Haplotype-based association study of TCF7L2 gene variants with the development of diabetic retinopathy in an Iranian population.

BACKGROUND: Diabetic retinopathy (DR) is recognized as one of the most prevalent complications of diabetes and a major cause of morbidity. Transcription factor 7-like 2 (TCF7L2), a pivotal component in the Wnt-signaling pathway, plays a significant role in ß-cell development, blood-glucose homeostasis, cell survival, cell migration, and cell proliferation. Thus, this study aimed to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs12255372) with DR in a population-based association study. MATERIALS AND METHODS: DNA was extracted from whole blood of all subjects by salting-out procedure. Total 524 T2DM patients including 234 T2DM individuals without DR and 290 T2DM individuals with DR were genotyped by TaqMan assay technology. Clinical characteristics of subjects were conducted to evaluate the plausible association between TCF7L2 variants and DR with univariate linear regression analysis. RESULTS: Demographic analysis between case and control groups revealed significant differences in FBS, HbA1c, lipidemia, heart disease, and family history of T2DM (p < 0.05). No significant difference was observed in either genotypes distribution or allele frequency (p > 0.05) between T2DM individuals with and without DR in any models of inheritance. Genotype-phenotype association showed no significant association. Result of analysis indicated that HbAlc with adjusted OR of 1.8 (p < 0.0001) and first-degree relatives of family history with adjusted OR of 3.04 (p < 0.0001) were significantly associated with DR. Finally, haplotype analysis showed no noticeable association. CONCLUSION: In conclusion, there was no significant genetic association between rs7903146, rs11196205, and rs12255372 with DR among T2DM Iranians; however, these variants may play unknown roles in other populations.

Prevalence of Chromosomal Abnormalities in Iranian Patients with Infertility.

BACKGROUND: The numerical and structural abnormalities of chromosomes are the most common cause of infertility. Here, we evaluated the prevalence and types of chromosomal abnormalities in Iranian infertile patients. METHODS: We enrolled 1750 couples of reproductive age with infertility, who referred to infertility clinics in Tehran during 2014- 2019, in order to perform chromosomal analysis. Peripheral blood samples were obtained from all couples and chromosomal abnormalities were evaluated by G-banded metaphase karyotyping. In some cases, the detected abnormalities were confirmed using fluorescence in-situ hybridization (FISH). RESULTS: We detected various chromosomal abnormalities in 114/3500 (3.257%) patients with infertility. The prevalence of chromosomal abnormalities was 44/114 (38.596%) among infertile females and 70/114 (61.403%) among infertile males. Structural chromosomal abnormalities were found in 27/1750 infertile females and 35/1750 infertile males. Numerical chromosomal abnormalities were found in 17/1750 of females and 35/1750 of males. The 45, XY, rob (13;14) (p10q10) translocation and Klinefelter syndrome (47, XXY) were the most common structural and numerical chromosomal abnormalities in the Iranian infertile patients, respectively. CONCLUSION: In general, we found a high prevalence of chromosomal abnormalities in Iranian patients with reproductive problems. Our study highlights the importance of cytogenetic studies in infertile patients before starting infertility treatments approaches.

Role of ENPP1 Gene Variants in the Susceptibility to Diabetic Nephropathy in Patients with type 2 Diabetes Mellitus.

Genetic factors are known to play a significant role in the susceptibility of diabetic patients to severe complications such as diabetic nephropathy (DN). This study aimed to evaluate the association between polymorphism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) variants (rs997509, K121Q, rs1799774, and rs7754561) and DN in patients with type 2 diabetes mellitus (T2DM). A total number of 492 patients with T2DM with and without DN were categorized into case and control groups. The extracted DNA samples were genotyped using TaqMan allelic discrimination assay amplified by polymerase chain reaction (PCR). The haplotype analysis among the case and control groups was performed using an expectation-maximization algorithm by the maximum-likelihood method. The analysis of laboratory findings demonstrated significant differences in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) between the case and control groups (P < 0.05). The results showed that K121Q was significantly related to DN under a recessive model of inheritance (P = 0.006); however, rs1799774 and rs7754561 both were protective for DN under a dominant model of inheritance (P = 0.034 and P = 0.010, respectively) among four studied variants. Two haplotypes, including C-C-delT-G with a frequency < 0.02 and T-A-delT-G with a frequency < 0.01, were associated with the increased risk of DN (P < 0.05). The present study demonstrated that K121Q was associated with the susceptibility of DN; however, rs1799774 and rs7754561 were protecrtive variants for DN in patients with T2DM.

