Contributions of IKZF1, DDC, CDKN2A, CEBPE, and LMO1 Gene Polymorphisms to Acute Lymphoblastic Leukemia in a Yemeni Population.

BACKGROUND: Genome-wide and candidate gene association studies have previously revealed links between a predisposition to acute lymphoblastic leukemia (ALL) and genetic polymorphisms in the following genes: IKZF1 (7p12.2; ID: 10320), DDC (7p12.2; ID: 1644), CDKN2A (9p21.3; ID: 1029), CEBPE (14q11.2; ID: 1053), and LMO1 (11p15; ID: 4004). In this study, we aimed to conduct an investigation into the possible association between polymorphisms in these genes and ALL within a sample of Yemeni children of Arab-Asian descent. METHODS: Seven single-nucleotide polymorphisms (SNPs) in IKZF1, three SNPs in DDC, two SNPs in CDKN2A, two SNPs in CEBPE, and three SNPs in LMO1 were genotyped in 289 Yemeni children (136 cases and 153 controls), using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Logistic regression analyses were used to estimate ALL risk, and the strength of association was expressed as odds ratios with 95% confidence intervals. RESULTS: We found that the IKZF1 SNP rs10235796 C allele (p = 0.002), the IKZF1 rs6964969 A>G polymorphism (p = 0.048, GG vs. AA), the CDKN2A rs3731246 G>C polymorphism (p = 0.047, GC+CC vs. GG), and the CDKN2A SNP rs3731246 C allele (p = 0.007) were significantly associated with ALL in Yemenis of Arab-Asian descent. In addition, a borderline association was found between IKZF1 rs4132601 T>G variant and ALL risk. No associations were found between the IKZF1 SNPs (rs11978267; rs7789635), DDC SNPs (rs3779084; rs880028; rs7809758), CDKN2A SNP (rs3731217), the CEBPE SNPs (rs2239633; rs12434881) and LMO1 SNPs (rs442264; rs3794012; rs4237770) with ALL in Yemeni children. CONCLUSION: The IKZF1 SNPs, rs10235796 and rs6964969, and the CDKN2A SNP rs3731246 (previously unreported) could serve as risk markers for ALL susceptibility in Yemeni children.

Association of ARID5B gene variants with acute lymphoblastic leukemia in Yemeni children.

Studies have shown an association between ARID5B gene polymorphisms and childhood acute lymphoblastic leukemia. However, the association between ARID5B variants and acute lymphoblastic leukemia among the Arab population still needs to be studied. The aim of this study was to investigate the association between ARID5B variants with acute lymphoblastic leukemia in Yemeni children. A total of 14 ARID5B gene single nucleotide polymorphisms (SNPs) were genotyped in 289 Yemeni children, of whom 136 had acute lymphoblastic leukemia and 153 were controls, using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Using logistic regression adjusted for age and gender, the risks of acute lymphoblastic leukemia were presented as odds ratios and 95% confidence intervals. We found that nine SNPs were associated with acute lymphoblastic leukemia under additive genetic models: rs7073837, rs10740055, rs7089424, rs10821936, rs4506592, rs10994982, rs7896246, rs10821938, and rs7923074. Furthermore, the recessive models revealed that six SNPs were risk factors for acute lymphoblastic leukemia: rs10740055, rs7089424, rs10994982, rs7896246, rs10821938, and rs7923074. The gender-specific impact of these SNPs under the recessive genetic model revealed that SNPs rs10740055, rs10994982, and rs6479779 in females, and rs10821938 and rs7923074 in males were significantly associated with acute lymphoblastic leukemia risk. Under the dominant model, SNPs rs7073837, rs10821936, rs7896246, and rs6479778 in males only showed striking association with acute lymphoblastic leukemia. The additive model revealed that SNPs with significant association with acute lymphoblastic leukemia were rs10821936 (both males and females); rs7073837, rs10740055, rs10994982, and rs4948487 (females only); and rs7089424, rs7896246, rs10821938, and rs7923074 (males only). In addition, the ARID5B haplotype block (CGAACACAA) showed a higher risk for acute lymphoblastic leukemia. The haplotype (CCCGACTGC) was associated with protection against acute lymphoblastic leukemia. In conclusion, our study has shown that ARID5B variants are associated with acute lymphoblastic leukemia in Yemeni children with several gender biases of ARID5B single nucleotide polymorphisms reported.

Altered circulating concentrations of active glucagon-like peptide (GLP-1) and dipeptidyl peptidase 4 (DPP4) in obese subjects and their association with insulin resistance.

