2型糖尿病候选基因TCF7L2的研究进展

自发现转录因子7类似物2(TCF7L2)基因多态性与成人2型糖尿病(T2D)相关以来,该结论在不同人种中得到广泛证实.研究认为它可能通过影响肠胰岛素轴Wnt信号传导通路的胰高血糖素样肽-1(GLP-1)的表达或通过在胰岛β细胞的表达,或参与胰岛素的合成、加工、分泌,影响胰岛素敏感性等方式导致糖尿病发生.本文对该基因目前的研究成果及趋势进行相关论述.     

TCF7L2 gene polymorphism as a risk for type 2 diabetes mellitus and diabetic microvascular complications

Molecular Biology Reports - Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic condition with various genetics and environmental influences that affects the capacity of the body to produce or...     

Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample

Many reports in different populations have demonstrated linkage of the 10q24–q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24–q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01×10⁻⁶) and of the nearby intergenic SNP, rs1033772, (p = 6.59×10⁻⁶) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required.     

A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci

Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10⁻¹¹) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10⁻⁹) resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10⁻⁹) lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.     

ADIPOQ,KCNJ11 and TCF7L2 polymorphisms in type 2 diabetes in Kyrgyz population: A case‐control study

The aim of this study was to ascertain the polymorphic markers profile of ADIPOQ, KCNJ11 and TCF7L2 genes in Kyrgyz population and to analyze the association of polymorphic markers and combinations of ADIPOQ gene's G276T locus, KCNJ11 gene's Glu23Lys locus and TCF7L2 gene's VS3C>T locus with type two diabetes (T2D) in Kyrgyz population. In this case‐control study, 114 T2D patients 109 non‐diabetic participants were genotyped using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). Two individual polymorphisms (ADIPOQ rs1501299, KCNJ11 rs5219) were found to be associated with T2D. We found two (Lys23Lys/CC and Glu23Lys/CT) of the overall nine combinations, which were more prevalent in T2D group compared to controls (χ² = 4.21, P = 0.04). Lys23Lys/CC combination was associated with a 2.65‐fold increased likelihood of T2D (OR = 2.65, 95% CI 1.12‐6.28), whereas the Glu23Lys/CT combination also increased such likelihood (OR = 3.88, 95% CI 1.27‐11.91). This study demonstrated some association of 276T allele and ADIPOQ gene G276T heterozygous genotype as well as KCNJ11 gene 23Lys allele with T2D in ethnic Kyrgyz, but study results should be interpreted with caution because of the limited statistical power.     

Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10⁻⁴, permutation p = 1.0×10⁻³). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10⁻⁷). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.     

Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer's disease

Recent GWAS studies focused on uncovering novel genetic loci related to AD have revealed associations with variants near CLU, CR1, PICALM and BIN1. In this study, we conducted a genome-wide association study in an independent set of 1034 cases and 1186 controls using the Illumina genotyping platforms. By coupling our data with available GWAS datasets from the ADNI and GenADA, we replicated the original associations in both PICALM (rs3851179) and CR1 (rs3818361). The PICALM variant seems to be non-significant after we adjusted for APOE e4 status. We further tested our top markers in 751 independent cases and 751 matched controls. Besides the markers close to the APOE locus, a marker (rs12989701) upstream of BIN1 locus was replicated and the combined analysis reached genome-wide significance level (p = 5E-08). We combined our data with the published Harold et al. study and meta-analysis with all available 6521 cases and 10360 controls at the BIN1 locus revealed two significant variants (rs12989701, p = 1.32E-10 and rs744373, p = 3.16E-10) in limited linkage disequilibrium (r² = 0.05) with each other. The independent contribution of both SNPs was supported by haplotype conditional analysis. We also conducted multivariate analysis in canonical pathways and identified a consistent signal in the downstream pathways targeted by Gleevec (P = 0.004 in Pfizer; P = 0.028 in ADNI and P = 0.04 in GenADA). We further tested variants in CLU, PICALM, BIN1 and CR1 for association with disease progression in 597 AD patients where longitudinal cognitive measures are sufficient. Both the PICALM and CLU variants showed nominal significant association with cognitive decline as measured by change in Clinical Dementia Rating-sum of boxes (CDR-SB) score from the baseline but did not pass multiple-test correction. Future experiments will help us better understand potential roles of these genetic loci in AD pathology.     

Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals

The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.