Single-locus and Haplotype Associations of GRIN2B Gene with Autism Spectrum Disorders and the Demographic and Clinical Characteristics of Patients in Guilan, Iran.

Autism spectrum disorders (ASDs) are described as generalized developmental disorders, with an average age of onset of 36 months. Genetic and environmental factors may contribute to this multifactorial disorder. The present study aimed to investigate the association of three GRIN2B polymorphisms, including rs1019385, rs1024893, and rs3764028, with ASDs. Based on the results, there was a significant difference regarding the genotype frequency of rs3764028 polymorphism between the control and case (ASD) groups (P = 0.027). According to the recessive model, this variant was associated with ASDs (P = 0.23). None of the eight haplotype models with frequencies above 0.5 showed significant differences between the case and control groups in terms of allelic frequency. The present results showed that the rs376028 variant was directly related to the phenotypic symptoms of ASDs.

A study on methylation of two CpG islands of MAOA gene promoter among opium-addicted males undergoing methadone treatment.

The association between methylation of MAOA gene promoter and alcohol and nicotine dependence has been demonstrated in women but not in men yet. Antisocial personality disorder (ASPD) and substance use disorders (SUD) are two types of disorders that could highly be influenced by methylation-induced changes in MAOA function. The aim of the current study is to investigate the effect of opioid addiction on methylation of MAOA gene promoter in males. DNA was extracted from the whole blood of all samples (29 opium-addicted individuals undergoing methadone treatment and 28 healthy people) according to the extraction protocol, followed by treating these samples with bisulfite kits. The investigated region including two CpG islands in the promoter region of MAOA gene contained 35 CpG dinucleotides investigated through Sanger sequencing method. The frequency of methylation at two CpG islands of MAOA gene promoter regions was equal to zero among addicted individuals undergoing methadone treatment and healthy peoples. Then, comparing methylation levels among the study group is not applicable. In conclusion, there was no association between opium addiction and methylation of the MAOA promoter regions in opium-addicted male undergoing methadone treatment.

Association Study of Opioid Receptor Delta-Type 1 (OPRD1) Gene Variants with Nicotine Dependence in an Iranian Population.

Twins studies indicate that many individual factors are associated with genetic polymorphisms in tobacco use, dependence vulnerability, and the ability to quit smoking. Opioid receptor delta-type 1 (OPRD1) is one of the most important genes in the opioid pathway. Therefore, the current study aimed to investigate the association of variants located in the intron 1 of the OPRD1 gene, including rs2236857, rs2236855, and rs760589, with susceptibility to nicotine dependence among northern Iranians. DNA of 426 individuals, including 224 smokers and 202 healthy people, were extracted with the salting-out standard technique, qualified with Agarose gel, then quantified with Nanodrop, and finally genotyped by Amplification Refractory Mutation System (ARMS) PCR. All statistical analyses were performed by SNPAlyze version 8.1 and SPSS version 20. Results revealed no significant association of all three studied variants with the susceptibility to nicotine dependence in any models of inheritance. However, there were five haplotypes with an overall frequency higher than 0.05; no significant impact of any of them on nicotine dependence was observed. Altogether, rs2236857, rs2236855, and rs760589 were not associated with nicotine dependence among northern Iranians.

Significant Destructive Interaction of BDNF Val>Met Polymorphism with Stroke Severity and Family History of Dementia for Cognitive Impairments.

