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1.  Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases 
PLoS Genetics  2011;7(8):e1002216.
The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10−10): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).
Author Summary
Autoantibodies are important markers for autoimmune diseases such as type 1 diabetes and Graves' disease. However, little is known about the genetic factors that control their production. To improve our understanding of this genetic basis, we measured four autoantibodies in a collection of up to 8,300 type 1 diabetes cases plasma samples. We combined these measurements with genome-wide genotype data to conduct four independent genome-wide association studies. Two loci showed unequivocal evidence of autoantibody association: the FCRL3 locus and the ABO blood group locus. Variants in the FCRL3 gene have been previously associated with autoimmune diseases, but such associations have not been reported for ABO blood group genotypes. In addition, we found extensive overlap between type 1 diabetes and autoantibody loci, and these findings provide new information about the role of these risk variants. Lastly, we hypothesized that loci associated with thyroid autoantibodies are strong candidates for association with thyroid autoimmune disorders. We confirmed this hypothesis by genotyping these variants in an independent cohort of Graves' disease cases, and we found evidence for two new Graves' disease loci.
doi:10.1371/journal.pgen.1002216
PMCID: PMC3150451  PMID: 21829393
2.  Improving Prediction of Type 1 Diabetes by testing Non-HLA Genetic Variants in addition to HLA Markers 
Pediatric diabetes  2013;15(5):355-362.
Objective
The purpose of this study was to explore whether non-HLA genetic markers can improve type 1 diabetes (T1D) prediction in a prospective cohort with high-risk HLA-DR,DQ genotypes.
Methods
The Diabetes Autoimmunity Study in the Young (DAISY) follows prospectively for development of T1D and islet autoimmunity (IA) children at increased genetic risk. A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms and one microsatellite.
Results
In multivariate analyses adjusting for family history and HLA-DR3/4 genotype, PTPN22 (rs2476601) and two UBASH3A (rs11203203 and rs9976767) SNPs were associated with development of IA (HR=1.87, 1.55 and 1.54 respectively, all p≤0.003), while GLIS3 and IL2RA showed borderline association with development of IA. INS, UBASH3A and IFIH1 were significantly associated with progression from IA to diabetes (HR=1.65, 1.44 and 1.47 respectively, all p≤0.04), while PTPN22 and IL27 showed borderline association with progression from IA to diabetes. In survival analysis, 45% of general population DAISY children with PTPN22 rs2476601 TT or HLA-DR3/4 and UBASH3A rs11203203 AA developed diabetes by age 15, compared to 3% of children with all other genotypes (p<0.0001). Addition of non-HLA markers to HLA-DR3/4,DQ8 did not improve diabetes prediction in first-degree relatives.
Conclusion
Addition of PTPN22 and UBASH3A SNPs to HLA-DR,DQ genotyping can improve T1D risk prediction.
PMCID: PMC4116638  PMID: 25075402
Type 1 diabetes; islet autoimmunity; non-HLA genetic markers; prediction
3.  A Variant in the BACH2 Gene Is Associated With Susceptibility to Autoimmune Addison's Disease in Humans 
Context:
Autoimmune Addison's disease (AAD) is a rare but highly heritable condition. The BACH2 protein plays a crucial role in T lymphocyte maturation, and allelic variation in its gene has been associated with a number of autoimmune conditions.
Objective:
We aimed to determine whether alleles of the rs3757247 single nucleotide polymorphism (SNP) in the BACH2 gene are associated with AAD.
Design, Setting, and Patients:
This case-control association study was performed in two phases using Taqman chemistry. In the first phase, the rs3757247 SNP was genotyped in 358 UK AAD subjects and 166 local control subjects. Genotype data were also available from 5154 healthy UK controls from the Wellcome Trust (WTCCC2) for comparison. In the second phase, the SNP was genotyped in a validation cohort comprising 317 Norwegian AAD subjects and 365 controls.
Results:
The frequency of the minor T allele was significantly higher in subjects with AAD from the United Kingdom compared to both the local and WTCCC2 control cohorts (58% vs 45 and 48%, respectively) (local controls, P = 1.1 × 10−4; odds ratio [OR], 1.68; 95% confidence interval [CI], 1.29–2.18; WTCCC2 controls, P = 1.4 × 10−6; OR, 1.44; 95% CI, 1.23–1.69). This finding was replicated in the Norwegian validation cohort (P = .0015; OR, 1.41; 95% CI, 1.14–1.75). Subgroup analysis showed that this association is present in subjects with both isolated AAD (OR, 1.53; 95% CI, 1.22–1.92) and autoimmune polyglandular syndrome type 2 (OR, 1.37; 95% CI, 1.12–1.69) in the UK cohort, and with autoimmune polyglandular syndrome type 2 in the Norwegian cohort (OR, 1.58; 95% CI, 1.22–2.06).
Conclusion:
We have demonstrated, for the first time, that allelic variability at the BACH2 locus is associated with susceptibility to AAD. Given its association with multiple autoimmune conditions, BACH2 can be considered a “universal” autoimmune susceptibility locus.
We performed a two-stage case control association study in UK and Norwegian cohorts and found that allelic variability in BACH2 locus confers susceptibility to autoimmune Addison's disease.
doi:10.1210/jc.2016-2368
PMCID: PMC5095240  PMID: 27680876
4.  Pilot Genome Wide Association Search Identifies Potential loci for Risk of Erectile Dysfunction in Type 1 Diabetes Using the DCCT/EDIC Study Cohort 
The Journal of urology  2012;188(2):514-520.
