Genetics Of Type 2 Diabetes Research Articles

The Missing Heritability in T1D and Potential New Targets for Prevention.

Type 1 diabetes (T1D) is a T cell-mediated disease. It is strongly associated with susceptibility haplotypes within the major histocompatibility complex, but this association accounts for an estimated 50% of susceptibility. Other studies have identified as many as 50 additional susceptibility loci, but the effect of most is very modest (odds ratio (OR) <1.5). What accounts for the “missing heritability” is unknown and is often attributed to environmental factors. Here we review new data on the cognate ligand of MHC molecules, the T cell receptor (TCR). In rats, we found that one allele of a TCR variable gene, Vβ13A, is strongly associated with T1D (OR >5) and that deletion of Vβ13+ T cells prevents diabetes. A role for the TCR is also suspected in NOD mice, but TCR regions have not been associated with human T1D. To investigate this disparity, we tested the hypothesis in silico that previous studies of human T1D genetics were underpowered to detect MHC-contingent TCR susceptibility. We show that stratifying by MHC markedly increases statistical power to detect potential TCR susceptibility alleles. We suggest that the TCR regions are viable candidates for T1D susceptibility genes, could account for “missing heritability,” and could be targets for prevention.

Insights into type 1 diabetes provided by genetic analyses

Recent identification of over 60 loci contributing to the susceptibility of developing type 1 diabetes (T1D) provides a timely opportunity to assess what is currently known of the genetics of T1D, and what these discoveries may tell us about the disease itself. The major findings will be discussed under five main themes: T1D risk gene identification, molecular mechanisms of susceptibility, shared genetic cause with other diseases, development of novel analytical methods, and understanding disease heterogeneity. The plethora of T1D risk genes that have been identified risk overwhelming clinicians with lists of gene names and symbols that have little bearing on management, and provide a challenge for researchers to place the genetics of T1D in a more amenable clinical context.

The genetic interface between gestational diabetes and type 2 diabetes

Objective: Although the Western diet and lifestyle has contributed to an increase in the prevalence of gestational diabetes (GDM) worldwide, genetic predisposition also plays an important role. This article reviews the current state of knowledge regarding the genetic interface between type 2 diabetes (T2D) and GDM. Methods: Review of the current literature on genetics of T2D and GDM. Results: Maturity Onset Diabetes of the Young (MODY) due to glucokinase mutations may account for as much as 5% of GDM patients. Knowledge of both maternal and fetal genotypes may be useful for individualizing glycemic goals during pregnancy in families harboring these mutations. Of the 38 common T2D susceptibility variants identified to date, several are also associated with GDM. Presumably, these mutations increase GDM risk through decreased ability of β-cells to compensate for the insulin resistance associated with pregnancy. The effect of these alleles on risk for GDM is modest (odds ratios (odds ratio (OR)~1.1–1.6); thus, they individually are poorly predictive. Conclusions: Future studies must concentrate on understanding the biological underpinnings of known T2D risk alleles and the discovery of new alleles for both GDM and T2D. These insights may lead to more effective strategies for preventing and treating GDM.

Determining Genetic Risk Factors for Pediatric Type 2 Diabetes

The prevalence of type 2 diabetes (T2D) is increasing significantly in the pediatric population. A strong family history of the disease suggests the involvement of genetic factors for diabetes development, but defining the molecular genetics of T2D in children is difficult due to a low number of subjects and the lack of robust diagnostic criteria. Thus, genetic studies of T2D have been carried out almost exclusively in adults. In this review, the genetics of T2D is summarized and options for discovering the missing heritability explored. The review concludes with a discussion of future research that will be required for determining genetic risk factors for pediatric T2D.

Identification of Type 1 Diabetes–Associated DNA Methylation Variable Positions That Precede Disease Diagnosis

Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D–discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D–associated methylation variable positions (T1D–MVPs). We confirmed these T1D–MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D–discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D–MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D–MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D–MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.

Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC

The human leukocyte antigen (HLA) class II genes HLA-DRB1, -DQA1 and -DQB1 are the strongest genetic factors for type 1 diabetes (T1D). Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region’s high gene density and complex linkage disequilibrium (LD). To facilitate the association analysis, two novel algorithms were implemented in this study: one for phasing the multi-allelic HLA genotypes in trio families, and one for partitioning the HLA strata in conditional testing. Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case–Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families. After imputation, the two datasets have 1,941 common SNPs in the MHC, of which 22 were successfully tested and replicated based on the statistical testing stratifying on the detailed DRB1 and DQB1 genotypes. Further conditional tests using the combined dataset confirmed eight novel SNP associations around 31.3 Mb on chromosome 6 (rs3094663, p = 1.66 × 10−11 and rs2523619, p = 2.77 × 10−10 conditional on the DR/DQ genotypes). A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-010-0908-2) contains supplementary material, which is available to authorized users.

GRB10 gene and type 2 diabetes in Whites

GRB10 encodes for an inhibitor of insulin receptor signaling [1] and is therefore a candidate for type 2 diabetes (T2D). In a preliminary study, the minor allele (MA) of GRB10 rs4947710 was associated with a reduced T2D risk in Whites from Italy, whereas a trend in the opposite direction, albeit not significant, was observed in Whites from the US [2], making the overall observation uncertain. A different GRB10 single nucleotide polymorphism (SNP) (rs2237457) has been recently associated with T2D among Amish but not in other populations [3], suggesting the possibility of allelic heterogeneity. To further investigate the role of GRB10 variability in modulating susceptibility to T2D in Whites, we genotyped rs4947710 and rs2237457 in a total of 3,433 diabetic cases (1899 males/1534 females; age=61.4±9.2 yrs; BMI=31.5±6.1 Kg/m2) and 2,660 non-diabetic controls (1153 males/1507 females; age=45.5±16.0 yrs; BMI=27.8±6.1 Kg/m2) of European origin included in the “GENetics of T2D in Italy and United States (GENIUS) Consortium”. The clinical characteristics of these subjects have been previously reported in details [4]. All samples, which included those from the previous smaller study (2), were genotyped by TaqMan allelic discrimination assay. The average agreement rate of duplicate samples was >99%. Failure rate of genotyping was <3.0%. Both rs4947710 (MA frequency=0.073) and rs2247457 (MA frequency=0.39) were in Hardy Weinberg equilibrium in controls and cases. Since no genetic heterogeneity across the four centers of recruitment was evident (p values for heterogeneity = 0.11 and 0.16 for rs4947710 and rs2247457, respectively), data were analyzed after pooling the four data sets together and adjusting for center of recruitment, age and sex. No significant association with T2D was observed with either rs4947710 (allelic OR, 95% CI=1.11, 0.92-1.33, adjusted p=0.30) or rs2247457 (OR, 95%CI=0.98, 0.89-1.09, adjusted p=0.73). These results are in agreement with those from the DIAGRAM data set [5], which did not show a significant association between T2D and either rs4947710 (OR, 95% CI =1.08, 0.99-1.17; p=0.1) or rs2237457 (OR, 95% CI=1.06, 0.99-1.13; p=0.1). In conclusion, GRB10 rs2237457 and rs4947710 do not seem to play a significant role in modulating susceptibility for T2D in individuals of European ancestry.

Genome-wide end-sequenced BAC resources for the NOD/MrkTac☆ and NOD/ShiLtJ☆☆ mouse genomes