PURPOSE: The patients with more severe stroke, have more chance to develop higher levels of cognitive impairments; and family history of dementia as a genetic background, can give rise to an increased risk of the severity of cognitive deterioration. In this study, we sought to investigate whether the risk alleles of Val66Met of brain-derived neurotrophic factor (BDNF) polymorphism, has a destructive interaction with the stroke severity (SS) and family history of dementia (FHD) for cognitive impairments? METHOD: In a case-control study, the carriers of at least one Val allele (n=56) were compared to the carriers of Met/Met homozygotes (n=156) in terms of FHD and SS (through National Institutes of Health Stroke Scale) on the north of Iran. To determine the cognitive functions, the third version of Addenbrooke's Cognitive Examination (ACE-III) was used. RESULT: The mean age of patients was 64.52±11.71, and in average 202 day had passed from their stroke. The interactive effects of genotypes Val66Met BDNF with SS[F=8.95, ή2=0.04, P=0.003] and FHD[F=4.59, ή2=0.02, P=0.03] were significant for total score of ACE-III. It means that the Met/ Met homozygosity, modulated the effect of risk factors of SS and FHD on the cognitive function. Such homozygosity protects the attentional function and language abilities against the SS and FHD(P≤0.05). CONCLUSION: It can be speculated that presence of Val/Met heterozygosity has a destructive interaction with the SS and FHD for decreasing the cognitive function, particularly in attention and language domains. Our findings suggested that the inhibition of signaling and trafficking of Val/Met heterozygosity is possibly a practical strategy in reducing the cognitive impairments following the stroke.

Evaluation of beta-thalassemia in the fetus through cffDNA with multiple polymorphisms as a haplotype in the beta-globin gene.

OBJECTIVE: Invasive biopsy during the pregnancy is associated with an abortion risk of approximately 1% for the fetus. Free fetal DNA in maternal plasma is an excellent source of genetic material for prenatal molecular diagnoses. This study was conducted to investigate beta-thalassemia mutation in the fetus through maternal blood with multiple polymorphisms as haplotypes in the beta-globin gene. METHODS: In this study, a total of 33 beta-thalassemia carrier (minor) couples were genotyped by ARMS-PCR for IVSII-IG>A mutation. During pregnancy, 10mL of blood was collected from pregnant women, and DNA was extracted by the magnetic bead-based extraction, and fetal DNA was enriched with AMPure XP kit. Five polymorphisms in 4 haplotype groups were evaluated by the Sanger Sequencing method. Finally, results were compared with those of the invasion method. RESULTS: Participants in study were 33 couples, mean age of the men was 26±5 years, and mean age of women was 23±4 years, and mean MCV, MCH, HbA2 blood parameters were 62.4±5.3, 19.6±3.1, 4.2±2.1 respectively. A total of 33 fetuses were genotyped for IVSII-IG>A mutation. Nine fetuses were affected, 10 fetuses were normal and 14 fetuses were carrier of beta-thalassemia. Sensitivity and specificity of Sanger Sequencing were equal to 88.8% and 91.6% respectively. Positive and negative predictive values were obtained as 80% and 95.6%, respectively. CONCLUSION: Mutational status of the fetus can be assessed by determining inheritance of paternally-derived alleles based on detection of haplotype-associated SNP in maternal plasma. Magnetic-based DNA extraction and fetal DNA enrichment are very simple and easy to perform and have satisfactory accuracy.

Single locus and haplotype association of ENPP1 gene variants with the development of retinopathy among type 2 diabetic patients.

PURPOSE: The present study was designed to investigate the associations of ENPP1 variants (rs997509, rs1799774, rs1044498 (K121Q), and rs7754561) with diabetic retinopathy (DR) derived from type 2 diabetes mellitus (T2DM). METHODS: Total 501 T2DM patients with and without DR were studied as the case and control group, respectively. All four variants were genotyped by TaqMan assay. Statistical analyses were performed through SNPAlyze and SPSS software. RESULTS: The statistical analysis of clinical characteristics represented significant differences of HbA1c, and fasting blood sugar between two study groups. The results indicated that among four studied variants, rs997509 and rs7754561 were significantly associated with DR under recessive (P = 0.01) and dominant (P = 0.01) models of inheritance, respectively. One haplotype (T-A-T-A) with a frequency higher than 0.05 was associated with the increased risk of DR (P = 0.04). Genotype-phenotype sub-analysis of rs997509 and rs7754561 showed that only rs7754561 had significant associations with systolic and diastolic blood pressures (P = 0.03 and P = 0.01, respectively); more specifically, A allele carriers of rs7754561 were in a higher risk of blood pressures. CONCLUSIONS: This study suggested that rs997509 and rs7754561 were associated with the increased risk of DR among Iranians with T2DM and rs7754561 might be a potential genetic marker for prognosis and diagnosis of DR.

