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

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.

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CRP Gene Polymorphism and Their Risk Association With Type 2 Diabetes Mellitus

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2019.014 ◽

2019 ◽

Vol 7 (1) ◽

pp. 33-37

Author(s):

Hakim Bahlok Jebur ◽

Mirza Masroor ◽

Hafiz Ahmad ◽

Naushad Ahmad Khan ◽

Juheb Akther ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gene Polymorphism ◽

Inflammatory Marker ◽

Genotype Distribution ◽

Reactive Protein ◽

Specific Pcr ◽

Increased Risk ◽

Significant Difference ◽

Allele Specific

BACKGROUND: C-reactive protein (CRP) is an inflammatory marker associated with T2DM, obesity, insulin resistance, and cardiovascular disease. AIM: The present study evaluates the association of CRP +1059 G/C polymorphism of the CRP gene in 100 T2D cases and 100 healthy controls. METHODS: Present study was done by allele specific PCR method to study the CRP gene polymorphism in study subjects. RESULTS: Study found that CRP (+1059 G/C) genotype distribution among case and controls was found to be significant (p=0.001), Higher CRP C allele frequency (0.16) was observed compared to controls (0.04). CRP +1059 GC and CC had 2.72 (1.12-6.61), 20.56 (1.16-362.1) risk for T2D. It has been observed, HTN, Obesity, Smoking and alcoholism was found to be associated with increased risk of T2D, and a significant difference was observed in biochemical parameters. CONCLUSION: Study concluded that CRP gene polymorphism was found to be associated with risk of Type 2 Diabetes and risk was linked with heterozygosity and mutant homozygosity. Hypertension, Obesity, Smoking and alcoholism increases the risk of occurrence of Type 2 Diabetes.

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A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum

International Journal of Molecular Sciences ◽

10.3390/ijms20133257 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3257 ◽

Cited By ~ 2

Author(s):

Sophie Gravel ◽

Benoit Panzini ◽

Francois Belanger ◽

Jacques Turgeon ◽

Veronique Michaud

Keyword(s):

Type 2 Diabetes ◽

Mrna Expression ◽

Drug Metabolizing Enzymes ◽

Mrna Levels ◽

Metabolizing Enzymes ◽

Expression Levels ◽

The Impact ◽

Duodenal Biopsies ◽

Mrna Expression Levels

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein−1 min−1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.

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Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues

Pharmaceutics ◽

10.3390/pharmaceutics9040040 ◽

2017 ◽

Vol 9 (4) ◽

pp. 40 ◽

Cited By ~ 9

Author(s):

Sarah Maximos ◽

Michel Chamoun ◽

Sophie Gravel ◽

Jacques Turgeon ◽

Veronique Michaud

Keyword(s):

Type 2 Diabetes ◽

Drug Metabolizing Enzymes ◽

Mrna Levels ◽

Metabolizing Enzymes ◽

Tissue Specific ◽

Diet Induced Obesity ◽

Obesity In Mice ◽

The Impact

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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

Clinical Chemistry ◽

10.1373/clinchem.2017.277103 ◽

2017 ◽

Vol 63 (12) ◽

pp. 1866-1876 ◽

Cited By ~ 14

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.

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

10.2337/figshare.12906803 ◽

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 in vivo mosaic transgenesis assays in zebrafish to quantitatively test the enhancer activity of type 2 diabetes-associated loci. 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 SLC30A8 exon, encoding a tryptophan-to-arginine substitution that decreases SLC30A8 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 in vivo 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.

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

BioMed Research International ◽

10.1155/2018/8167538 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

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.

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

Annals of Nutrition and Metabolism ◽

10.1159/000508024 ◽

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.

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

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2017-0232 ◽

2017 ◽

Vol 42 (12) ◽

pp. 1316-1321 ◽

Cited By ~ 4

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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