sulfonylurea-induced hypoglycemia (p > 0.05). Prior history of hypoglycemia admission (odds ratio = 16.44; 95% CI: 1.74–154.33, p = 0.014) independently predicted its risk. Conclusion: Sulfonylurea-treated T2D patients who experienced severe hypoglycemia are at increased risk of future hypoglycemia episodes.

scholarly journals Interactions between genetic polymorphisms of glucose metabolizing genes and smoking and alcohol consumption in the risk of type 2 diabetes mellitus

2017 ◽  
Vol 42 (12) ◽  
pp. 1316-1321 ◽  
Author(s):  
Kaiping Gao ◽  
Yongcheng Ren ◽  
Jinjin Wang ◽  
Zichen Liu ◽  
Jianna Li ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Lifestyle Factors ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Gene Environment ◽  
Increased Risk ◽  
The Impact

The impact of gene-environment interaction on diabetes remains largely unknown. We aimed to investigate if interaction between glucose metabolizing genes and lifestyle factors is associated with type 2 diabetes mellitus (T2DM). Interactions between genotypes of 4 glucose metabolizing genes (MTNR1B, KCNQ1, KLF14, and GCKR) and lifestyle factors were estimated in 722 T2DM patients and 759 controls, using multiple logistic regression. No significant associations with T2DM were detected for the single nucleotide polymorphisms of MTNR1B, KLF14 and GCKR. However, rs151290 (KCNQ1) polymorphisms were found to be associated with risk of T2DM. Compared with AA, the odds ratios (ORs) of AC or CC genotypes for developing T2DM were 1.545 (P = 0.0489) and 1.603 (P = 0.0383), respectively. In stratified analyses, the associations were stronger in smokers with CC than smokers with AA (OR = 3.668, P = 0.013); drinkers with AC (OR = 5.518, P = 0.036), CC (OR = 8.691, P = 0.0095), and AC+CC (OR = 6.764, P = 0.016) than drinkers with AA. Compared with nondrinkers with AA, drinkers who carry AC and CC had 12.072-fold (P = 0.0007) and 8.147-fold (P = 0.0052) higher risk of developing T2DM. In conclusions, rs151290 (KCNQ1) polymorphisms are associated with increased risk of T2DM, alone and especially in interaction with smoking and alcohol.

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