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We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12-46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency., Exome sequencing recently led to the discovery that heterozygous GATA6 mutations are the most common cause of pancreatic agenesis, accounting for 15 of 27 patients with neonatal diabetes (NDM) requiring [...]

OBJECTIVE--Mixed-meal tolerance test (MMTT) area under the curve C-peptide (AUC CP) is the gold-standard measure of endogenous insulin secretion in type 1 diabetes but is intensive and invasive to perform. [...]

OBJECTIVE--Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K+ channel ([K.sub.ATP] channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought to understand why mutations at the same residue can cause either neonatal diabetes or hyperinsulinemia. RESEARCH DESIGN AND METHODS--Neonatal diabetic patients were sequenced for mutations in ABCC8 (SUR1) and KCNJ11 (Kir6.2). Wild-type and mutant [K.sub.ATP] channels were expressed in Xenopus laevis oocytes and studied with electrophysiological methods. RESULTS--Oocytes expressing neonatal diabetes mutant channels had larger resting whole-cell [K.sub.ATP] currents than wild-type, consistent with the patients' diabetes. Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. [K.sub.ATP] channels are activated by Mg-nucleotides (via SUR1) and blocked by ATP (via Kir6.2). All mutations decreased channel activation by MgADP but had little effect on MgATP activation, as assessed using an ATP-insensitive Kir6.2 subtmit. Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (>300 µmol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. This difference in MgATP inhibition may explain the difference in resting whole-cell currents found for the neonatal diabetes and hyperinsulinemia mutations. CONCLUSIONS--Mutations in the same residue can cause either hyperinsulinemia or neonatal diabetes. Differentially altered nucleotide regulation by NBD2 of SUR1 can explain the respective clinical phenotypes. Diabetes 60:1813-1822, 2011, The ATP-sensitive [K.sup.+] ([K.sub.ATP]) channel plays a central role in glucose-stimulated insulin secretion from the pancreatic β-cell by linking the metabolic state of the cell to its electrical excitability (1-3). [...]

OBJECTIVE--NEUROG3 plays a central role in the development of both pancreatic islets and enteroendocrine cells. Homozygons hypomorphic missense mutations in NEUROG3 have been recently associated with a rare form of congenital malabsorptive diarrhea secondary to enteroendocrine cell dysgenesis. Interestingly, the patients did not develop neonatal diabetes but childhood-onset diabetes. We hypothesized that null mutations in NEUROG3 might be responsible for the disease in a patient with permanent neonatal diabetes and severe congenital malabsorptive diarrhea. RESEARCH DESIGN AND METHODS--The single coding exon of NEUROG3 was amplified and sequenced from genomic DNA. The mutant protein isoforms were functionally characterized by measuring their ability to bind to an E-box element in the NEUROD1 promoter in vitro and to induce ectopic endocrine cell formation and cell delamination after in ovo chicken endoderm electroporation. RESULTS--Two different heterozygous point mutations in NEUROG3 were identified in the proband [c.82G>T (p.E28X) and c.404T>C (p.L135P)], each being inherited from an unaffected parent. Both in vitro and in vivo functional studies indicated that the mutant isoforms are biologically inactive. In keeping with this, no enteroendocrine cells were detected in intestinal biopsy samples from the patient. CONCLUSIONS--Severe deficiency of neurogenin 3 causes a rare novel subtype of permanent neonatal diabetes. This finding confirms the essential role of NEUROG3 in islet development and function in humans., Permanent neonatal diabetes (PNDM), defined as diabetes diagnosed within the first 6 months of life, is a rare condition with an estimated incidence of 1 in 260,000 live births (1). [...]

OBJECTIVE--The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS--We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS--Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in [log.sub.10] triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). CONCLUSIONS--Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal., Raised circulating triglyceride levels are strongly correlated with insulin resistance, raised glucose levels, and type 2 diabetes (1-8), but the causal nature of these associations is unclear because of the [...]

OBJECTIVE--Hepat0cyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-(α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood [...]

OBJECTIVE--Common genetic variants in GCK and TCF7L2 are associated with higher fasting glucose and type 2 diabetes in nonpregnant populations. However, their associations with glucose levels from oral glucose tolerance tests (OGTTs) in pregnancy have not been assessed in a large sample. We hypothesized that these variants are associated with quantitative measures of glycemia in pregnancy. RESEARCH DESIGN AND METHODS--We analyzed the associations between variants rs1799884 (GCK) and rs7903146 (TCF7L2) and OGTT outcomes at 24-32 weeks' gestation in 3,811 mothers of European (U.K. and Australia) and 1,706 mothers of Asian (Thailand) ancestry from the HAPO cohort. We also tested associations with offspring birth anthropometrics. RESULTS--The maternal GCK variant was associated with higher fasting glucose in Europeans (P = 0.001) and Thais (P < 0.0001), 1-h glucose in Europeans (P = 0.001), and 2-h glucose in Thais (P = 0.005). It was also associated with higher European offspring birth weight, fat mass, and skinfold thicknesses (P < 0.05). The TCFTL2 variant was associated with all three maternal glucose outcomes (P = 0.03, P < 0.0001, and P < 0.0001 for fasting and 1-h and 2-h glucose, respectively) in the Europeans but not in the Thais (P > 0.05). In both populations, both variants were associated with higher odds of gestational diabetes mellitus according to the new International Association of Diabetes and Pregnancy Study Groups recommendations (P = 0.001-0.08). CONCLUSIONS--Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes. Further studies will be important to determine the variance in maternal glucose explained by all known genetic variants. Diabetes 59:2682-2689, 2010, Maternal glycemia in pregnancy is associated with adverse pregnancy outcomes including birth weight >90th percentile, delivery by cesarean section, neonatal hypoglycemia, and fetal hyperinsulinemia (1). These associations occur across the [...]