Purpose
To identify genetic predictors of diabetes-associated ED using genome wide and candidate gene approaches in a cohort of men with type I diabetes.
Methods
We examined 528 white men with T1D (125 with ED) from the DCCT and its observational follow up EDIC Study. ED was defined from a single item of the IIEF. An Illumina Human1M BeadChip was used for genotyping. 867,125 single nucleotide polymorphisms (SNPs) were subjected to analysis. Whole genome and candidate gene approaches tested the hypothesis that genetic polymorphisms may predispose men with T1D to ED. Univariate and multivariate models were used controlling for age, HbA1c, diabetes duration, and prior randomization to intensive or conventional insulin therapy during DCCT. A stratified false discovery rate was used to perform the candidate gene approach.
Results
Two SNPs located on chromosome 3 in one genomic loci were associated with ED with p < 1×10−6. rs9810233 had a p-value of 7 × 10−7 and rs1920201 had a p-value of 9×10−7 The nearest gene to these two SNPs is ALCAM. The genetic association results at these loci were similar in univariate and multivariate analysis. No candidate genes met criteria for statistical significance.
Conclusions
Two SNPs, rs9810233 and rs1920101, which are 25 kb apart, are both associated with ED, albeit not meeting the standard GWAS significance criteria of p < 5 × 10−8. Other studies with larger sample sizes will be required to determine whether ALCAM represents a novel gene in the pathogenesis of diabetes associated ED.
doi:10.1016/j.juro.2012.04.001
PMCID: PMC3764461  PMID: 22704111
Erectile Dysfunction; Diabetes; Genetics
5.  PUMA: A Unified Framework for Penalized Multiple Regression Analysis of GWAS Data 
PLoS Computational Biology  2013;9(6):e1003101.
Penalized Multiple Regression (PMR) can be used to discover novel disease associations in GWAS datasets. In practice, proposed PMR methods have not been able to identify well-supported associations in GWAS that are undetectable by standard association tests and thus these methods are not widely applied. Here, we present a combined algorithmic and heuristic framework for PUMA (Penalized Unified Multiple-locus Association) analysis that solves the problems of previously proposed methods including computational speed, poor performance on genome-scale simulated data, and identification of too many associations for real data to be biologically plausible. The framework includes a new minorize-maximization (MM) algorithm for generalized linear models (GLM) combined with heuristic model selection and testing methods for identification of robust associations. The PUMA framework implements the penalized maximum likelihood penalties previously proposed for GWAS analysis (i.e. Lasso, Adaptive Lasso, NEG, MCP), as well as a penalty that has not been previously applied to GWAS (i.e. LOG). Using simulations that closely mirror real GWAS data, we show that our framework has high performance and reliably increases power to detect weak associations, while existing PMR methods can perform worse than single marker testing in overall performance. To demonstrate the empirical value of PUMA, we analyzed GWAS data for type 1 diabetes, Crohns's disease, and rheumatoid arthritis, three autoimmune diseases from the original Wellcome Trust Case Control Consortium. Our analysis replicates known associations for these diseases and we discover novel etiologically relevant susceptibility loci that are invisible to standard single marker tests, including six novel associations implicating genes involved in pancreatic function, insulin pathways and immune-cell function in type 1 diabetes; three novel associations implicating genes in pro- and anti-inflammatory pathways in Crohn's disease; and one novel association implicating a gene involved in apoptosis pathways in rheumatoid arthritis. We provide software for applying our PUMA analysis framework.
Author Summary
Genome-wide association studies (GWAS) have identified hundreds of regions of the human genome that are associated with susceptibility to common diseases. Yet many lines of evidence indicate that many susceptibility loci, which cannot be detected by standard statistical methods, remain to be discovered. We have developed PUMA, a framework for applying a family of penalized regression methods that simultaneously consider multiple susceptibility loci in the same statistical model. We demonstrate through simulations that our framework has increased power to detect weak associations compared to both standard GWAS analysis methods and previous applications of penalized methods. We applied PUMA to identify novel susceptibility loci for type 1 diabetes, Crohn's disease and rheumatoid arthritis, where the novel disease loci we identified have been previously associated with similar diseases or are known to function in relevant biological pathways.
doi:10.1371/journal.pcbi.1003101
PMCID: PMC3694815  PMID: 23825936
6.  A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans 
PLoS ONE  2012;7(1):e29202.
