Slc30a8 And Monocyte Chemoattractant Protein 1 Polymorphism And Susceptibility To Type 2 Diabetes

Type 2 diabetes is a chronic disease; the prevalence of type 2 diabetes is increasing worldwide. Growing public health burden of diabetes has acrossed the world. Type 2 diabetes remains a major public health issue in China and it will threaten to the health of our population. Type 2 diabetes is a complex, multistep and multifactorial process, it is the result of interactions between environmental factors and genetic factors of the host. Epidemiological studies have also provided evidence that the risk of type 2 diabetes was influenced by polymorphisms of many genes including inflammatory response, oxidative damage, cation diffusion facilitator family and chemokine family. In the present study, we explored the molecular markers with potential to predict occurrence and progression of type 2 diabetes, based on the hypothesis that there might be a similar genetic background that makes some individuals more susceptible to type 2 diabetes. We particularly focused on the polymorphisms of cation diffusion facilitator family and chemokine family.Recently, Zinc Transporter Protein Member 8 (ZnT-8, also known as SLC30A8) and Monocyte Chemoattractant Protein 1 (MCP-1) have been linked to the pathogenesis of type 2 diabetes. Single nucleotide polymorphisms (SNP) of these genes including ZnT-8 Arg325Trp and MCP-1–2518 A/G have been confirmed to influence the expression of the genes and the function of the proteins. Therefore, our study focused on evidence-based study and case-control study to assess the association between the risk of type 2 diabetes and the ZnT-8 Arg325Trp and MCP-1–2518 A/G polymorphism by univariate and multivariate analysis.It is important to find the polymorphisms which could be used as the markers for genetic susceptibility to type 2 diabetes. Identification of genetic factors that are responsible for susceptibility to type 2 diabetes is indispensable for establishing novel and efficient ways of preventing the disease.PartⅠ: SLC30A8 polymorphism and type 2 diabetes risk: Evidence from 27 study groupsZinc transporter protein member 8 (ZnT-8), which is a member of the zinc transporter family, expressed only in pancreatic beta cells and provided zinc to insulin maturation and/or storage processes in insulin-secreting pancreatic beta cells. ZnT-8 (SLC30A8) is a 369-amino acid protein coded by the gene SLC30A8 (chromosome 8q24.11). The non-synonymous single-nucleotide polymorphism (SNP) in SLC30A8 (rs13266634) causing an arginine to tryptophan change (Arg325Trp) in the last exon of the solute carrier family 30. There is accruing evidence that SLC30A8 polymorphism was associated withβ-cell dysfunction. A recently genome-wide association study of the French population by Sladek et al. identified four novel risk loci for type 2 diabetes, and the rs13266634 in the SLC30A8 gene locus has been detected to be associated with type 2 diabetes. Subsequently, replication studies have been performed in various ethnic populations on association between SLC30A8 (rs13266634) polymorphism and type 2 diabetes susceptibility, but the results were inconclusive. Therefore, we conducted a meta-analysis on SLC30A8 (rs13266634) polymorphism and type 2 diabetes susceptibility based on various ethnic groups from Europe, Asia and Africa.In the present study, there were a total of 24 groups from twenty case-control studies and 3 groups from two prospective studies. Obvious heterogeneity was observed in European groups, then we performed a stepwise process sensitivity analysis and the result indicated that the second group in the study by Cauchi et al. was the main source of the heterogeneity in European groups, however, after exclusion of one study group that caused the heterogeneity, no evidence of heterogeneity was observed (P = 0.300). In the analyses by ethnicity (European, Asian and African) of the case-control studies, the results indicated that SLC30A8 polymorphism was related to elevate risks of type 2 diabetes both in European groups (OR = 1.15, 95% CI, 1.11–1.18, Z = 8.31, P < 0.001) and Asian groups (OR = 1.15, 95% CI, 1.11–1.19, Z = 7.54, P < 0.001), however, the results from the African groups rejected the significantly statistical association between SLC30A8 polymorphism and type 2 diabetes risk (OR = 1.09, 95% CI, 0.89–1.33, Z = 0.83, P = 0.404). When we separated hospital-based case-control studies from population-based case-control studies, there was statistically significant in the population-based case-control study groups (OR = 1.15, 95% CI, 1.12–1.17, Z = 11.42, P < 0.001), the similar result was observed in the hospital-based case-control study groups (OR = 1.16, 95% CI, 1.07–1.25, Z = 3.69, P < 0.001). Of all the included studies, no evidence of obvious asymmetry was observed which indicated that no publication bias was revealed by Egger's test (t =–0.65, P = 0.519). In conclusion, our present meta-analysis provided evidence that SLC30A8 (rs13266634) C allele carriers could elevate the risk of type 2 diabetes, especially in Europeans and Asians.PartⅡ: Monocyte Chemoattractant Protein 1–2518 A/G Polymorphism and Susceptibility to Type 2 DiabetesMonocyte chemoattractant protein 1 (MCP-1), a member of chemokine family, is released by endothelial cells, monocytes, and smooth muscle cells in response to stimuli such as endotoxin or cytokines. Hyperglycemia could accelerate MCP-1 production in monocytes and vascular endothelial cells. Since a novel variant (–2518 A/G) in the promoter of MCP-1 has been reported could influence the expression of MCP-1, subsequently, researches have been carried out on the association with different diseases, such as hypertension, coronary artery disease, Behcet's disease. A large cohort study of Caucasians revealed that the MCP-1 G–2518 gene variant was negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and type 2 diabetes. To investigate the association between MCP-1–2518 A/G polymorphism and type 2 diabetes risk in Han Chinese, we conducted a population-based case-control study of 416 type 2 diabetes cases and 416 controls matched on age and gender. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Compared with the wild genotype AA, MCP-1 G–2518 gene variant could significantly decreased the prevalence of type 2 diabetes in Han Chinese (adjusted OR = 0.49, 95% CI, 0.32–0.77, P < 0.0001). The results of stratified analyses revealed that decreased risk of type 2 diabetes related with variant genotypes was evident in younger participants (age≤50) (adjusted OR = 0.35, 95% CI, 0.20–0.61, P < 0.0001), the similar results were observed in males (adjusted OR = 0.37, 95% CI, 0.21–0.66, P = 0.001) and urban participants (adjusted OR = 0.35, 95% CI, 0.21–0.58, P < 0.0001). In addition, statistically significant difference was observed between MCP-1–2518 A/G polymorphism and waist to hip ratio (WHR).In conclusion, our present pilot study indicated that MCP-1 G–2518 gene variant could significantly decrease the risk of type 2 diabetes in the Chinese population.