Haplotype-Based Association and In Silico Studies of OPRM1 Gene Variants with Susceptibility to Opioid Dependence Among Addicted Iranians Undergoing Methadone Treatment.

The associations of OPRM1 gene variants with opioid dependence have been demonstrated. This study investigated the association of rs495491, rs1799971 (A118G), rs589046, and rs10457090 variants of OPRM1 gene with opium dependence and their haplotypes among addicted individuals undergoing methadone treatment. Moreover, we investigated whether any of these variants were associated with libido dysfunction or insomnia among addicted people. A total of 404 individuals were genotyped by amplification refractory mutation system (ARMS) PCR. In silico studies were designed through homology modeling of A118G structures (N40 and D40) and docked with 41 FDA-approved drugs of OPRM1 protein by SWISS-MODEL, COACH, MolProbity, ProSA, Errat, Glide XP, and Autodock 4. Results revealed that rs495491, A118G, rs589046, and rs10457090 were significantly associated with opium dependence under recessive (P = 6.66E-10), dominant (P = 0.017), co-dominant (P = 0.001), and recessive (P = 9.28E-6) models of inheritance, respectively. Further analyses indicated three significant haplotypes including A-A-A-C (P-permutation < 1E-9), G-G-A-C (P-permutation = 0.04), and G-A-G-C (P-permutation = 8.69E-4). Genotype-phenotype associations of OPRM1 variants with insomnia and libido dysfunction showed no significant association. Docking showed the higher binding affinity of N40 rather than D40 model; however, methadone and morphine were bonded with D40 structure more powerful. Consequently, rs495491, A118G, rs589046, and rs10457090 were associated with opioid dependence among Iranians; also, A118G might be the most remarkable marker of OPRM1 owing to its vital structural roles.

Single and multi-locus association study of TCF7L2 gene variants with susceptibility to type 2 diabetes mellitus in an Iranian population.

Prior studies indicated that some of transcription factor 7-like 2 (TCF7L2) gene variants such as rs7903146, rs12255372 and rs11255372 are constantly associated with Type 2 diabetes mellitus (T2DM) in various populations and ethnic groups. The purpose of this study was to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs11255372) and T2DM by TaqMan assay. Statistical analysis was performed through SNPAlyze and SPSS. Significant associations of rs7903146 (P = 1.9 × 10-7), and rs11255372 (P = 2.98 × 10-10) both under a dominant model were found. Based on allele frequency, there was a significant difference between the two study groups at rs7903146 and rs12255372 variants (P = 6.8 × 10-10, and P = 9.3 × 10-11, respectively). Two haplotypes including Hap-1 (C-G-G) and Hap-2 (T-G-T) indicated a significant difference between the two study groups (P = 1.174 × 10-9and P = 7.432 × 109 respectively). In conclusion, rs7903146 and rs12255372 were significantly associated with T2DM in the specified Northern Iranian population.

Association and in silico studies of ENPP1 gene variants with type 2 diabetes mellitus in a Northern Iranian population.

In the current study, a sample population of Northern Iranians was selected to investigate the association of K121Q, rs1799774, rs7754561, and rs997509 ENPP1 gene variants and their haplotypes with T2DM. Genomic DNAs of 978 samples were extracted by Salting Out standard technique and then genotyped by the TaqMan assay. The results show significant differences between study groups for K121Q (p = 0.0004) under a Dominant and rs7754561 (p = 0.002) under a co-dominant hereditary model. Based on allele frequency, there was a significant difference between two study groups at K121Q and rs7754561 variants (p = 0.010 and p = 0.01, respectively). There was no evidence for an association between ENPP1 haplotypes and overall risk of T2DM. Genotype-phenotype sub-analyses showed no significant relationship of four studied polymorphisms with age, gender, FBS, and systolic and diastolic blood pressures. Homology modeling and molecular docking of ENPP1 in K173 and Q173 models with ATP, AMP, and 2'3'-cGAMP as ligands revealed that all ligands had a more binding affinity to Lys173 protein model, and 2'3'-cGAMP had a higher affinity to both ENPP1 protein models compared to ATP and AMP. These findings suggest that ENPP1 gene variants may have a potential impact on the occurrence of T2DM in Northern Iranians.