African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10−8). SNP rs7560163 (P = 7.0×10−9, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10−5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
doi:10.1371/journal.pone.0029202
PMCID: PMC3251563  PMID: 22238593
7.  Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes 
Ng, Maggie C. Y. | Shriner, Daniel | Chen, Brian H. | Li, Jiang | Chen, Wei-Min | Guo, Xiuqing | Liu, Jiankang | Bielinski, Suzette J. | Yanek, Lisa R. | Nalls, Michael A. | Comeau, Mary E. | Rasmussen-Torvik, Laura J. | Jensen, Richard A. | Evans, Daniel S. | Sun, Yan V. | An, Ping | Patel, Sanjay R. | Lu, Yingchang | Long, Jirong | Armstrong, Loren L. | Wagenknecht, Lynne | Yang, Lingyao | Snively, Beverly M. | Palmer, Nicholette D. | Mudgal, Poorva | Langefeld, Carl D. | Keene, Keith L. | Freedman, Barry I. | Mychaleckyj, Josyf C. | Nayak, Uma | Raffel, Leslie J. | Goodarzi, Mark O. | Chen, Y-D Ida | Taylor, Herman A. | Correa, Adolfo | Sims, Mario | Couper, David | Pankow, James S. | Boerwinkle, Eric | Adeyemo, Adebowale | Doumatey, Ayo | Chen, Guanjie | Mathias, Rasika A. | Vaidya, Dhananjay | Singleton, Andrew B. | Zonderman, Alan B. | Igo, Robert P. | Sedor, John R. | Kabagambe, Edmond K. | Siscovick, David S. | McKnight, Barbara | Rice, Kenneth | Liu, Yongmei | Hsueh, Wen-Chi | Zhao, Wei | Bielak, Lawrence F. | Kraja, Aldi | Province, Michael A. | Bottinger, Erwin P. | Gottesman, Omri | Cai, Qiuyin | Zheng, Wei | Blot, William J. | Lowe, William L. | Pacheco, Jennifer A. | Crawford, Dana C. | Grundberg, Elin | Rich, Stephen S. | Hayes, M. Geoffrey | Shu, Xiao-Ou | Loos, Ruth J. F. | Borecki, Ingrid B. | Peyser, Patricia A. | Cummings, Steven R. | Psaty, Bruce M. | Fornage, Myriam | Iyengar, Sudha K. | Evans, Michele K. | Becker, Diane M. | Kao, W. H. Linda | Wilson, James G. | Rotter, Jerome I. | Sale, Michèle M. | Liu, Simin | Rotimi, Charles N. | Bowden, Donald W.
PLoS Genetics  2014;10(8):e1004517.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Author Summary
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
doi:10.1371/journal.pgen.1004517
PMCID: PMC4125087  PMID: 25102180
Diabetes  2009;58(6):1403-1410.
OBJECTIVE
Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection.
RESEARCH DESIGN AND METHODS
We genotyped ∼360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications.
RESULTS
A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 × 10−5. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 × 10−7). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 × 10−6). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney.
CONCLUSIONS
We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.
doi:10.2337/db08-1514
PMCID: PMC2682673  PMID: 19252134
Biomedical Reports  2015;3(3):327-332.
Genetic factors are indicated in the development of type 1 diabetes (DM1). Recently, nucleotide variants of BACH2 and SOD2 have been associated with this chronic condition. Therefore, the purpose of the present study was to investigate the contribution of BACH2 rs3757247 and SOD2 rs4880 (Ala16Val) polymorphisms to the risk of DM1 and diabetes long-term complications. Selected polymorphic variants of BACH2 and SOD2 were investigated in a group of 141 patients with DM1 and in a group of age, gender-matched healthy subjects (n=369) using a high-resolution melting curve method. There was no evidence for either allelic or genotypic association with the risk of DM1 and diabetes chronic complications for analysed polymorphisms. In addition, no interaction between BACH2 and SOD2 variants in the development of this condition was observed. However, the frequency of BACH2 rs3757247 AG and AA genotypes was statistically different between DM1 patients with retinopathy and healthy individuals (odds ratio, 2.455; 95% confidence interval, 0.999–6.035; P=0.044), but this result did not survive multiple testing corrections. The present study did not confirm the involvement of BACH2 rs3757247 and SOD2 rs4880 polymorphisms in the development of DM1 and diabetes long-term complications. Further studies in a larger population sample are required.
doi:10.3892/br.2015.424
PMCID: PMC4461856  PMID: 26137231
type 1 diabetes; BACH2 rs3757247 polymorphism; SOD2 rs4880 polymorphism
PLoS ONE  2008;3(8):e3019.
Background
Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic β-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined roles in the pathogenesis of type 2 diabetes. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic variants with the predominant prediabetes traits, i.e., obesity, impaired insulin secretion, and insulin resistance.
Methodology/Principal Findings
One thousand five hundred and seventy-eight metabolically characterized non-diabetic German subjects were genotyped for the reported candidate single nucleotide polymorphisms (SNPs) JAZF1 rs864745, CDC123/CAMK1D rs12779790, TSPAN8/LGR5 rs7961581, THADA rs7578597, ADAMTS9 rs4607103, NOTCH2 rs10923931, DCD rs1153188, VEGFA rs9472138, and BCL11A rs10490072. Insulin sensitivity was derived from fasting glucose and insulin concentrations, oral glucose tolerance test (OGTT), and hyperinsulinemic-euglycemic clamp. Insulin secretion was estimated from OGTT data. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons (corrected α-level: p = 0.0014), none of the SNPs was reliably associated with adiposity, insulin sensitivity, or insulin secretion (all p≥0.0117, dominant inheritance model). The risk alleles of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 tended to associate with more than one measure of insulin sensitivity and insulin secretion, respectively, but did not reach formal statistical significance. The study was sufficiently powered (1-β = 0.8) to detect effect sizes of 0.19≤d≤0.25 (α = 0.0014) and 0.13≤d≤0.16 (α = 0.05).
Conclusions/Significance
In contrast to the first series of GWA-derived type 2 diabetes candidate SNPs, we could not detect reliable associations of the novel risk loci with prediabetic phenotypes. Possible weak effects of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 on insulin sensitivity and insulin secretion, respectively, await further confirmation by larger studies.
doi:10.1371/journal.pone.0003019
PMCID: PMC2500187  PMID: 18714373
Genes and immunity  2009;10(Suppl 1):S85-S94.
