A comparative analysis of genetic diversity of candidate genes associated with type 2 diabetes in worldwide populations.

Considering that MAPK (mitogen- activated protein kinase) signaling pathway has an important role in the progression of inflammatory cytokine secretion in type 2 diabetes mellitus (T2DM), we have recently investigated the reported genetic polymorphism from genome wide association study in MAP3K1 (mitogen-activated protein kinase kinase kinase 1) in diabetes as an important member of MAPK signaling. This study aimed to investigate the possible association of rs10461617 at the upstream of MAP3K1 gene in an Iranian case-control study with the risk of T2DM. The study population was comprised of 342 unrelated Iranian individuals including 177 patients with T2DM and 165 unrelated healthy control subjects. Genotyping was performed using PCR-RFLP and confirmed with sequencing. In a logistic regression analysis, the rs10461617A allele was associated with a significantly higher risk of T2DM assuming the log- additive model (OR: 1.44, 95% CI: 1.01-2.05, P = 0.039). In conclusion, we provided the first evidence for the association of rs10461617 at the upstream of MAP3K1 with the risk of T2DM in an Iranian population.

Objective To study the association of transcription factor 7-like 2(TCF7L2)polymorphisms with tvpe 2 diabetes mellitus in Chinese Han population. Methods Two polymorphisms (rs7903146 and rs12255372)of TCF7L2 gene were genotyped in 446 patients with type 2 diabetes mellitus(T2DM group)and 303 normal subiects (NC group) by PCR-restriction fragment length polymorphism(PCR-RFLP).Waist circumference.body mass index,plasma glucose,serum insulin,lipid profiles,high-sensitivity C-reactive protein and non-esterified fatty acid were measured.Homeostasis model assessment of insulin resistance(HOMA-IR)and β-cell function(HOMA-β)were calculated.Results (1) In T2DM group,T allele frequency and CT,TY geno tvpe frequeneies of rs7903146 were significantly higher than those in NC group(0.093,0.150,0.018 vs 0.043, 0.079,0.003,respectively,a11 P<O.O 1).Logistic regression analysis showed that the CT/TT genotype was a risk factor of tvpe 2 diabetes(OR=2.25,95%CI 1.39-3.62,P=0.001)and was associated with the decrease of insulin secretion. (2) No significant association was observed in vs12255372 alleles and genotypes with type 2 diabetes mellitus.Conclusion These results indicate that TCF7L2 might be one of the candidate genes for confe ring susceptibi lity to type 2 diabetes mellitus in the Chinese Han population. Key words: Polymorphism,single nucleotide; TCF7L2 gene; Diabetes mellitus,type 2; Association study

Genome-wide association studies ( CWAS) use high-throughout genotyping technologies to investigate the relation of hundreds of thousands of gene markers(genotype) with clinical conditions and measurable traits (phenotype). Type 2 diabetes mellitus results from the interaction of environmental factors with genetic variants. Many progresses have been acquired from GWAS. New gene regions have been discovered to be involved in the development and function of islet (3-cells, which provides new strategies for the etiology investigation, prevention, and treatment of type 2 diabetes mellitus. Key words: Genome-wide association study; Diabetes mellitus,type 2; Polymorphism,single nucleotide; Islet β-cells; Gene region

Type 2 Diabetes Mellitus is a disease with multifactorial inheritance because of insulin resistance or insufficient compensatory insulin secretion at later stage.The article Summaries the mode of hereditary about Type 2 Diabetes Mellitus,analysis of some predisposing genes using strategy of candidate gene and linked orientation,and the advances in genetic epidemiology about Type 2 Diabetes Mellitus. Key words: Type 2 Diabetes Mellitus ; Predisposing genes; Genetic epidemiology