OBJECTIVE--NEUROD1 is expressed in both developing and mature p-cells. Studies in mice suggest that this basic helix-loophelix transcription factor is critical in the development of endocrine cell lineage. Heterozygous mutations have previously been identified as a rare cause of maturity-onset diabetes of the young (MODY). We aimed to explore the potential contribution of NEUROD1 mutations in patients with permanent neonatal diabetes. RESEARCH DESIGN AND METHODS--We sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology. RESULTS--Two homozygous mutations in NEUROD1 (c.427_ 428del and c.364dupG) were identified in two patients. Both mutations introduced a frameshift that would be predicted to generate a truncated protein completely lacking the activating domain. Both patients had permanent diabetes diagnosed in the first 2 months of life with no evidence of exocrine pancreatic dysfunction and a morphologically normal pancreas on abdominal imaging. In addition to diabetes, they had learning difficulties, severe cerebellar hypoplasia, profound sensorineural deafness, and visual impairment due to severe myopia and retinal dystrophy. CONCLUSIONS--We describe a novel clinical syndrome that results from homozygous loss of function mutations in NEUROD1. It is characterized by permanent neonatal diabetes and a consistent pattern of neurological abnormalities including cerebellar hypoplasia, learning difficulties, sensorineural deafness, and visual impairment. This syndrome highlights the critical role of NEUROD1 in both the development of the endocrine pancreas and the central nervous system in humans. Diabetes 59:2326-2331, 2010, Monogenic permanent neonatal diabetes (PNDM) is typically diagnosed within the first 6 months of birth in contrast to polygenic autoimmune type 1 diabetes, which is usually diagnosed later in childhood [...]

OBJECTIVE--Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS--For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between ease and control subjects. RESULTS--Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x [10.sup.-7] on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) ([r.sup.2] = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] CONCLUSIONS--We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing. Diabetes 59:741-746, 2010, The post genome-wide association study era presents several challenges. These include fine-mapping association signals to genes and/or variants within the genomic regions of interest, assessing the impact of low frequency [...]

OBJECTIVE--Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS--Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS--We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years ff present, P = 1.6 x [10.sup.-10]) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x [10.sup.-2]). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x [10.sup.-4]) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x [10.sup.-38]). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x [10.sup.-3]). CONCLUSIONS--We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants., Maturity-onset diabetes of the young (MODY) is a young-onset, dominantly inherited noninsulin-dependent diabetes resulting from β-cell dysfunction (1). There are at least eight genetic subgroups of MODY (1,2), with most [...]

OBJECTIVE--Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci. RESEARCH DESIGN AND METHODS--We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and BioCarta databases. RESULTS---After correcting for the number of pathways tested, we found no strong evidence for any pathway showing association with type 2 diabetes (top [P.sub.adj] = 0.31). The candidate WNT-signaling pathway ranked top (nominal P = 0.0007, excluding TCF7L2; P = 0.002), containing a number of promising single gene associations. These include CCND2 (rs11833537; P = 0.003), SMAD3 (rs7178347; P = 0.0006), and PRICKLE1 (rs1796390; P = 0.001), all expressed in the pancreas. CONCLUSIONS--Common variants involved in type 2 diabetes risk are likely to occur in or near genes in multiple pathways. Pathway-based approaches to genome-wide association data may be more successful for some complex traits than others, depending on the nature of the underlying disease physiology., Recent genome-wide association (GWA) studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. There are now 18 common variants with [...]

OBJECTIVE--Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C RESULTS--A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56). CONCLUSIONS--The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes., Metformin is recommended as first-line oral treatment in the joint American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines on the treatment of type 2 diabetes (1) [...]

OBJECTIVE--Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS--We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC3OA8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS--We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95)A CI 11-31], P = 2 X [10.sup.-5], and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none ([P.sub.trend] = 5 X 10-7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS--Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype., Reduced birth weight is associated with late-onset diseases including type 2 diabetes, hypertension, and heart disease (1). The cause of this association is not known. It is often proposed to [...]