The advent of genome-wide association (GWA) studies has revolutionized the detection of disease loci and provided abundant evidence for previously undetected disease loci that can be pooled together in meta-analysis studies or used to design followup studies. A total of 1715 SNPs from the Wellcome Trust Case Control Consortium GWA study of type I diabetes (T1D) were selected and a follow-up study was conducted in 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. In addition to the support for previously identified loci (PTPN22/1p13; ERBB3/12q13; SH2B3/12q24; CLEC16A/16p13; UBASH3A/21q22), evidence supporting two new and distinct chromosome locations associated with T1D was observed: FHOD3/18q12 (rs2644261, P=5.9×10−4) and Xp22 (rs5979785, P=6.8×10−3; http://www.T1DBase.org). There was independent support for both SNPs in a GWA meta-analysis of 7514 cases and 9045 controls (P values=5.0×10−3 and 6.7×10−6, respectively). The chromosome 18q12 region contains four genes, none of which are obvious functional candidate genes. In contrast, the Xp22 SNP is located 30 kb centromeric of the functional candidate genes TLR8 and TLR7 genes. Both TLR8 and TLR7 are functional candidate genes owing to their key roles as pathogen recognition receptors and, in the case of TLR7, overexpression has been associated directly with murine autoimmune disease.
doi:10.1038/gene.2009.97
PMCID: PMC2805462  PMID: 19956107
genome-wide association; type I diabetes; follow-up study; T1DGC
Diabetes  2008;57(10):2858-2861.
OBJECTIVE— The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled and genotyped a large collection of multiplex families for the purpose of mapping genomic regions linked to type 1 diabetes. In the current study, we tested for evidence of loci associated with type 1 diabetes utilizing genome-wide linkage scan data and family-based association methods.
RESEARCH DESIGN AND METHODS— A total of 2,496 multiplex families with type 1 diabetes were genotyped with a panel of 6,090 single nucleotide polymorphisms (SNPs). Evidence of association to disease was evaluated by the pedigree disequilibrium test. Significant results were followed up by genotyping and analyses in two independent sets of samples: 2,214 parent-affected child trio families and a panel of 7,721 case and 9,679 control subjects.
RESULTS— Three of the SNPs most strongly associated with type 1 diabetes localized to previously identified type 1 diabetes risk loci: INS, IFIH1, and KIAA0350. A fourth strongly associated SNP, rs876498 (P = 1.0 × 10−4), occurred in the sixth intron of the UBASH3A locus at chromosome 21q22.3. Support for this disease association was obtained in two additional independent sample sets: families with type 1 diabetes (odds ratio [OR] 1.06 [95% CI 1.00–1.11]; P = 0.023) and case and control subjects (1.14 [1.09–1.19]; P = 7.5 × 10−8).
CONCLUSIONS— The T1DGC 6K SNP scan and follow-up studies reported here confirm previously reported type 1 diabetes associations at INS, IFIH1, and KIAA0350 and identify an additional disease association on chromosome 21q22.3 in the UBASH3A locus (OR 1.10 [95% CI 1.07–1.13]; P = 4.4 × 10−12). This gene and its flanking regions are now validated targets for further resequencing, genotyping, and functional studies in type 1 diabetes.
doi:10.2337/db08-0753
PMCID: PMC2551699  PMID: 18647951
PLoS Genetics  2011;7(2):e1002004.
Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Author Summary
Celiac disease (CD) and rheumatoid arthritis (RA) are two autoimmune diseases characterized by distinct clinical features but increased co-occurrence in families and individuals. Genome-wide association studies (GWAS) performed in CD and RA have identified the HLA region and 26 non-HLA genetic risk loci in each disease. Of the 26 CD and 26 RA risk loci, previous studies have shown that six are shared between the two diseases. In this study we aimed to identify additional shared risk alleles and, in doing so, gain more insight into shared disease pathogenesis. We first empirically investigated the distribution of putative risk alleles from GWAS across both diseases (after removing known risk loci for both diseases). We found that CD risk alleles are non-randomly distributed in the RA GWAS (and vice versa), indicating that CD risk alleles have an increased prior probability of being associated with RA (and vice versa). Next, we performed a GWAS meta-analysis to search for shared risk alleles by combing the RA and CD GWAS, performing both directional and opposite allelic effect analyses, followed by replication testing in independent case-control datasets in both diseases. In addition to the already established six non-HLA shared risk loci, we observed statistically robust associations at eight SNPs, thereby increasing the number of shared non-HLA risk loci to fourteen. Finally, we used gene expression studies and pathway analysis tools to identify the plausible candidate genes in the fourteen associated loci. We observed remarkable overrepresentation of T-cell signaling molecules among the shared genes.
doi:10.1371/journal.pgen.1002004
PMCID: PMC3044685  PMID: 21383967
Pediatric diabetes  2012;13(8):611-615.
Objective
To evaluate UBASH3A (rs11203203) as a predictor of persistent islet autoimmunity and type 1 diabetes.
Research Design and Methods
The Diabetes Autoimmunity Study in the Young (DAISY) followed prospectively for development of persistent islet autoimmunity (IA; autoantibodies to insulin, GAD65, IA-2 or ZnT8 on at least 2 consecutive exams) and diabetes 1715 non-Hispanic white children at increased genetic risk for type 1 diabetes. The DAISY participants were genotyped for rs11202203 (UBASH3A).
Results
UBASH3A allele A was associated with development of IA (HR=1.46, 95%CI=1.11–1.91, p=0.007) and diabetes (HR=1.84, 95%CI=1.28–2.64, p=0.001), controlling for presence of HLA-DR3/4,DQB1*0302 and having a first-degree relative with type 1 diabetes. The UBASH3A AA genotype conferred higher risk of persistent IA (12.7%) and diabetes (6.1%) by age 10 than for AG (7.7% and 3.1%, respectively) or GG (5.3% and 2.0%) genotype (p=0.009 for IA, p=0.0004 for diabetes). Among children with no family history of type 1 diabetes, but HLA-DR3/4,DQB1*0302 and UBASH3A AA genotype, 35.9% developed IA and 50.6% developed diabetes by age 15.