Background Genome-wide association studies have linked several single nucleotide polymorphisms with type 2 diabetes mellitus (T2DM). The present case–control study explored the probable association between the rs10811661 CDKN2A/B gene polymorphism and the risk of T2DM in a Saudi Arabian population. Patients and methods The study included 526 T2DM patients and 567 healthy control participants. The CDKN2A/B (rs10811661) polymorphism was genotyped using the TaqMan allelic discrimination method. Results The results identified single nucleotide polymorphism rs10811661 of CDKN2A/B as a risk factor for T2DM (odds ratio = 1.9; 95% confidence interval: 1.57–2.30; P= 0.0001). Levels of fasting plasma glucose and 2-h postprandial plasma glucose were significantly higher in patients with normal glucose tolerance but carrying the rs10811661 (C/T) risk allele compared with noncarriers. Conclusion A significant association was observed between CDKN2A/B rs10811661 (C/T) and susceptibility to T2DM in the Saudi Arabian population. Furthermore, the T allele is associated with an increased risk in patients with T2DM. The findings show that T2DM may interact with CDKN2A/B rs10811661 (C/T), which increases the risk of T2DM.

To investigate the association of the D358A polymorphism of interleukin 6 receptor( IL6R ) gene with type 2 diabetes mellitus (T2DM) in Hubei Han Chinese. The single nucleotide polymorphism D358A of the IL6R gene was genotyped in 581 T2DM patients and 353 healthy controls. Meta-analysis was used to assess the reported association between the IL6R D358A and T2DM. The frequencies of CC genotype and C allele of IL6R D358A in the patients were significantly lower than those in controls (CC: 13.4% vs. 20.7%, P=0.003; C: 36.0% vs. 41.8%, P=0.012), with the CC genotype being a protective factor for T2DM (OR=0.595, P=0.003). Logistic regression analysis suggested that the CC genotype was significantly associated with T2DM after adjusted for age, sex, blood pressure and obesity (OR=0.615, 95% CI: 0.407- 0.928, P=0.021). Meta-analysis of 6 studies indicated that there existed genetic heterogeneity, and the CC genotype was associated with lower risk of T2DM (P=0.009, OR=0.64, 95% CI: 0.48-0.85). IL6R is a susceptibility gene for T2DM in Han Chinese population of Hubei, and the CC genotype may serve as a genetic protective factor of T2DM.

Objective To study the association of TCF7L2 gene rs11196218,rs290487 polymorphisms with metabolic syndrome in type 2 diabetes mellitus population.Methods According to the diagnostic criteria of international diabetes federation (IDF),680 cases of type 2 diabetes patients were divided into metabolic syndrome (MS) group and non metabolic syndrome (control) group.DNA was extracted from peripheral mononuclear cells,and then PCR was performed to specifically amplify TCF7L2 gene fragments.Gene polymorphisms were determined by connected enzyme detection reaction.After population representative was checked by Hardy-Weinberg equilibrium,statistical analysis was completed by software SPSS 13.0.Results The population was accorded with Hardy-Weinberg equilibrium and possessed the population representative.Frequency distributions of genotypes (GG,AG and AA) in TCF7L2 gene rs11196218 in MS and control groups were 55.6％(233/419),35.8％(150/419),8.6％ (36/419) and 54.8％ (126/230),39.1％ (90/230),6.1％ (14/230),respectively.Frequency distributions of alleles(G and A) in TCF7L2 gene rs11196218 in MS and control groups were 73.5％(616/838),26.5％(222/838)and 74.3％(342/460),25.7％(118/460),respectively.Frequency distributions of genotypes (GG,AG and AA) in TCF7L2 gene rs290487 in MS and control groups were 14.8％(62/418),42.3％(177/418),42.9％(179/418) and 15.0％(34/226),48.2％(109/226),36.8％(83/226),respectively.Frequency distributions of alleles(G and A) in TCF7L2 gene rs11196218 in MS and control groups were 36.0％ (301/836),64.0％ (535/836) and 39.1％ (177/452),60.9％ (275/452),respectively.Frequency distribution of allele and genotype in TCF7L2 genes rsl 1196218 and rs290487 between the two groups were not associated with metabolic syndrome in type 2 diabetes population (P ＞ 0.05).Conclusions TCF7L2 gene rs11196218,rs290487 polymorphisms has not association with metabolic syndrome of type 2 diabetes. Key words: Type 2 diabetes; Metabolic syndrome; TCF7L2; Polymorphism

