Association between type 2 diabetes mellitus & TCF7L2 gene variants in the Emirati population: Genetics of diabetes in the United Arab Emirates.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) has a multifactorial etiology involving a complex interplay between genes and the environment. The prevalence of T2DM among the countries of the Gulf Corporation Council (GCC), including the United Arab Emirates (UAE), ranks among the top 15 in the world. A number of studies have shown an increase in T2DM risk for the "TT" genotype at the rs4506565 and rs12255372 Single Nucleotide Polymorphisms (SNP) of the TCF7L2 gene. However, the association between TCF7L2 and T2DM still needs to be investigated in the UAE population. Therefore, this study analyzed the potential associations with rs4506565 and rs12255372 in UAE subjects. METHODS: For this case-control study, T2DM patients (n = 890) and healthy subjects (n = 686) were genotyped using a Taqman Real-Time PCR assay. Statistical analysis was performed with the resulting data using the R (version 3.3.1) and STATA (version 13) software packages. RESULTS: The rs12255372 SNP was significantly associated with T2DM (OR = 1.16, 95% CI = 1.00-1.34; P = .042). However, no significant association was found for the rs4506565 SNP (P = .120). After gender stratification, a significant association was found for both SNPs in males (Prs4506565 = .009 and Prs12255372 = .021). Interestingly, we found the interaction between the SNP rs4506565 with gender alone (P = .032) and in conjunction with BMI and age (P = .036) confers associations with T2DM. CONCLUSIONS: These findings suggest that the genetic variants of the TCF7L2 gene are associated with an increased susceptibility to T2DM, especially in Emirati males. Our study also highlights the impact of biological and environmental risk factors including age, BMI, and gender on the genetic susceptibility to T2DM.

Establishing a genetic link between FTO and VDR gene polymorphisms and obesity in the Emirati population.

BACKGROUND: Obesity is a metabolic disease that is widely prevalent with approximately 600 million people classified as obese worldwide. Its etiology is multifactorial and involves a complex interplay between genes and the environment. Over the past few decades, obesity rates among the Emirati population have been increasing. The aim of this study was to investigate the association of candidate gene single nucleotide polymorphisms (SNPs), namely FTO (rs9939609) and VDR (rs1544410), with obesity in the UAE population. METHODS: This is a case-control study in which genomic DNA was extracted from saliva samples of 201 obese, 115 overweight, and 98 normal subjects in the United Arab Emirates (UAE). Genotyping for the variants was performed using TaqMan assay. RESULTS: The mean Body Mass Index (BMI) ± SD for the obese, overweight, and normal subjects was 35.76 ± 4.54, 27.53 ± 1.45, and 22.69 ± 1.84 kg/m2, respectively. Increasing BMI values were associated with increase in values of HbA1c, systolic and diastolic blood pressure. There was a significant association observed between the FTO SNP rs9939609 and BMI (p = 0.028), with the minor allele A having a clear additive effect on BMI values. There was no significant association detected between BMI and rs1544410 of VDR. Moreover, significant interaction between the FTO rs9939609 and physical activity reduced the "AA" genotype effect on increase in BMI (p = 0.027). CONCLUSIONS: Our study findings indicate that the minor allele A of the rs9939609 has a significant association with increasing BMI values. Moreover, our findings support the fact that increasing BMI is associated with increasing risks of other comorbidities such as higher blood pressure, poorer glycemic control, and higher triglycerides. In addition, physical activity was found to attenuate the effect of the "AA" genotype on the predisposition to higher BMI values.

Folate- and vitamin B12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor α.

Deficiency in the methyl donors vitamin B12 and folate during pregnancy and postnatal life impairs proper brain development. We studied the consequences of this combined deficiency on cerebellum plasticity in offspring from rat mothers subjected to deficient diet during gestation and lactation and in rat neuroprogenitor cells expressing cerebellum markers. The major proteomic change in cerebellum of 21-d-old deprived females was a 2.2-fold lower expression of synapsins, which was confirmed in neuroprogenitors cultivated in the deficient condition. A pathway analysis suggested that these proteomic changes were related to estrogen receptor α (ER-α)/Src tyrosine kinase. The influence of impaired ER-α pathway was confirmed by abnormal negative geotaxis test at d 19-20 and decreased phsophorylation of synapsins in deprived females treated by ER-α antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP). This effect was consistent with 2-fold decreased expression and methylation of ER-α and subsequent decreased ER-α/PPAR-γ coactivator 1 α (PGC-1α) interaction in deficiency condition. The impaired ER-α pathway led to decreased expression of synapsins through 2-fold decreased EGR-1/Zif-268 transcription factor and to 1.7-fold reduced Src-dependent phosphorylation of synapsins. The treatment of neuroprogenitors with either MPP or PP1 (4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-N-(4-phenoxyphenyl)-4-quinazolinamine, SKI-1, Src-l1) Src inhibitor produced similar effects. In conclusion, the deficiency during pregnancy and lactation impairs the expression of synapsins through a deregulation of ER-α pathway.

Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups.

Early deficiency of the methyl donors folate and vitamin B12 produces hyperhomocysteinemia and cognitive and motor disorders in 21-day-old rat pups from dams fed a diet deficient in methyl donors during gestation and lactation. These disorders are associated with impaired neurogenesis and altered synaptic plasticity in cerebellum. We aimed to investigate whether these disorders could be related to impaired expression of neurosteroidogenesis-associated proteins, key regulator receptors, and some steroid content in the cerebellum. The methyl donor deficiency produced a decreased concentration of folate and vitamin B12, along with accumulation of homocysteine in Purkinje cells in both sexes, whereas the S-adenosylmethionine/S-adenosylhomocysteine ratio was reduced only in females. The transcription level and protein expression of StAR, aromatase, ERα, ERß, and LH receptors were decreased only in females, with a marked effect in Purkinje cells, as shown by immunohistochemistry. Consistently, reduced levels of estradiol and pregnenolone were measured in cerebellar extracts of females only. The decreased expression levels of the transcriptional factors CREB, phospho-CREB, and SF-1, the lesser increase of cAMP concentration, and the lower level of phospho-PKC in the cerebellum of deficient females suggest that the activation of neurosteroidogenesis via cAMP-mediated signaling pathways associated with LHR activation would be altered. In conclusion, a gestational methyl donor deficiency impairs neurosteroidogenesis in cerebellum in a sex-dependent manner.

Gestational methyl donor deficiency alters key proteins involved in neurosteroidogenesis in the olfactory bulbs of newborn female rats and is associated with impaired olfactory performance.

Gestational methyl donor deficiency (MDD) leads to growth retardation as well as to cognitive and motor disorders in 21-d-old rat pups. These disorders are related to impaired neurogenesis in the cerebral neurogenic areas. Olfactory bulbs (OB), the main target of neuronal progenitors originating from the subventricular zone, play a critical role during the postnatal period by allowing the pups to identify maternal odour. We hypothesised that growth retardation could result from impaired suckling due to impaired olfactory discrimination through imbalanced apoptosis/neurogenesis in the OB. Since neurosteroidogenesis modulates neurogenesis in OB, in the present study, we investigated whether altered neurosteroidogenesis could explain some these effects. Pups born to dams fed a normal diet (n 24) and a MDD diet (n 27) were subjected to olfactory tests during the lactation and weaning periods (n 24 and 20, respectively). We studied the markers of apoptosis/neurogenesis and the expression levels of the key neurosteroidogenic enzyme aromatase, the cholesterol-transfer protein StAR (steroidogenic acute regulatory protein) and the ERα oestrogen receptor and the content of oestradiol in OB. The 21-d-old MDD female pups displayed lower body weight and impaired olfactory discrimination when compared with the control pups. MDD led to greater homocysteine accumulation and more pronounced apoptosis, along with impaired cell proliferation in the OB of female pups. The expression levels of aromatase, StAR and ERα as well as the content of oestradiol were lower in the OB of the MDD female pups than in those of the control female pups. In conclusion, gestational MDD may alter olfactory discrimination performances by affecting neurogenesis, apoptosis and neurosteroidogenesis in OB in a sex-dependent manner. It may be involved in growth retardation through impaired suckling.

