Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide ...association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Type 2 diabetes has become an enormous public health burden, making diabetes prevention a pressing issue. While lifestyle modification is the most effective preventive strategy, it is ...resource‐intensive and not universally sustainable. We review the evidence on pharmacological options for diabetes prevention, in search of a medication that is efficacious, easy to adhere to, well tolerated, and cost‐effective. With the exception of metformin, most other drugs have either limited efficacy or costly side effects.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims/hypothesis The single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity associated gene (FTO) and the rs7566605 SNP located 10 kb upstream of the insulin-induced gene 2 gene ...(INSIG2) have been proposed as risk factors for common obesity. Methods We tested for genotype-treatment interactions on changes in obesity-related traits in the Diabetes Prevention Program (DPP). The DPP is a randomised controlled trial of 3,548 high-risk individuals from 27 participating centres throughout the USA who were originally randomised to receive metformin, troglitazone, intensive lifestyle modification or placebo to prevent the development of type 2 diabetes. Measures of adiposity from computed tomography were available in a subsample (n = 908). This report focuses on the baseline and 1 year results. Results The minor A allele at FTO rs9939609 was positively associated with baseline BMI (p = 0.003), but not with baseline adiposity or the change at 1 year in any anthropometric trait. For the INSIG2 rs7566605 genotype, the minor C allele was associated with more subcutaneous adiposity (second and third lumbar vertebrae L2/3) at baseline (p = 0.04). During follow-up, CC homozygotes lost more weight than G allele carriers (p = 0.009). In an additive model, we observed nominally significant gene-lifestyle interactions on weight change (p = 0.02) and subcutaneous (L2/3 p = 0.01 and L4/5 p = 0.03) and visceral (L2/3 p = 0.02) adipose areas. No statistical evidence of association with physical activity energy expenditure or energy intake was observed for either genotype. Conclusions/interpretation Within the DPP study population, common variants in FTO and INSIG2 are nominally associated with quantitative measures of obesity, directly and possibly by interacting with metformin or lifestyle intervention. Trial registration: ClinicalTrials.gov NCT00004992 Funding: The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), the National Institute of Child Health and Human Development (NICHD), the National Center on Minority Health and Health Disparities (NCMHD) and the Office of Research on Women's Health (ORWH).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists ...of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio OR 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.
Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin ...secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10−8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
Broadaway et al. describe a genome-wide association meta-analysis in which they identify 36 proinsulin signals. Identification and integration of the proinsulin signals with glycemic traits, expression data in trait-relevant tissues, and functional follow-up provide hypotheses about potential mechanistic pathways for T2D loci.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Haplotype Structure and Genotype-Phenotype Correlations of the Sulfonylurea Receptor and the Islet ATP-Sensitive Potassium
Channel Gene Region
Jose C. Florez 1 2 3 4 ,
Noël Burtt 3 ,
Paul I.W. de ...Bakker 1 3 5 ,
Peter Almgren 6 ,
Tiinamaija Tuomi 7 ,
Johan Holmkvist 6 ,
Daniel Gaudet 8 ,
Thomas J. Hudson 9 ,
Steve F. Schaffner 3 ,
Mark J. Daly 3 ,
Joel N. Hirschhorn 3 5 10 ,
Leif Groop 6 and
David Altshuler 1 2 3 4 5
1 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
2 Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
3 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
4 Department of Medicine, Harvard Medical School, Boston, Massachusetts
5 Department of Genetics, Harvard Medical School, Boston, Massachusetts
6 Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
7 Department of Medicine, Helsinki University Central Hospital and Folkhalsan Research Institute, Helsinki, Finland
8 University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
9 McGill University and Genome Quebec Innovation Centre, Montreal, Canada
10 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
Leif Groop, Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden. E-mail: leif.groop{at}endo.mas.lu.se
Address correspondence and reprint requests to David Altshuler, Department of Molecular Biology, Massachusetts General Hospital,
Boston, MA 02114. E-mail: altshuler{at}molbio.mgh.harvard.edu
Abstract
The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8 ) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11 ) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2
with risk of type 2 diabetes. Whether and how E23K itself—or other variant(s) in either of these two closely linked genes—influences
type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate
gene locus, we 1 ) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and
both genes; 2 ) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously
reported in the literature; and 3 ) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K
with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 ( P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data ( P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S)
in the neighboring SUR1 gene ( r 2 > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region
are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion
in glucose-tolerant control subjects, supporting a mechanism whereby β-cell dysfunction contributes to the common form of
type 2 diabetes. Like peroxisome proliferator–activated receptor γ, the SUR1/Kir6.2 gene region both contributes to the inherited
risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between
the underlying mechanism of disease and validated targets for pharmacological treatment.