Objective To investigate the relationship between single nucleotide polymorphisms of LEP rs4731426 locus and genetic susceptibility to type 2 diabetes mellitus. Methods This study employed a case-control study design. The genotype of LEP rs4731426 locus in 1092 patients with type 2 diabetes mellitus and 1092 normal controls was detected by SNPscan™ single nucleotide polymorphism classification technology. We used SPSS 20.0 software to analyze the data. Genotype and allele frequencies were distributed in both groups, and the statistical analysis was conducted by using Chi-square test, Student-t test and logistic regression model. Results In case group, frequencies of the alleles on LEP rs4731426, C and G were 68.4% and 31.6%, respectively, while in control group, frequencies were 70.6% and 29.4% respectively, which was not statistically significant (P=0.132). There was also no difference in CC, CG and GG genotypes between the case and the control groups (P=0.174). The genetic models of co-dominance, dominance, recessiveness, superdominance to the rs4731426 were not significantly different between the two groups before and after adjusting for covariates. Conclusion Genetic susceptibility to type 2 diabetes mellitus in Han population in Guangdong province may be associated with LEP rs4731426 single nucleotide polymorphism. Key words: Type 2 diabetes mellitus; Single nucleotide polymorphism; LEP gene

Objective To screen the variation in NeuroD1 gene and to study its function in vitro and its clinical phenotypes and genetic characteristics in Chinese early-onset type 2 diabetic probands. Methods PCR-direct sequencing of NeuroD1 gene was performed in 85 early-onset type 2 diabetic probands, 95 late-onset type 2 diabetics with strong diabetic history and 87 non-diabetic control subjects. Distributions of the identified variation were calculated and compared among the three groups. Expression vectors with mouse NeuroD1 (mND1)cDNA wild type or mutant type and reporter vectors with human insulin promotor-linked luciferase were constructed. Then the above vectors were co-transfected into rat INS-1 cells. Relative luciferase activities were measured to compare transcriptional activities of insulin gene between WT and MT. Results S159P (T→C), a new mutation was identified in a proband, which was co-segregated with diabetes in 4 carriers from the paternal side. The functional study showed that the S159P mutant exhibited a 25% reduction in transcriptional activity of insulin gene as compared with the wild type. A45T (G→A), a common variation was identified. The AA + GA genotypic frequencies were markedly increased in early-onset type 2 diabetic probands as compared with late-onset type 2 diabetic probands and non-diabetic control subjects (P=0.006 and P=0.014, respectively). Conclusion The novel S159P mutation in the NeuroDl gene seems to contribute to the development of diabetes in the Chinese early-onset type 2 diabetic family. The A45T variation may increase susceptibility to or be in disequilibrium with early-onset type 2 diabetes mellitus in Chinese population. In addition, the A45T variation may affect the onset pattern of type 2 diabetes mellitns, such as early-onset but not late-onset type 2 diabetes mellitus. Key words: NeuroD1 gene; Diabetes mellitus, type 2; Pedigree

Objective To constitute a crowd of multiple familial type 2 diabetes mellitus(T2DM) and to observe the effects of several risk factors of hypertension, lipid metabolic disorder, obesity and insulin resist. Methods According to American Diabetes Association criteria of diabetes, pedigrees with two or over two T2DM patients were chosen and all people were diagnosed by OGTT.Eight hundred and sixty–five persons from 182 pedigrees with two or more T2DM patients were analyzed after the type 1 diabetes mellitus, maturity onset diabetes of the young(MODY) and mitochondrial gene mutation pedigrees were excluded.The survey includes tests of blood glucose, insulin, C–peptide, lipids, etc. Results The prevalence of T2DM and impared glucose regulation impaired glucose regulation(IGR) was 59.88%, the prevalence of T2DM was 45.43%, including 94 T2DM and 102 IGR newly discovered, the prevalence of T2DM and IGR in the diabetes family was significant higher than those in the common populations. The systolic pressure, diastolic pressure blood lipid, BMI, HOMA–IR in diabetic group were obviously higher than those in IGR group or normal group. Conclusion There is significant familial aggregation in T2DM.The history of hypertension and hyperlipidemia and obesity are the risk factors of T2DM or IGR patients.Insulin resistance exists before the attack of diabetes mellitus. Key words: Diabetes mellitus, type 2; Pedigree; Population