Conclusions
UBASH3A appears to be an independent predictor of IA and type 1 diabetes in children, including those free of family history of type 1 diabetes but carrying the HLA-DR3/4,DQB1*0302 genotype. If confirmed, UBASH3A may prove useful in type 1 diabetes risk prediction and pre-screening of the general population children for clinical trials.
doi:10.1111/j.1399-5448.2012.00888.x
PMCID: PMC4886718  PMID: 22776074
UBASH3A; Islet Autoimmunity; Type 1 Diabetes
Diabetes care  1999;22(1):99-111.
OBJECTIVE
The Diabetes Control and Complications Trial (DCCT) demonstrated the powerful impact of glycemic control on the early manifestations of microvascular complications. Contemporary prospective data on the evolution of macrovascular and late microvascular complications of type 1 diabetes are limited. The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter, longitudinal, observational study designed to use the well-characterized DCCT cohort of >1,400 patients to determine the long-term effects of prior separation of glycemic levels on micro- and macrovascular outcomes.
RESEARCH DESIGN AND METHODS
Using a standardized annual history and physical examination, 28 EDIC clinical centers that were DCCT clinics will follow the EDIC cohort for 10 years. Annual evaluation also includes resting electrocardiogram, Doppler ultrasound measurements of ankle/arm blood pressure, and screening for nephropathy. At regular intervals, a timed 4-h urine is collected, lipid profiles are obtained, and stereoscopic fundus photographs are taken. In addition, dual B-mode Doppler ultrasound scans of the common and internal carotid arteries will be performed at years 1 and 6 and at study end.
RESULTS
Written informed consent was obtained from 96% of the DCCT subjects. The participants, compared with nonparticipants, tended to have better glycemic control at the completion of the DCCT and were more likely to have their diabetes care provided by DCCT personnel. The EDIC baseline measurement stratified by sex delineates multiple cardiovascular disease risk factor differences such as age (older in men), waist-to-hip ratio (higher in men), HDL cholesterol (lower in men), hypertension (more prevalent in men), and maximum intimal-medial thickness of common and internal carotid arteries (thicker in men). Of the original conventional treatment group, 69% have changed to continuous subcutaneous insulin infusion or multiple daily injections. Although the mean HbA1c difference between the intensive and conventional treatment groups narrowed at EDIC years 1 and 2, HbA1c remained significantly lower in the intensive group. Of all expected clinic visits, 95% were completed, and the quality of EDIC data is very similar to that observed in the DCCT.
CONCLUSIONS
Although obvious problems exist in extended follow-up studies of completed clinical trials, these are balanced by the value of continued systematic observation of the DCCT cohort. In contrast to other epidemiologic studies, EDIC will provide 1) definitive data on type 1 as distinct from type 2 diabetes; 2) reliance on prospective rather than on cross-sectional analysis; 3) long-term follow-up in a large population; 4) consistent use of objective, reliable measures of outcomes and glycemia; and 5) observation of patients from before the onset of complications.
PMCID: PMC2745938  PMID: 10333910
Diabetes  2005;54(4):1238-1244.
The development and progression of microvascular complications have been extensively documented in a cohort of type 1 diabetic subjects enrolled in the Diabetes Control and Complications Trial (DCCT) and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. We describe the association of genetic variation in the ACE gene in 1,365 DCCT/EDIC subjects with incident persistent microalbuminuria (n = 312) and severe nephropathy (n = 115). We studied three markers (rs1800764, insertion/deletion, and rs9896208) in the ACE gene that allowed us to capture genetic variation in the common haplotypes occurring at frequencies of >5% in Caucasians. Compared with the more frequent genotype (D/I) for the insertion/deletion polymorphism, in multivariate models, the I/I genotype conferred a lower risk for persistent microalbuminuria (hazard ratio [HR] 0.62 [95% CI 0.43–0.89], P = 0.009) and severe nephropathy (0.56 [0.32–0.96], P = 0.033). Variation at the two other markers, rs1800764 and rs9896208, were also associated with these renal outcomes. In addition, homozygosity for the common haplotype TIC (which corresponded to the T, insertion, and C alleles at the three markers, rs1800764, insertion/deletion, and rs9896208, respectively) versus the CDT/TIC haplotype pair was associated with lower risk for development of persistent microalbuminuria (HR 0.49 [0.32–0.75], P = 0.0009) and severe nephropathy (0.41 [0.22–0.78], P = 0.006). Our findings in the DCCT/EDIC cohort provide strong evidence that genetic variation at the ACE gene is associated with the development of nephropathy in patients with type 1 diabetes.
PMCID: PMC1621110  PMID: 15793268
PLoS ONE  2013;8(4):e60646.