CEPH, Centre d’Etude du Polymorphisme Humain
ISI, insulin sensitivity index
LD, linkage disequilibrium
OGTT, oral glucose tolerance test
SNP, single-nucleotide polymorphism
SUR1, sulfonylurea receptor
TDT, transmission disequilibrium test
Footnotes
Additional information for this article can be found in an online appendix at http://www.diabetes.diabetesjournals.org .
L.G. and D.A. jointly supervised the project.
Accepted January 26, 2004.
Received January 12, 2004.
DIABETES
Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program
Jose C. Florez 1 2 3 ...4 ,
Kathleen A. Jablonski 5 ,
Steven E. Kahn 6 ,
Paul W. Franks 7 8 ,
Dana Dabelea 9 ,
Richard F. Hamman 9 ,
William C. Knowler 8 ,
David M. Nathan 2 3 ,
David Altshuler 1 2 3 4 10 and
for the Diabetes Prevention Program Research Groupy *
1 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
2 Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
3 Department of Medicine, Harvard Medical School, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge,
Massachusetts
5 Biostatistics Center, George Washington University, Rockville, Maryland
6 Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University
of Washington, Seattle, Washington
7 Genetic Epidemiology and Clinical Research Group, Institute of Public Health and Clinical Medicine, Umeå University Hospital,
Umeå, Sweden
8 Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix,
Arizona
9 Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
10 Department of Genetics, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Jose C. Florez, Diabetes Prevention Program Coordinating Center, Biostatistics
Center, George Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD 20852. E-mail: dppmail{at}biostat.bsc.gwu.edu
Abstract
The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with
progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention
Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention,
and their interactions as predictors of diabetes incidence over ∼3 years. We also assessed the effect of genotype on insulin
secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes.
Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes ( P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control
analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize
that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.
DPP, Diabetes Prevention Program
IGT, impaired glucose tolerance
OGTT, oral glucose tolerance test
SNP, single nucleotide polymorphism
Footnotes
*
* A list of the members of the Diabetes Prevention Program Research Group can be found in ref. 16 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 12, 2006.
Received July 12, 2006.
DIABETES
Sex and genetic variation influence the risk of developing diabetic nephropathy and ESRD in patients with type 1 diabetes. We performed a genome-wide association study in a cohort of 3652 patients ...from the Finnish Diabetic Nephropathy (FinnDiane) Study with type 1 diabetes to determine whether sex-specific genetic risk factors for ESRD exist. A common variant, rs4972593 on chromosome 2q31.1, was associated with ESRD in women (P<5×10(-8)) but not in men (P=0.77). This association was replicated in the meta-analysis of three independent type 1 diabetes cohorts (P=0.02) and remained significant for women (P<5×10(-8); odds ratio, 1.81 95% confidence interval, 1.47 to 2.24) upon combined meta-analysis of the discovery and replication cohorts. rs4972593 is located between the genes that code for the Sp3 transcription factor, which interacts directly with estrogen receptor α and regulates the expression of genes linked to glomerular function and the pathogenesis of nephropathy, and the CDCA7 transcription factor, which regulates cell proliferation. Further examination revealed potential transcription factor-binding sites within rs4972593 and predicted eight estrogen-responsive elements within 5 kb of this locus. Moreover, we found sex-specific differences in the glomerular expression levels of SP3 (P=0.004). Overall, these results suggest that rs4972593 is a sex-specific genetic variant associated with ESRD in patients with type 1 diabetes and may underlie the sex-specific protection against ESRD.
OBJECTIVEMany genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell ...function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.RESEARCH DESIGN AND METHODSWe conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.RESULTSWe observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.CONCLUSIONSOur results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular ...disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.
We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.
We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.
We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
•Identification of a novel proinsulin-associated locus on chromosome 15.•Lead chromosome 15 SNP rs8029765 influences expression of UNC45A in liver.•Proinsulin effects on carotid intima-media thickness are segment-specific.•Proinsulin-increasing SNP scores had limited effects on carotid intima-media thickness.•Proinsulin is unlikely to have causal effects on intima-media thickness.
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