Assessment of EGFR Gene Expression Following Vitrification of 2-cell and Blastocyst Mouse Embryos.

BACKGROUND: Exact mechanisms of fetal harm following vitrification are still unknown. This study was conducted to evaluate the cryopreservation impact on the expression of Epidermal Growth Factor Receptor (EGFR) gene in mouse 2-cell and blastocysts. METHODS: To stimulate ovulation in mice, hCG was injected, followed by collecting 2-cells and blastocysts after 44-46 and 88-89 hr, respectively. These embryos were divided into two case and control groups. The fresh case group was cryopreserved using cryotop and warmed after 4 mounts. Normal 2-cells were selected based on their morphology and their RNA was extracted. Quantitative expression of EGFR gene in both groups was investigated by applying real time-PCR. RESULTS: The statistical Real-Time (RT)-PCR analyses performed using SPSS revealed that the expression level of EGFR gene was diminished in the case group compared to the control group. CONCLUSION: The current study indicated the negative effect of cryopreservation on expression amount of EGFR gene in 2-cell and blastocyst mouse embryos.

Association of OPRK1 gene polymorphisms with opioid dependence in addicted men undergoing methadone treatment in an Iranian population.

Previous studies have shown significant associations between OPRK1 and susceptibility to opioid dependence and the relationships between libido dysfunction and insomnia among opium addicts who underwent methadone maintenance treatment. The authors investigated the single locus and haplotype association of rs997917, rs6985606, and rs6473797 with susceptibility to opioid addiction. Samples were selected among 202 healthy individuals and 202 opium addicts undergoing methadone maintenance treatment. Genomic DNA was extracted from the whole blood samples of all subjects through a salting out procedure. All three variants were genotyped in the studied subjects using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). The whole analysis process was performed using SNPAlyze and SPSS ver.20 software packages. According to the single locus analyses, rs997917 and rs6985606 represented significant associations with opium addiction under recessive (p = 0.0128) and co-dominant (p = 0.0001) inheritance models, respectively. The haplotypes C-T-C (Permutation p = 0.014) and C-T-T (Permutation p = 0.0002) were significantly associated with opioid dependence. Among methadone maintenance treatment individuals, rs997917 was significantly associated with insomnia in both allelic and genotypic levels (p = 0.0001 and p = 0.038, respectively). Furthermore, rs6985606 had the only significant association with the co-incidence of insomnia and libido dysfunction in the methadone maintenance treatment group (p = 0.038). The OPRK1 gene variants showed significant association with susceptibility to opioid dependence among Iranians.

Association of OPRD1 Gene Variants with Opioid Dependence in Addicted Male Individuals Undergoing Methadone Treatment in the North of Iran.

Genetic association of rs678849 along with neuroimaging and biomarker phenotypes, parallel with the known involvements of the OPRD1 in drug abuse, provided additional support for targeting these receptors as potential therapeutic targets in both neurodegenerative diseases and neuropsychiactric disorders such as Alzheimer's disease. Samples were selected among 202 opium-addicted participants undergoing methadone treatment and 202 healthy controls. Genomic DNA of all subjects was extracted from whole blood samples through a Salting Out procedure. Four variants (rs678849, 2236857, 2236855, and 760589) were genotyped in the studied subjects using ARMS-PCR. The analysis was performed using SNPalyze and SPSS ver.20 software. According to single locus analysis, rs678849 under dominant model (p < 0.001), rs2236857 under recessive model (p = 0.006), and the two variants, rs2236855 and rs760589 under co-dominant model, showed significant contributions between groups (p = 0.001 and p = 0.009, respectively). rs2236855 was associated with the development of libido dysfunction in opium-addicted patients undergoing methadone treatment (p = 0.011). Through haplotype analyses, five haplotypes with frequency of more than 5% displayed significant association with opioid dependence in study participants. In conclusion, the four studied OPRD1 gene variants and their haplotypes can play important roles in susceptibility to opioid dependence.