The ubiquitin associated and Src-homology 3 (SH3) domain containing A (UBASH3a) is a suppressor of T-cell receptor signaling, underscoring antigen presentation to T-cells as a critical shared mechanism of diseases pathogenesis. The aim of the present study was to determine whether the UBASH3a gene influence the susceptibility to systemic lupus erythematosus (SLE) in Caucasian populations. We evaluated five UBASH3a polymorphisms (rs2277798, rs2277800, rs9976767, rs13048049 and rs17114930), using TaqMan® allelic discrimination assays, in a discovery cohort that included 906 SLE patients and 1165 healthy controls from Spain. The SNPs that exhibit statistical significance difference were evaluated in a German replication cohort of 360 SLE patients and 379 healthy controls. The case-control analysis in the Spanish population showed a significant association between the rs9976767 and SLE (Pc = 9.9E-03 OR = 1.21 95%CI = 1.07–1.37) and a trend of association for the rs2277798 analysis (P = 0.09 OR = 0.9 95%CI = 0.79–1.02). The replication in a German cohort and the meta-analysis confirmed that the rs9976767 (Pc = 0.02; Pc = 2.4E-04, for German cohort and meta-analysis, respectively) and rs2277798 (Pc = 0.013; Pc = 4.7E-03, for German cohort and meta-analysis, respectively) UBASH3a variants are susceptibility factors for SLE. Finally, a conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs9976767 polymorphism. Our results suggest that UBASH3a gene plays a role in the susceptibility to SLE. Moreover, our study indicates that UBASH3a can be considered as a common genetic factor in autoimmune diseases.
doi:10.1371/journal.pone.0060646
PMCID: PMC3614928  PMID: 23565265
PLoS ONE  2014;9(4):e93193.
Five novel loci recently found to be associated with body mass in two GWAS of East Asian populations were evaluated in two cohorts of Swedish and Greek children and adolescents. These loci are located within, or in the proximity of: CDKAL1, PCSK1, GP2, PAX6 and KLF9. No association with body mass has previously been reported for these loci in GWAS performed on European populations. The single nucleotide polymorphisms (SNPs) with the strongest association at each loci in the East Asian GWAS were genotyped in two cohorts, one obesity case control cohort of Swedish children and adolescents consisting of 496 cases and 520 controls and one cross-sectional cohort of 2293 nine-to-thirteen year old Greek children and adolescents. SNPs were surveyed for association with body mass and other phenotypic traits commonly associated with obesity, including adipose tissue distribution, insulin resistance and daily caloric intake. No association with body mass was found in either cohort. However, among the Greek children, association with insulin resistance could be observed for the two CDKAL1-related SNPs: rs9356744 (β = 0.018, p = 0.014) and rs2206734 (β = 0.024, p = 0.001). CDKAL1-related variants have previously been associated with type 2 diabetes and insulin response. This study reports association of CDKAL1-related SNPs with insulin resistance, a clinical marker related to type 2 diabetes in a cross-sectional cohort of Greek children and adolescents of European descent.
doi:10.1371/journal.pone.0093193
PMCID: PMC3973700  PMID: 24695378
Genome-wide Association Studies (GWAS) revealed novel genetic markers for breast cancer susceptibility. But little is known about the risk factors and molecular events associated with breast cancer in Arab Population. Therefore, we designed a broad study to investigate the susceptibility and prognostic implications of the GWAS breast cancer loci in the Tunisian population. In a cohort of 640 unrelated patients with breast cancer and 371 healthy control subjects, we characterized the variation of 9 single nucleotide polymorphisms (SNPs), namely rs1219648, rs2981582; rs8051542, rs12443621, and rs3803662; rs889312; rs3817198; rs13387042 and rs13281615. Only 5 out of 9 GWAS breast cancer loci were found to be significantly associated with breast cancer in Tunisians: The rs1219648 (G vs. A allele: OR = 1.36, P = 1 × 10−3) and rs2981582 (A vs. G allele: OR = 1.55, P = 3 × 10−6) of FGFR2 gene; the rs8051542 of the TNRC9 gene (T vs. C allele: OR = 1.40, P = 4 × 10−4); the rs889312 of the MAP3K1 gene (C vs. A allele: OR = 1.33, P = 3 × 10−3) and the rs13281615 located on 8q24 (G vs. A allele: OR = 1.21, P = 0.03). Homozygous variant genotypes of rs2981582 were strongly related to lymph node negative breast cancer (OR = 3.33, P = 6 × 10−7) and the minor allele of rs2981582 was associated with increased risk of ER+ tumors (OR = 1.57, P = 0.02; OR = 2.15, P = 0.001, for heterozygous and homozygous variant genotypes, respectively) and increased risk of distant metastasis development (OR = 2.30, P = 4 × 10−3; OR = 3.57, P = 6 × 10−5, for heterozygous and homozygous variant genotypes, respectively) in a dose dependent manner. The association for rs8051542 was stronger for high-grade SBR tumors (OR = 2.54, P = 2 × 10−4). GG genotype of rs13387042 on 2q35 showed a significant association with the risk of developing distant metastasis (OR = 1.94, P = 0.02). The G allele of rs1219648 in FGFR2 and the A allele of rs13387042 on 2q35 indicated a better prognosis by showing a significantly higher overall survival rates (P = 0.013 and P = 0.005, respectively). In conclusion, GWAS breast cancer FGFR2, TNRC9, MAP3K1, and 8q24 loci are associated with an increased risk of breast cancer and genetic variation in FGFR2 gene may predict the aggressiveness of breast cancer in Tunisians.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-012-2202-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-012-2202-6
PMCID: PMC3439608  PMID: 22910930
Breast cancer; Tunisians; Arabs; GWAS; Prognosis; Survival
Diabetes  1999;48(2):383-390.
