Genetic Association of LEP Gene Polymorphisms with Obesity in Moroccan Individuals: Case-Control Study and Updated Meta-analysis.

Obesity is a global epidemic disease representing the fifth leading cause of death in the world. It was shown that it is caused by the interaction between environmental factors and genes including leptin gene (LEP). This paper aimed to analyze the association between the LEP gene polymorphisms rs7799039 and rs11761556 with obesity in Moroccan individuals as well as to perform an update meta-analysis of this genetic association. Both polymorphisms were genotyped in 146 obesity patients and 104 controls using real-time PCR technique. The genetic association analysis and the comparison of quantitative parameters were carried out using the R language. Moreover, a meta-analysis including 20 genetic association studies was performed using Review Manager 5.3 software. No significant association was found between the polymorphisms rs7799039 and rs11761556 and the risk of obesity. The comparison of biochemical and clinical parameters between the genotypes of the rs7799039 polymorphism, showed a significant increased triglycerides levels in carriers of AA or GA genotypes (P value = 0.040). The meta-analysis showed no significant association between the rs7799039 polymorphism and obesity under all genetic models. In conclusion, the case-control study and meta-analysis demonstrated that the LEP gene polymorphisms rs7799039 and rs11761556 cannot be considered as genetic risk factors for obesity.

Association of HNF1A gene variants and haplotypes with metabolic syndrome: a case-control study in the Tunisian population and a meta-analysis.

BACKGROUND: Variants in the Hepatocyte Nuclear Factor 1 Alpha gene (HNF1A) are associated with lipoproteins levels and type 2 diabetes. In this study, we aimed to assess the association of HNF1A gene and haplotypes with the metabolic syndrome (MetS) and its components through an association study in the Tunisian population as well as by a meta-analysis. METHODS: A total of 594 Tunisian individuals were genotyped for three variants (rs1169288, rs2464196 and rs735396) located in HNF1A gene using KASPar technology. Statistical analyses were performed with R software. The association was furthermore evaluated through a meta-analysis of our results with those obtained in a Moroccan population. RESULTS: Our results showed no association between HNF1A variants and MetS in the Tunisian population. However, a significant association was observed between the variant rs735396 and a higher waist circumference. The stratified analysis according to the sex highlighted a significant association between the variant rs1169288 and high cholesterol levels only in women. Similarly, Haplotype analysis showed an association between the HNF1A minor haplotype and high total cholesterol mainly in women. Finally, our meta-analysis showed no association between HNF1A variants and MetS. CONCLUSIONS: Our findings exclude the involvement of the three HNF1A variants rs1169288, rs2464196 and rs735396 in the susceptibility to MetS in our studied Tunisian population but emphasize the role of these variants in the cholesterol homeostasis with sex-specific differences, which may serve to rise clinical consideration to early statin therapy in women carrying these genetic variants.

Association of c.56C > G (rs3135506) Apolipoprotein A5 Gene Polymorphism with Coronary Artery Disease in Moroccan Subjects: A Case-Control Study and an Updated Meta-Analysis.

PURPOSE: Coronary artery diseases (CAD) are clinical cardiovascular events associated with dyslipidemia in common. The interaction between environmental and genetic factors can be responsible for CAD. The present paper aimed to examine the association between c.56C > G (rs3135506) APOA5 gene polymorphism and CAD in Moroccan individuals and to perform an association update meta-analysis. MATERIALS AND METHODS: The c.56C > G variant was genotyped in 122 patients with CAD and 134 unrelated controls. Genetic association analysis and comparison of biochemical parameters were performed using R statistical language. In addition, a comprehensive meta-analysis including eleven published studies in addition to our case-control study results was conducted using Review Manager 5.3. Publication bias was examined by Egger's test and funnel plot. RESULTS: The case-control study data showed that the c.56C > G polymorphism was associated with CAD susceptibility under codominant (P-value = 0.001), recessive (P-value <0.001) and log-additive (P-value = 0.008) inheritance models. In addition, this polymorphism was significantly associated with increased levels of systolic and diastolic blood pressures, triglycerides, glycemia, and total cholesterol. Furthermore, meta-analysis showed a significant association between the c.56C > G gene polymorphism and increased risk of CAD under recessive (OR = 3.39[1.77-6.50], P value <0.001) and homozygote codominant (OR = 3.96[2.44-6.45], P value <0.001) models. CONCLUSION: Our case-control study revealed a significant association between c.56C > G polymorphism and CAD in the Moroccan population. In addition, meta-analysis data supported the implication of this polymorphism in CAD susceptibility.

Identification of deleterious missense variants of human Piwi like RNA-mediated gene silencing 1 gene and their impact on PAZ domain structure, stability, flexibility and dimension: in silico analysis.

Communicated by Ramaswamy H. Sarma.

Prediction and Structural Comparison of Deleterious Coding Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in Human LEP Gene Associated with Obesity.