OBJECTIVES: Soluble DPP4 (sDPP4) is a novel adipokine that degrades glucagon-like peptide (GLP-1). We evaluated the fasting serum levels of active GLP-1 and sDPP4 in obese, overweight and normal weight subjects to assess the association between sDPP4 levels, active GLP-1 levels and insulin resistance in obese subjects. METHODS: The study involved 235 Malaysian subjects who were randomly selected (66 normal weight subjects, 97 overweight, 59 obese subjects, and 13 subjects who were underweight). Serum sDPP4 and active GLP-1 levels were examined by enzyme-linked immunosorbent assay (ELISA). Also, body mass index kg/m2 (BMI), lipid profiles, insulin and glucose levels were evaluated. Insulin resistance (IR) was estimated via the homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: Serum sDPP4 levels were significantly higher in obese subjects compared to normal weight subjects (p=0.034), whereas serum levels of active GLP-1 were lower (p=0.021). In obese subjects, sDPP4 levels correlated negatively with active GLP-1 levels (r2=-0.326, p=0.015). Furthermore, linear regression showed that sDPP4 levels were positively associated with insulin resistance (B=82.28, p=0.023) in obese subjects. CONCLUSION: Elevated serum sDPP4 levels and reduced GLP-1 levels were observed in obese subjects. In addition, sDPP4 levels correlated negatively with active GLP-1 levels but was positively associated with insulin resistance. This finding provides evidence that sDPP4 and GLP-1 may play an important role in the pathogenesis of obesity, suggesting that sDPP4 may be valuable as an early marker for the augmented risk of obesity and insulin resistance.

Association of DPP4 Gene Polymorphisms with Type 2 Diabetes Mellitus in Malaysian Subjects.

BACKGROUND: Genetic polymorphisms of the Dipeptidyl Peptidase 4 (DPP4) gene may play a role in the etiology of type 2 diabetes mellitus (T2DM). This study aimed to investigate the possible association of single nucleotide polymorphisms (SNPs) of the DPP4 gene in Malaysian subjects with T2DM and evaluated whether they had an effect on the serum levels of soluble dipeptidyl peptidase 4 (sDPP-IV). METHOD: Ten DPP4 SNPs were genotyped by TaqMan genotyping assays in 314 subjects with T2DM and 235 controls. Of these, 71 metabolic syndrome (MetS) subjects were excluded from subsequent analysis. The odds ratios (ORs) and their 95% confidence interval (CIs) were calculated using multiple logistic regression for the association between the SNPs of DPP4 and T2DM. In addition, the serum levels of sDPP-IV were investigated to evaluate the association of the SNPs of DPP4 with the sDPP-IV levels. RESULTS: Dominant, recessive, and additive genetic models were employed to test the association of DPP4 polymorphisms with T2DM, after adjusting for age, race, gender and BMI. The rs12617656 was associated with T2DM in Malaysian subjects in the recessive genetic model (OR = 1.98, p = 0.006), dominant model (OR = 1.95, p = 0.008), and additive model (OR = 1.63, p = 0.001). This association was more pronounced among Malaysian Indians, recessive (OR = 3.21, p = 0.019), dominant OR = 3.72, p = 0.003) and additive model (OR = 2.29, p = 0.0009). The additive genetic model showed that DPP4 rs4664443 and rs7633162 polymorphisms were associated with T2DM (OR = 1.53, p = 0.039), and (OR = 1.42, p = 0.020), respectively. In addition, the rs4664443 G>A polymorphism was associated with increased sDPP-IV levels (p = 0.042) in T2DM subjects. CONCLUSIONS: DPP4 polymorphisms were associated with T2DM in Malaysian subjects, and linked to variations in sDPP-IV levels. In addition, these associations were more pronounced among Malaysian Indian subjects.