Objective To investigate the association of the ghrelin gene Arg51Gln and Leu72Met polymorphisms with type 2 diabetes mellitus and lipid metabolism in Dongxiang, Hui, Han population in Gansu province. Methods From October 2008 to February 2010, 744 patients(386 males and 358 females) with type 2 diabetes mellitus(T2DM group) from Gansu Provincial People's Hospital, People's Hospital of Linxia and Dongxiang County Hospital were recruited, including 242 cases of Dongxiang nationality, 242 cases of Hui nationality, 260 cases of Han nationality. Total of 673 healthy volunteers from above 3 hospitals at the same time were regarded as the control group, including 223 Dongxiang nationality, 203 Hui nationality and 247 Han nationality. Ghrelin gene Arg51Gln and Leu72Met polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Plasma glucose, lipids and other clinical indicators were detected. The genotype and allele frequency distribution were compared with the χ2 test, while the correlation of genotype and plasma lipid levels were compared using correlation analysis and logistic regression analysis. Results (1)The carriers of A (GA+ AA) had a higher risk tendency in T2DM group than the non-carriers in Arg51Gln, and the carriers of A (CA+ AA) had a higher risk tendency than the non-carriers in Leu72Met, but the differences were no statistical significance(all OR>1, all P>0.05). No correlations were found in Arg51Gln, Leu72Met polymorphisms with T2DM after adjusted the gender, age, body mass index(BMI) and blood pressure, etc(all P>0.05). (2)In the T2DM group, Arg51Gln genotype(GA+ AA) in Dongxiang and Hui population was positively correlated with low-density lipoprotein cholesterol (LDL-C) level after adjusted for gender, age, BMI and total cholesterol(r=0.406, 0.377, all P<0.05). Leu72Met genotype(GA+ AA) in Dongxiang and Hui population was positively correlated with total cholesterol level after adjusted for gender, age, BMI and LDL-C(r=0.189, 0.208, all P<0.05). Conclusions Arg51Gln, Leu72Met polymorphisms in ghrelin gene are probably unrelated to T2DM in Dongxiang, Hui and Han population, but might related to lipid metabolism in Dongxiang and Hui population. Key words: Diabetes mellitus, type 2; Dyslipidemias; Polymorphism, single nucleotide; Ghrelin

Objective To explore the correlation of rs2802288 (G/A) in forkhead box class O3A (FOXO3A)gene and rs8192678 (G/A) in peroxisome proliferators-activated receptor-γ coactivator-1 (PPARGC1A) gene to the risk of type 2 diabetes mellitus(T2DM) in longevity and general subjects with Han nationality from Guangxi. Methods By stratified random sampling, a total of 506 longevity subjects (above 90-years old) and 830 general subjects from Guangxi Yongfu County were included in this study from July 2008 to August 2010.The diagnosis for T2DM was based on the 1999 WHO criteria.Based on high resolution melting (HRM) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods, respectively, rs2802288 and rs8192678 were genotyped.The association was estimated by logistic regression.The risk allele accumulation effect and nonparametric multifactor dimension reduction (MDR) were conducted to estimate the gene-gene interaction. Results Based on the recessive genetic model, a positive contribution of FOXO3A rs2802288(G) for T2DM was detected only in longevity subjects (χ2=10.933, P<0.05). A synergy between FOXO3A rs2802288(G) and PPARGC1A rs8192678(A)(χ2=9.617, P<0.05) was observed.In addition, the risk of T2DM was increased with the accumulation of risk alleles, and the carriers with 4 risk alleles had the highest risk (OR=6.482, P<0.001). The MDR analysis indicated the combined effect among rs2802288, rs8192678 and ageing was the best interaction model, resulting in an increased T2DM risk (cross validation consistency=10/10, P<0.05). Conclusion FOXO3A rs2802288(G) is associated with T2DM in South Chinese Han longevity subjects, and PPARGC1A rs8192678(A) could increase the risk by a synergy effect. Key words: Diabetes mellitus, type 2; Forkhead box class O3A; Peroxisome proliferators-activated receptor-γ coactivator 1A; Longevity