Whole-Exome Sequencing in Family Trios Reveals De Novo Mutations Associated with Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by insulin deficiency and loss of pancreatic islet ß-cells. The objective of this study is to identify de novo mutations in 13 trios from singleton families that contribute to the genetic basis of T1DM through the application of whole-exome sequencing (WES). Of the 13 families sampled for this project, 12 had de novo variants, with Family 7 having the highest number (nine) of variants linked to T1DM/autoimmune pathways, whilst Family 4 did not have any variants past the filtering steps. There were 10 variants of 7 genes reportedly associated with T1DM (MST1; TDG; TYRO3; IFIHI; GLIS3; VEGFA; TYK2). There were 20 variants of 13 genes that were linked to endocrine, metabolic, or autoimmune diseases. Our findings demonstrate that trio-based WES is a powerful approach for identifying new candidate genes for the pathogenesis of T1D. Genotyping and functional annotation of the discovered de novo variants in a large cohort is recommended to ascertain their association with disease pathogenesis.

Implication of genetic variants in overweight and obesity susceptibility among the young Arab population of the United Arab Emirates.

OBJECTIVE: Overweight and obesity are major risk factors for Type 2 Diabetes Mellitus (T2DM), cardiovascular disease (CVD) and cancer. Genetic predisposition has been shown to play a key role in obesity, and genome-wide association studies (GWAS) have identified multiple loci linked with obesity in various ethnic groups. The aim of this study was to validate the reported genetic variants associated with obesity and overweight in a young UAE Arab population. METHODS: Twenty-two associated single nucleotide polymorphisms (SNPs) at 11 loci (FTO, MC4R, TMEM18, KCTD15, MTCH2, SH2B1, TFAP2B, GNPDA2, NEGR1, PCSK1 and BDNF) were studied in 392 controls and 318 overweight/obese young Emiratis (aged 18-35 years). RESULTS: After adjusting for age and smoking, rs3751812 of the FTO gene was associated with overweight/obesity in male participants (p-value < 0.016), while SNPs rs17782313, rs571312 of the MC4R gene and rs12463617 of the TMEM18 gene were significantly associated with overweight/obesity in female participants (p-value = 0.001, 0.028, 0.044, respectively). Follow-up association tests and logistic regression revealed the contribution of the FTO rs3751812 and MC4R rs571213 SNPs to the risk of overweight/obesity after adjusting for age, sex and smoking (p-value = 0.044, 0.049, respectively). In addition, the FTO rs3751812 was associated with the risk of overweight/obesity after adjusting for the effect of other markers (rs17782313, rs571312, rs2867125, rs6548238 and rs12463617) (p-value = 0.035). A significant gene-gene interaction was seen between FTO, MCR4 and TMEM18 (p-value = 0.013). CONCLUSIONS: Our data demonstrates that rs3751812 of the FTO gene is the key SNP associated with risk of overweight/obesity among the young UAE Arab population, in alignment with previous findings. Our results also indicate that the identified genes stratify with sex and risk of overweight/obesity. In addition to their direct association with overweight/obesity, rs17782313 and rs571312, as well as rs2867125 and rs6548238, may have a modifying effect on the risk of overweight/obesity caused by the rs3751812. Population-specific, sex-specific genetic profiling is important in understanding the heritability of obesity.

Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population.

PURPOSE: Type 2 diabetes mellitus (T2DM) is the most common form of diabetes with clinical consequences giving rise to chronic multiple organ complications. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are genetic variations that have been linked to T2DM, and micro/macrovascular complications. The link between MTHFR and T2DM however is strongly dependent on the ethnic group studied. The objective of this study was to investigate the possible association between two MTHFR polymorphisms (C677T and A1298C) and T2DM and specifically examine if there are any associations with clinical and demographic characteristics among patients in the United Arab Emirates (UAE). METHODS: The study included 169 T2DM patients and 209 healthy controls. Genomic DNA was isolated and genotyped using TaqMan real-Time PCR assays for the MTHFR C677T and A1298C polymorphisms. RESULTS: There were no significant differences in genotype and haplotype distributions observed between groups. A significant association was observed between the C677T polymorphism and history of cerebrovascular accident (CVA) (p = 0.0330), history of nephropathy (p = 0.0280) and levels of LDL cholesterol (p = 0.0409). Also, the A1298C polymorphism was associated with hypertriglyceridemia (p = 0.0305) in T2DM patients. CONCLUSION: These findings demonstrate that the MTHFR gene polymorphisms are not related to T2DM in the Emirati population. However, these polymorphisms can be used as risk markers for CVA, nephropathy, high LDL cholesterol and triglycerides in T2DM patients and allow timely treatment.