Conflicting reports on the role of the glycemic effect of Catha edulis (Khat): A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, the leaves of Catha edulis Forsskal (Khat) are consumed by the people of Yemen primarily for its recreational effect, and secondarily, for achieving certain tasks. Additionally, Yemeni diabetics chew such leaves in the belief that this can control their elevated blood glucose level. AIMS: This review focuses on outlining the findings of studies that have been conducted to display the glycemic effect of Catha edulis, while trying to balance it with findings of the association of its chewing with the development of type 2 diabetes mellitus (DM). MATERIALS AND METHODS: The search strategy adopted was based on a comprehensive research in Medline, PubMed, Web of Science, JSTOR, Scopus and Cochrane for articles, proceeding abstracts and theses to identify complete reports written in the English language about the glycemic effect of Catha edulis in humans and animals from 1976 to 2016. In addition, bibliographies were also reviewed to find additional reports not otherwise published. Thirty seven records were identified of which, 25 eligible studies were included in the meta-analysis using blood glucose as an outcome measurement. Studies were divided into four subgroups according to the experimental model, namely; non-diabetic animals, diabetic animals, non-diabetic humans and diabetic humans. The pooled mean difference (MD) of blood glucose between experimental and control were calculated using random effects model of the weighted mean difference of blood glucose with 95% confidence interval (CI). Heterogeneity between studies was tested using I(2) statistic and a value of P<0.05 was considered to indicate statistical significance. RESULTS: The scientific reports in the literature prevailed that the glycemic effect of Catha edulis were greatly conflicting with the majority of studies indicating that Catha edulis has a mild hypoglycemic effect. However, the meta-analysis indicted that the overall result showed an insignificant reduction in blood glucose (MD=-9.70, 95% CI: -22.17 to 2.76, P=0.13, with high heterogeneity between subgroups, I(2)=88.2%, P<0.0001). In addition, pooled mean difference of blood glucose of non-diabetic animals, diabetic animals and non-diabetic humans showed an insignificant reduction in blood glucose (MD=-18.55, 95% CI: -39.55 to 2.50, P<0.08, MD=-52.13%, 95% CI: -108.24 to 3.99, P=0.07 and MD=-2.71%, 95% CI: -19.19 to -13.77, P=0.75) respectively. Conversely, a significant elevation in the pooled mean difference of blood glucose in diabetic humans was indicated (MD=67.18, 95% CI: 36.93-97.43, P<0.0001). The conflict shown in the glycemic effect of Catha edulis is thought to be cultivar-related, while demographic and epidemiological reports suggested that chewing Catha edulis might be a predisposing factor contributing to the development of type 2 DM. CONCLUSION: It was difficult to draw a meaningful conclusion from both the systematic and the meta-analysis with respect to the glycemic effect of Catha edulis since the meta-analysis results were insignificant with high heterogeneity among subgroups and are greatly conflicting. The variation is most likely due to unadjusted experimental factors or is related to Catha edulis itself, such as the differences in the phytochemical composition. Therefore, it is highly recommended that further studies of the glycemic effect of the cultivar of Catha edulis being studied should come with the identification and quantification of phytochemical content so that a meaningful assessment can be made with regard to its hypoglycemic properties. In addition, well-controlled clinical studies should be conducted to confirm whether or not chewing Catha edulis is associated with the development of type 2 DM, since this would be a source of concern seeing that the plant is widely consumed in certain populations.

Serum Levels of Soluble CD26/Dipeptidyl Peptidase-IV in Type 2 Diabetes Mellitus and Its Association with Metabolic Syndrome and Therapy with Antidiabetic Agents in Malaysian Subjects.

BACKGROUND: A soluble form of CD26/dipeptidyl peptidase-IV (sCD26/DPP-IV) induces DPP-IV enzymatic activity that degrades incretin. We investigated fasting serum levels of sCD26/DPP-IV and active glucagon-like peptide-1 (GLP-1) in Malaysian patients with type 2 diabetes mellitus (T2DM) with and without metabolic syndrome (MetS), as well as the associations between sCD26/DPP-IV levels, MetS, and antidiabetic therapy. METHODS: We assessed sCD26/DPP-IV levels, active GLP-1 levels, body mass index (BMI), glucose, insulin, A1c, glucose homeostasis indices, and lipid profiles in 549 Malaysian subjects (including 257 T2DM patients with MetS, 57 T2DM patients without MetS, 71 non-diabetics with MetS, and 164 control subjects without diabetes or metabolic syndrome). RESULTS: Fasting serum levels of sCD26/DPP-IV were significantly higher in T2DM patients with and without MetS than in normal subjects. Likewise, sCD26/DPP-IV levels were significantly higher in patients with T2DM and MetS than in non-diabetic patients with MetS. However, active GLP-1 levels were significantly lower in T2DM patients both with and without MetS than in normal subjects. In T2DM subjects, sCD26/DPP-IV levels were associated with significantly higher A1c levels, but were significantly lower in patients using monotherapy with metformin. In addition, no significant differences in sCD26/DPP-IV levels were found between diabetic subjects with and without MetS. Furthermore, sCD26/DPP-IV levels were negatively correlated with active GLP-1 levels in T2DM patients both with and without MetS. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-cholesterol (LDL-c) levels. CONCLUSION: Serum sCD26/DPP-IV levels increased in T2DM subjects with and without MetS. Active GLP-1 levels decreased in T2DM patients both with and without MetS. In addition, sCD26/DPP-IV levels were associated with Alc levels and negatively correlated with active GLP-1 levels. Moreover, metformin monotherapy was associated with reduced sCD26/DPP-IV levels. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-c.