To analyze the association between HLA DRB(1), DQB(1) allele and pulmonary tuberculosis complicated with type 2 diabetes mellitus among Han nationality of northern Chinese. By using PCR-SSP technique, the genomic DNA typing was applied to compare the difference of the gene frequency between patients and normal controls. The relative risks (RR) of the disease were also estimated. 214 cases were observed, including 123 pulmonary tuberculosis complicated with type 2 diabetes mellitus, 45 type 2 diabetes mellitus, and 46 normal subjects. All these cases were respectively hospitalized in Beijing Thoracic Tumor & Tuberculosis Hospital, Tianjin Lung Disease Hospital, Beijing Thoracic Disease Hospital, Shijiazhuang Diabetes Hospital, from 1998 to 1999. The frequency of DRB(1) * 09 allele in pulmonary tuberculosis complicated with type 2 diabetes mellitus cases was significantly higher than that of DRB(1) * 09 allele in normal controls, 25.10% Vs 14.03%, RR = 2.22, the frequency of DRB(1) * 09 allele in cases was also significantly higher than that of DRB(1) * 09 allele in type 2 diabetes mellitus controls, 25.1% Vs 9.32%, RR = 3.16; the frequency of DQB(1) * 05 allele was significantly lower than that of DQB(1) * 05 allele in normal controls and diabetes mellitus, 7.17% Vs 19.24%, RR = 0.30, 7.17% Vs 21.12%, RR = 0.26. The results indicate that the DRB(1) * 09 allele is susceptive to the pulmonary tuberculosis complicated with type 2 diabetes mellitus, the DQB(1) * 05 may be protective to the pulmonary tuberculosis complicated with diabetes mellitus. The DRB(1) * 09 allele and DQB(1) * 05 allele may affect the incidence of the pulmonary tuberculosis complicated with type 2 diabetes mellitus, or real effect genes link with them.

Objective To investigate the relationship between a novel polymorphism of C5L2 gene and type 2 diabetes mellitus (T2DM) in Uygur population from Xinjiang region.Methods A novel single nucleotide polymorphism(SNP),698C＞T(P233L) was found using a polymerase chain reaction direct-sequencing method.C5L2 gene 698C ＞ T variant from 252 patients with T2DM and 747 healthy control subjects was detected by polymerase chain reaction and restriction fragment length polymorphism.Result Heterozygote carriers of the 698CT genotype were more frequent among T2DM patients than that among controls (0.107 vs 0.036,x2 =18.576,P＜0.01) in the Uygur population. After adjustment of confounding factors such as sex,age,smoking,alcohol consumption,and hypertension,as well as serum levels of triglyceride,total cholesterol,low-density lipoproteincholesterol,and high-density lipoprotein-cholesterol,the difference remained significant ( P＜0.01,OR =3.373,95％ CI 1.736-6.553 ).Conclusion The CT genotype of the C5L2 gene might be a risk factor of T2DM in Uygur nationality population in Xinjiang. Key words: C5L2 gene; Acylation-stimulating protein; Diabetes mellitus, type 2; Uygur

Objective To investigate the relationship between RXRG rs1467664 and genetic susceptibility to type 2 diabetes mellitus. Methods A case-control study was used. Genotypes of RXRG rs1467664 in 1092 patients with type 2 diabetes mellitus and 1092 normal controls was detected by SNPscan™. Genotype and allele frequencies were analyzed by SPSS 20.0 software. Results There was no significant difference in allele frequency and genotype frequency of RXRG rs1467664 between case and control groups. Before and after adjusting for age, gender, and BMI, there was no statistically significant difference in rs1467664 in genetic models between the two groups (P>0.05). Conclusion Our result suggested that there is no significant association between RXRG rs1467664 and genetic susceptibility to type 2 diabetes mellitus in Guangdong Han population. Key words: Type 2 diabetes mellitus; Single nucleotide polymorphism; RXRG gene