Leptin is a peptide hormone that regulates fat stores in the body and appetite by controlling the feeling of satiety. This hormone is secreted by the white adipose tissue and plays a role in the storage and mobilization of fatty acids. Mutations of the LEP gene have been associated with obesity in different populations; it is a multifactorial disease that constitutes a major public health problem. In this study, we evaluated the impact of missense SNPs in the LEP gene extracted from dbSNP using 8 computational prediction tools. Out of the total of 4337 SNPs, 93 were nsSNPs (nonsynonymous single nucleotide polymorphisms). Among 93 nsSNPs, 12 (S46L, G59S, D61N, D100N, N103K, C117S, D76V, S88C, P90R, I95N, L161R, and R105W) variants were predicted to be the most deleterious by prediction software. On these 12 deleterious SNPs, 8 variants (S46L, G59S, D61N, D100N, N103K, C117S, L161R, and R105W) were located in the conserved positions and showed a decrease in structure stability which was evaluated by I-Mutant and Mupro. Then, by analyzing the different interactions between different amino acids in wild and mutated proteins, we assessed the structural impact of the deleterious modifications using the YASARA software. Among 8 deleterious nsSNPs, we revealed structure changes in the 6 variants S46L, G59S, D100N, L103K, R105W, L161R, two of which R105W, N103K were previously reported as associated with obesity. Our study suggests 6 deleterious mutations could play an important role in contributing to human obesity and worth to be included in association and functional studies, then may be a drug target.

In Silico Analysis of Coding/Noncoding SNPs of Human RETN Gene and Characterization of Their Impact on Resistin Stability and Structure.

Resistin (RETN) is a gene coding for proinflammatory adipokine called resistin secreted by macrophages in humans. Single nucleotide polymorphisms (SNPs) in RETN are linked to obesity and insulin resistance in various populations. Using dbSNP, 78 nonsynonymous SNPs (nsSNPs) were retrieved and tested on a PredictSNP 1.0 megaserver. Among these, 15 nsSNPs were predicted as highly deleterious and thus subjected to further analyses, such as conservation, posttranscriptional modifications, and stability. The 3D structure of human resistin was generated by homology modeling using Swiss model. Root-mean-square deviation (RMSD), hydrogen bonds (h-bonds), and interactions were estimated. Furthermore, UTRscan served to identify UTR functional SNPs. Among the 15 most deleterious nsSNPs, 13 were predicted to be highly conserved including variants in posttranslational modification sites. Stability analysis predicted 9 nsSNPs (I32S, C51Y, G58E, G58R, C78S, G79C, W98C, C103G, and C104Y) which can decrease protein stability with at least three out of the four algorithms used in this study. These nsSNPs were chosen for structural analysis. Both variants C51Y and C104Y showed the highest RMS deviations (1.137 Å and 1.308 Å, respectively) which were confirmed by the important decrease in total h-bonds. The analysis of hydrophobic and hydrophilic interactions showed important differences between the native protein and the 9 mutants, particularly I32S, G79C, and C104Y. Six SNPs in the 3'UTR (rs920569876, rs74176247, rs1447199134, rs943234785, rs76346269, and rs78048640) were predicted to be implicated in polyadenylation signal. This study revealed 9 highly deleterious SNPs located in the human RETN gene coding region and 6 SNPs within the 3'UTR that may alter the protein structure. Interestingly, these SNPs are worth to be analyzed in functional studies to further elucidate their effect on metabolic phenotype occurrence.

Association study of HNF1A polymorphisms with metabolic syndrome in the Moroccan population.

AIMS: Variants in Hepatocyte Nuclear Factor 1 alpha (HNF1A) gene are associated with Metabolic Syndromeand its components independently. In this study, we aimed to assess the statistical association of the rs1169288, rs2464196 and rs735396 variants and haplotypes of HNF1A gene with metabolic syndrome (MS) and its components in a Moroccan population sample. METHODS: Three variants in the HNF1A gene were genotyped, rs1169288 A>C, rs2464196 G>A and rs735396 T>C in cases and controls from Moroccan population using KASPar® technology (KBioscience, UK). Anthropometric and biochemical parameters were assessed. MS was defined according to the international Diabetes Federation (IDF). The effects of HNF1A polymorphisms and constructed haplotypes on MS were estimated using logistic regression analyses. RESULTS: The HNF1A gene, rs1169288 and rs2464196 variants conferred an increased risk to MS (OR=2.08, 95%CI=1.38-3.14, P=0.0005 and OR=1.52, 95%IC=1.05-2.20, P=0.03, respectively) when adjusted for BMI, sex and age. We found that the C allele of the variant rs735396 was associated with an increased triglycerides level (p-value=0.04434) among patients and high weist circumference (P=0.02005) and total cholesterol (P=0.03227) amount among controls. The haplotype AAT (OR=5.656, P<0.00001) was the most significantly associated with susceptibility to metabolic syndrome. CONCLUSION: The present study demonstrated that SNPs rs1169288 and rs2464196 of HNF1A gene were significantly associated with metabolic syndrome in a Morrocan population. Furthermore, the CAC, AAC, AAT and AGT haplotypes of these SNPs and rs735396 were significantly associated with metabolic syndrome.