Association of BDNF G196A Gene Polymorphism with Ischemic Stroke Occurrence and its 6-Month Outcome in an Iranian Population.

BACKGROUND: Genetic factors like the allele for Brain-Derived Neurotrophic Factor (BDNF) are associated with the outcome of ischemic stroke most likely through affecting neural differentiation and synaptic plasticity. Studies of the association of BDNF G196A gene polymorphism and long-term ischemic stroke outcome in various populations have not been concordant. OBJECTIVE: In this research, the association of BDNF G196A gene polymorphism and ischemic stroke occurrence were studied in a northern Iranian population with a glance to its 6-month outcome. METHODS: The genetic variant of BDNF G196A was examined in Ischemic Stroke (IS) patients (n = 206) and control group (n = 200). In IS individuals, outcome variables such as stroke severity, functional disability, and cognitive impairment were examined, respectively, by NIHSS, Barthel Index, and MoCA in an average of 202 days after the stroke occurrence. RESULTS: The frequency of risk allele G was 12.1% in IS patients and 5.5% in healthy individuals; and the difference was statistically significant (p < 0.0001). The frequency of risk genotype GG, heterozygote and homozygote were 0% and 1%, 24%.3% and 9%, 75.7% and 90%, respectively, for IS and control groups (p < 0.05). After controlling the phenotype confounding factors, logistic regression analysis showed that there was a borderline significant relationship between genotype BDNF GA + GG and IS occurrence (AOR = 1.997,95% CI: 0.252-1.010, p = 0.051). There was no significant difference between the various genotypic groups regarding the severity of the stroke and functional disability. Yet, G allele carriers had more cognitive impairment after IS (p = 0.002). CONCLUSION: For the first time in an Iranian population, it was demonstrated that BDNF G196A variant plays a major role in stroke occurrence and consequences. It is suggested that, after IS, G allele carriers should have precedence for medicinal and rehabilitation interventions, in order to reduce their cognitive deficiency.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and post-stroke dementia: a hospital-based study from northern Iran.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with functional and cognitive outcomes of stroke and plays a key role in preventing neuronal death. This study aimed to answer the following question: does BDNF Val66Met polymorphism prognosticate survival status and risk of post-stroke dementia (PSD)? In a retrospective cohort study, 206 patients with ischemic stroke (IS) entered the study. They were consecutively being admitted to the neurology clinic in Poursina Hospital (northern Iran) from 2012 to 2014. The diagnosis of PSD was based on DSM-5 criteria. The current and the premorbid cognitive statuses of the patients were respectively assessed through the third edition of Addenbrooke's Cognitive Examination and the Informant Questionnaire on Cognitive Decline in the Elderly. BDNF Val66Met gene polymorphism was determined by PCR-RFLP. On average, 48 patients (23.3 %) developed PSD 6 months after IS. Log-rank test showed that the survival rate of at least one Val-allele carriers was significantly lower than that of Met/Met homozygotes (P = 0.0005), and the former developed PSD sooner than the latter (375, 492 days, respectively). Cox model showed that heterozygous carriers of Val/Met were at greater risk of PSD over time (HR 2.280, 95 % CI 1.566-4.106, P = 0.006). However, the risk ratio of patients with PSD among different BDNF genotypes decreased after adjusting demographic, clinical, and vascular risk factors, and was no longer statistically significant (AHR 2.434, 95 % CI 0.597-9.926, P = 0.215). Val-allele carriers or Val/Met genotypes were more quickly diagnosed as having dementia after IS. However, this genetic vulnerability became more destructive when it was added to demographic, clinical, and vascular risk factors.

Lack of genetic susceptibility of KCNJ11 E23K polymorphism with risk of type 2 diabetes in an Iranian population.