The Epidemiology of Diabetes Interventions and Complications (EDIC) is a multicenter longitudinal observational study of the Diabetes Control and Complications Trial (DCCT) cohort. One of the major objectives of EDIC is to study the development and progression of atherosclerotic cardiovascular disease in type 1 diabetes. In this study, we evaluated the role of cardiovascular risk factors and antecedent therapy in the DCCT on carotid intima-media wall thickness (IMT) in type 1 diabetes. At ~18 months after the end of the DCCT, high-resolution B-mode ultrasonography was used to assess the carotid arteries of 1,325 patients with type 1 diabetes, 19–51 years of age, with duration of diabetes ranging from 6.3 to 26.1 years. An age- and sex-matched nondiabetic population (n = 153) was studied with the same protocol. The ultrasound protocol was carried out in 28 EDIC clinics by centrally trained and certified sonographers using one of three scanning systems. Determination of IMT from videotaped images was performed by a single reader at the Central Ultrasound Reading Unit. Univariate associations with greater IMT were strongest for older age and longer diabetes duration, greater waist-to-hip ratio (men only), higher blood pressure, higher LDL cholesterol, and smoking. The DCCT therapy group (intensive versus conventional) and HbA1c, measured at the time of the ultrasound or the mean HbA1c during the DCCT, were not significantly related to IMT. Multivariate analyses suggest that age, height, smoking, and BMI were the major predictors of common carotid IMT, whereas age, smoking, and LDL cholesterol predicted internal carotid IMT. There were significant differences between the IMT values of the internal carotid artery in the EDIC male cohort and similarly aged male nondiabetic control subjects. There were no significant differences between the IMT values in the EDIC female cohort and similarly aged female nondiabetic control subjects. At this point in the planned 10-year follow-up of the DCCT cohort, neither intensive therapy nor HbA1c level appears to influence the early signs of atherosclerosis. Traditional risk factors, including age, smoking, and LDL cholesterol, were related to IMT. As the cohort is only now entering the age interval during which rapid progression and clinical expression of atherosclerosis are expected, further follow-up will help to determine the role of hyperglycemia, and its interaction with other risk factors, on the development of atherosclerosis.
PMCID: PMC2622732  PMID: 10334318
Circulation  2009;119(22):2886-2893.
Background
The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a prospective observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort, reported persistent benefit of prior intensive therapy on retinopathy and nephropathy in type 1 diabetes. We evaluated the effects of prior intensive insulin therapy on the prevalence and incidence of cardiac autonomic neuropathy (CAN) in former DCCT intensive (INT) and conventional (CONV) therapy subjects13-to-14 (13/14) years after DCCT closeout.
Methods and Results
DCCT autonomic measures (R-R variation with paced breathing, Valsalva ratio, postural blood pressure changes, and autonomic symptoms) were repeated in 1,226 EDIC subjects in EDIC year 13/14. Logistic regression models were used to calculate the odds of incident CAN by DCCT treatment group after adjusting for DCCT baseline covariates, duration in the DCCT, and quantitative autonomic measures at DCCT closeout. In EDIC year 13/14, the prevalence of CAN using the DCCT composite definition was significantly lower in former INT group vs. former CONV group (28.9 vs. 35.2%; P = 0.018). Adjusted R-R variation was significantly greater in former DCCT INT vs. former CONV group (29.9 vs.25.9, P < 0.001). Prior DCCT intensive therapy reduced the risks of incident CAN by 31% [odds ratio(95% CI) 0.69 (0.51–0.93)] and of incident abnormal R-R variation by 30% [odds ratio(95%CI) 0.70 (0.51–0.96)] in EDIC year 13/14.
Conclusions
Although CAN prevalence increased in both groups, the incidence was significantly lower in former INT group compared to former CONV group. The benefits of former intensive therapy extend to measures of CAN up to 14 years after DCCT closeout.
doi:10.1161/CIRCULATIONAHA.108.837369
PMCID: PMC2757005  PMID: 19470886
type 1 diabetes mellitus; cardiac autonomic neuropathy; nervous system autonomic; intensive glucose control; metabolic memory
BMC Medical Genetics  2008;9:59.
Background
Recent genome-wide association (GWA) studies have identified several unsuspected genes associated with type 2 diabetes (T2D) with previously unknown functions. In this investigation, we have examined the role of 9 most significant SNPs reported in GWA studies: [peroxisome proliferator-activated receptor gamma 2 (PPARG2; rs 1801282); insulin-like growth factor two binding protein 2 (IGF2BP2; rs 4402960); cyclin-dependent kinase 5, a regulatory subunit-associated protein1-like 1 (CDK5; rs7754840); a zinc transporter and member of solute carrier family 30 (SLC30A8; rs13266634); a variant found near cyclin-dependent kinase inhibitor 2A (CDKN2A; rs10811661); hematopoietically expressed homeobox (HHEX; rs 1111875); transcription factor-7-like 2 (TCF7L2; rs 10885409); potassium inwardly rectifying channel subfamily J member 11(KCNJ11; rs 5219); and fat mass obesity-associated gene (FTO; rs 9939609)].
Methods
We genotyped these SNPs in a case-control sample of 918 individuals consisting of 532 T2D cases and 386 normal glucose tolerant (NGT) subjects of an Asian Sikh community from North India. We tested the association between T2D and each SNP using unconditional logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels using multiple linear regression analysis.
Results
Four of the nine SNPs revealed a significant association with T2D; PPARG2 (Pro12Ala) [odds ratio (OR) 0.12; 95% confidence interval (CI) (0.03–0.52); p = 0.005], IGF2BP2 [OR 1.37; 95% CI (1.04–1.82); p = 0.027], TCF7L2 [OR 1.64; 95% CI (1.20–2.24); p = 0.001] and FTO [OR 1.46; 95% CI (1.11–1.93); p = 0.007] after adjusting for age, sex and BMI. Multiple linear regression analysis revealed significant association of two of nine investigated loci with diabetes-related quantitative traits. The 'C' (risk) allele of CDK5 (rs 7754840) was significantly associated with decreased HDL-cholesterol levels in both NGT (p = 0.005) and combined (NGT and T2D) (0.005) groups. The less common 'C' (risk) allele of TCF7L2 (rs 10885409) was associated with increased LDL-cholesterol (p = 0.010) in NGT and total and LDL-cholesterol levels (p = 0.008; p = 0.003, respectively) in combined cohort.