Non-obese diabetic (NOD) mice spontaneously develop type 1 diabetes (T1D) due to the progressive loss of insulin-secreting β-cells by an autoimmune driven process. NOD mice represent a valuable tool for studying the genetics of T1D and for evaluating therapeutic interventions. Here we describe the development and characterization by end-sequencing of bacterial artificial chromosome (BAC) libraries derived from NOD/MrkTac (DIL NOD) and NOD/ShiLtJ (CHORI-29), two commonly used NOD substrains. The DIL NOD library is composed of 196,032 BACs and the CHORI-29 library is composed of 110,976 BACs. The average depth of genome coverage of the DIL NOD library, estimated from mapping the BAC end-sequences to the reference mouse genome sequence, was 7.1-fold across the autosomes and 6.6-fold across the X chromosome. Clones from this library have an average insert size of 150 kb and map to over 95.6% of the reference mouse genome assembly (NCBIm37), covering 98.8% of Ensembl mouse genes. By the same metric, the CHORI-29 library has an average depth over the autosomes of 5.0-fold and 2.8-fold coverage of the X chromosome, the reduced X chromosome coverage being due to the use of a male donor for this library. Clones from this library have an average insert size of 205 kb and map to 93.9% of the reference mouse genome assembly, covering 95.7% of Ensembl genes. We have identified and validated 191,841 single nucleotide polymorphisms (SNPs) for DIL NOD and 114,380 SNPs for CHORI-29. In total we generated 229,736,133 bp of sequence for the DIL NOD and 121,963,211 bp for the CHORI-29. These BAC libraries represent a powerful resource for functional studies, such as gene targeting in NOD embryonic stem (ES) cell lines, and for sequencing and mapping experiments.

The effect of the MHC locus on autoantibodies in type 1 diabetes

Objective:To investigate whether the presence of autoantibodies specific for type 1 diabetes (T1D) is determined by the major genetic susceptibility locus for the disease at the HLA genes, using the...

Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

The major histocompatibility complex (MHC) is known to harbour genetic risk factors for type 1 diabetes (T1D) additional to the class II determinants HLA-DRB1, -DQA1 and -DQB1, but strong linkage disequilibrium (LD) has made efforts to establish their location difficult. This study utilizes a dataset generated by the T1D genetics consortium (T1DGC), with genotypes for 2965 markers across the MHC in 2321 T1D families of multiple (mostly Caucasian) ethnicities. Using a comprehensive approach consisting of complementary conditional methods and LD analyses, we identified three regions with T1D association, independent both of the known class II determinants and of each other. A subset of polymorphisms that could explain most of the association in each region included single nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, particular HLA-B and HLA-DPB1 alleles, and SNPs close to the COL11A2 and RING1 genes. Apart from HLA-B and HLA-DPB1, all of these represent novel associations, and subpopulation analyses did not indicate large population-specific differences among Caucasians for our findings. On account of the unusual genetic complexity of the MHC, further fine mapping is demanded, with the possible exception of HLA-B. However, our results mean that these efforts can be focused on narrow, defined regions of the MHC.

14th International HLA and Immunogenetics Workshop: Report on the HLA component of type 1 diabetes

The type 1 diabetes (T1D) component of the 13th International Histocompatibility Workshop (IHW) obtained microsatellite (msat) and human leukocyte antigen (HLA)-DR/DQ data on case/control and family samples through an international collaboration. The aim was to detect the effects of susceptibility loci on the HLA complex independent of the primary determinants in the class II region (HLA-DR/DQ). As part of the activity of the 14th International HLA and Immunogenetics Workshop (14th IHIWS), a T1D workshop was held to present analyses of the 13th IHW data and to discuss the current status of knowledge about the genetics of T1D. These data are now available online through dbMHC, a web-based resource established by the National Center for Biotechnology. Continuing work since the 13th IHW has resulted in published work showing heterogeneity of DR3 haplotypes in data sets from the 13th IHW and Human Biological Data Interchange (HBDI). In addition, we identified markers that define DRB1*1501 DQB1*0602 haplotypes conferring reduced protection from diabetes in a Swedish 13th IHW data set. Further analyses of the 13th IHW data set not only showed some significant results but also demonstrated extensive heterogeneity reminiscent of non-HLA genes. The haplotype analysis in HBDI families identified two msats with significant effects on susceptibility and statistically significant age of onset effects at class III markers that are not because of linkage disequilibrium, with class I alleles known to affect age of onset. The above studies underscore the importance of refining our understanding of susceptibility associated with genes in the HLA complex.