AIMS: The KCNJ11 gene has a strong effect on glucose-stimulated insulin secretion. Common polymorphism KCNJ11 E23K has been reported to be associated with type 2 diabetes in various European-descent populations. However, there were inconsistent results in previous studies in Asian populations, and no study has been carried out in the Iranian population. We examined the contribution of KCNJ11 E23K variant in the susceptibility to type 2 diabetes in the Iranian population. METHODS: We undertook a population-based association study between type 2 diabetes and E23K mutation using 400 people with type 2 diabetes and 420 controls. Genotyping was performed using TaqMan technology on an ABI7300 system. RESULTS: No significant difference was observed in either genotype distribution (p = 0.71) or allele frequency (p = 0.88) between individuals with and without type 2 diabetes. After adjusting for the confounding effects of age, gender and body mass index (BMI), no significant effect of genotypes on type 2 diabetes was found regarding any genetic models tested (recessive, dominant or co-dominant models). Following subgroup analysis of individuals with and without diabetes based on BMI, a nominal significant association was observed between type 2 diabetes in the presence of obesity and E23K genotype in the recessive model (p = 0.03). CONCLUSION: The KCNJ11 E23K polymorphism is not associated with genetic susceptibility to type 2 diabetes in the Iranian population; however, it may play a role in disease progression in the presence of obesity.

Transgenic expression of a mutated cyclin-dependent kinase 4 (CDK4/R24C) in pancreatic beta-cells prevents progression of diabetes in db/db mice.

In an attempt to rectify the hyperglycemic state in obese insulin resistant db/db mice, a transgenic line was generated (db/db-CDK4(R24C)) that expresses a constitutively active form of cyclin-dependent kinase 4 (CDK4/R24C) under the control of the insulin promoter. Compared with non-transgenic db/db littermates, adult db/db-CDK4(R24C) mice show near-complete glycemic normalization and improved plasma lipid concentrations, but are also more susceptible to weight gain and have significantly lower plasma adiponection levels. They have striking islet hypertrophy and beta-cell hyperplasia, and retain an insulin secretory response during the glucose tolerance test. We examined the expression of several key regulatory transcription factor genes involved in lipid and glucose metabolism in insulin target tissues of db/db-CDK4(R24C) as well as db/db mice, and found that the expression levels of members of the peroxisome proliferator-activated receptor (PPAR) family are highly associated with metabolic alterations in a gene- and tissue-specific manner. We show for the first time that the Ppar-delta in skeletal muscle and white adipose tissues is transcriptionally down-regulated in db/db mice. The db/db-CDK4(R24C) mice present a novel model of leptin-resistant obesity with compensatory hyperinsulinemia and normalized blood glucose levels, and thus may be useful for future studies that aim to dissect relationships between insulin and leptin signaling.

Lack of association of genetic variation in chromosome region 15q14-22.1 with type 2 diabetes in a Japanese population.

BACKGROUND: Chromosome 15q14-22.1 has been linked to type 2 diabetes (T2D) and its related traits in Japanese and other populations. The presence of T2D disease susceptibility variant(s) was assessed in the 21.8 Mb region between D15S118 and D15S117 in a Japanese population using a region-wide case-control association test. METHODS: A two-stage association test was performed using Japanese subjects: The discovery panel (Stage 1) used 372 cases and 360 controls, while an independent replication panel (Stage 2) used 532 cases and 530 controls. A total of 1,317 evenly-spaced, common SNP markers with minor allele frequencies > 0.10 were typed for each stage. Captured genetic variation was examined in HapMap JPT SNPs, and a haplotype-based association test was performed. RESULTS: SNP2140 (rs2412747) (C/T) in intron 33 of the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) gene was selected as a landmark SNP based on repeated significant associations in Stage 1 and Stage 2. However, the marginal p value (p = 0.0043 in the allelic test, OR = 1.26, 95% CI = 1.07-1.48 for combined samples) was weak in a single locus or haplotype-based association test. We failed to find any significant SNPs after correcting for multiple testing. CONCLUSION: The two-stage association test did not reveal a strong association between T2D and any common variants on chromosome 15q14-22.1 in 1,794 Japanese subjects. A further association test with a larger sample size and denser SNP markers is required to confirm these observations.