Conclusion
To our knowledge, this is first study reporting the role of some recently emerged loci with T2D in a high risk population of Asian Indian origin. Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities.
doi:10.1186/1471-2350-9-59
PMCID: PMC2481250  PMID: 18598350
Journal of medical genetics  2010;47(6):10.1136/jmg.2009.073098.
Background
The evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well recognised, but the genes involved remain to be identified. It is hypothesised that mutations within the gene encoding connective tissue growth factor (CTGF/CCN2) will increase the propensity of diabetic subjects to develop nephropathy.
Methods and results
Genomic screening was performed for single nucleotide polymorphisms (SNPs) within the CTGF gene in 862 subjects from the DCCT/EDIC cohort of type 1 diabetes. A novel SNP was identified in the promoter region that changes a C-G at the position −20. The frequency of GG genotype in microalbuminuric patients (albumin excretion rate (AER) >40 mg/24 h) is significantly greater than diabetics with AER <40 mg/24 h, p<0.0001. The relative risk (RR) to develop microalbuminuria in diabetic subjects with the polymorphism is 3X higher than diabetic subjects without the polymorphism (RR 3.142, 95% CI 1.9238 to 5.1249; p<0.05). Kaplan–Meier survival curves demonstrated that the GG genotype group developed microalbuminuria and macroalbuminuria at a more rapid rate than the GC or CC genotypes. Functional studies demonstrated that the basal activity of the substituted allele/promoter (−20 GG allele) was significantly greater than that of the wild type promoter (−20 CC genotype). This higher level of basal activity of substituted allele CTGF/CCN2 promoter was abrogated upon suppression of Smad1 levels, indicating that SNP region in the CTGF/CCN2 promoter plays a vital role in the gene expression.
Conclusions
These findings provide the first evidence that variants within the promoter region of the CTGF/CCN2 gene predisposes diabetic subjects to develop albuminuria and demonstrate that Samd1 controls the expression of CTGF/CCN2 promoter through this region.
doi:10.1136/jmg.2009.073098
PMCID: PMC3828650  PMID: 20522428
BMC Medical Genetics  2011;12:20.
Background
Chronic hyperglycemia confers increased risk for long-term diabetes-associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes.
Methods
We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the BNC2, SORCS1, GSC and WDR72 loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model.
Results
No significant associations with HbA1c or glucose levels were found for the SORCS1, BNC2, GSC or WDR72 variants (all P-values > 0.05). Although the observed effects were non-significant and of much smaller magnitude than previously reported in type 1 diabetes, the SORCS1 risk variant showed a direction consistent with increased HbA1c and glucose levels, with an observed effect of 0.11% (P = 0.13) and 0.13 mmol/l (P = 0.43) increase per risk allele for HbA1c and glucose, respectively. In contrast, the WDR72 risk variant showed a borderline association with reduced HbA1c levels (β = -0.21, P = 0.06), and direction consistent with decreased glucose levels (β = -0.29, P = 0.29). The allele count model gave no evidence for a relationship between increasing number of risk alleles and increasing HbA1c levels (β = 0.04, P = 0.38).
Conclusions
The four recently reported SNPs affecting glycemic control in type 1 diabetes had no apparent effect on HbA1c in type 2 diabetes individually or by using a combined genetic score model. However, for the SORCS1 SNP, our findings do not rule out a possible relationship with HbA1c levels. Hence, further studies in other populations are needed to elucidate whether these novel sequence variants, especially rs1358030 near the SORCS1 locus, affect glycemic control in type 2 diabetes.
doi:10.1186/1471-2350-12-20
PMCID: PMC3044669  PMID: 21294870
Obesity (Silver Spring, Md.)  2011;20(3):622-627.
Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with obesity in Europeans but results in other ethnicities are less convincing. Here, we report a two-stage GWAS of BMI in African Americans. The GWAS was performed using the Affymetrix 6.0 platform in 816 nondiabetic and 899 diabetic nephropathy subjects. 746,626 single-nucleotide polymorphisms (SNPs) were tested for association with BMI after adjustment for age, gender, disease status, and population structure. Sixty high scoring SNPs that showed nominal association in both GWAS cohorts were further replicated in 3,274 additional subjects in four replication cohorts and a meta-analysis was computed. Meta-analysis of 4,989 subjects revealed five SNPs (rs6794092, rs268972, rs2033195, rs815611, and rs6088887) at four loci showing consistent associations in both GWAS (P < 0.0001) and replication cohorts (P < 0.05) with combined P values range from 2.4 × 10−6 to 5 × 10−5. These loci are located near PP13439-TMEM212, CDH12, MFAP3-GALNT10, and FER1L4 and had effect sizes between 0.091 and 0.167 s.d. unit (or 0.67–1.24 kg/m2) of BMI for each copy of the effect allele. Our findings suggest the presence of novel loci potentially associated with adiposity in African Americans. Further replication and meta-analysis in African Americans and other populations will shed light on the role of these loci in different ethnic populations.
doi:10.1038/oby.2011.154
PMCID: PMC3291470  PMID: 21701570

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