OBJECTIVE--This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genomewide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS--We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into 'obese' and 'nonobese') according to median BMI (30.2 kg/[m.sup.2]). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS--In the 'obese-type 2 diabetes' scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 x [10.sup.-13]), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the 'nonobese' scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 x [10.sup.-14]). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: [P.sub.DIFF] = 1.4 x [10.sup.-7]; TCF7L2: [P.sub.DIFF] = 4.0 x [10.sup.-6]). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone ([RR.sub.obese] 1.08 [1.01-1.15]; [RR.sub.nonobese] 1.18 [1.10-1.27]: [P.sub.DIFF] = 0.04). CONCLUSIONS--This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes., Over the past year, the capacity to perform large-scale high-density genome-wide association (GWA) analyses has provided the first global view of the genetic etiology of type 2 diabetes, albeit one [...]

OBJECTIVE--Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with [...]

OBJECTIVE--Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS--Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS--Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x [10.sup.-6]). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] ~1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]). CONCLUSIONS--These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations., The presence of type 2 diabetes susceptibility genes on chromosome 20 has been suggested by linkage scans in several populations. The 20q12-q13 region (Online Mendelian Inheritance in Man [OMIM] 603694) [...]

OBJECTIVES--Genome-wide association studies have dramatically increased the number of common genetic variants that are robustly associated with type 2 diabetes. A possible clinical use of this information is to identify individuals at high risk of developing the disease, so that preventative measures may be more effectively targeted. Here, we assess the ability of 18 confirmed type 2 diabetes variants to differentiate between type 2 diabetic case and control subjects. RESEARCH DESIGN AND METHODS--We assessed index single nucleotide polymorphisms (SNPs) for the 18 independent loci in 2,598 control subjects and 2,309 ease subjects from the Genetics of Diabetes Audit and Research Tayside Study. The discriminatory ability of the combined SNP information was assessed by grouping individuals based on number of risk alleles carried and determining relative odds of type 2 diabetes and by calculating the area under the receiver-operator characteristic curve (AUC). RESULTS--Individuals carrying more risk alleles had a higher risk of type 2 diabetes. For example, 1.296 of individuals with >24 risk alleles had an odds ratio of 4.2 (95% CI 2.11-8.56) against the 1.8% with 10-12 risk alleles. The AUC (a measure of discriminative accuracy) for these variants was 0.60. The AUC for age, BMI, and sex was 0.78, and adding the genetic risk variants only marginally increased this to 0.80. CONCLUSIONS--Currently, common risk variants for type 2 diabetes do not provide strong predictive value at a population level. However, the joint effect of risk variants identified subgroups of the population at substantially different risk of disease. Further studies are needed to assess whether individuals with extreme numbers of risk alleles may benefit from genetic testing., Recent genome-wide association (GWA) studies, which assay >300,000 single nucleotide polymorphisms (SNPs) across many thousands of individuals, have led to the discoveries of variants predisposing to many common complex diseases, [...]

Genetic factors for many decades have been known to play a critical role in the etiology of diabetes, but it has been only recently that the specific genes have been [...]

Background: A region of chromosome 16 containing the fat mass-and obesity-associated gene (FTO) is reproducibly associated with fat mass and body mass index (BMI), risk of obesity, and adiposity. Objectives: We aimed to assess the possibility that appetite plays a role in the association between FTO and BMI. Design: Detailed dietary report information from the Avon Longitudinal Study of Parents and Children allowed the exploration of relations between FTO variation and dietary intake. Analyses were performed to investigate possible associations between variation at the FTO locus and the intake of a range of micronutrients and macronutrients, with adjustment for the bias often found within dietary report data when factors related to BMI are assessed. To test the hypothesis that FTO may be influencing appetite directly, rather than indirectly via BMI and altered intake requirements, we also assessed associations between FTO and dietary intake independent of BMI. Results: Relations between a single-nucleotide polymorphism characterizing the FTO signal (rs9939609) and dietary variables were found and can be summarized by the effect of each additional allele (per-allele effects) on total energy and total fat (P < 0.001 for both). These associations were attenuated, but they persisted specifically for fat and energy consumption after adjustment for BMI [total daily fat consumption: [approximately equal to] 1.5 g/d (P = 0.02 for the per-allele difference); total daily energy consumption: [approximately equal to] 25 kJ/d (P = 0.03 for the per-allele difference)]. Conclusion: These associations suggest that persons carrying minor variants at rs9939609 were consuming more fat and total energy than were those not carrying such variants. They also suggest that this difference was not simply dependent on having higher average BMIs among the former group.

OBJECTIVE--The G319S HNF1A variant is associated with an increased risk of type 2 diabetes in the Canadian Oji-Cree population. We hypothesized that the variant site at the 3' end of exon 4 might influence splicing and characterized mRNA transcripts to investigate the mutational mechanism underlying this susceptibility to diabetes. RESEARCH DESIGN AND METHODS--We established lymphoblastoid cell lines from a G319S homozygote and controls. HNF1A transcripts were characterized in the cell lines and pancreatic tissue by sequence analysis of RT-PCR products and quantification using real-time PCR. Susceptibility to mRNA surveillance was investigated using cycloheximide. RESULTS--Full-length G319S mRNA accounted for 24% of mRNA transcripts in the homozygous G319S cell line. A novel isoform lacking the terminal 12 bases of exon 4 was upregulated (55% of mRNA transcripts) compared with control cell lines (33%) and human pancreatic tissue (17%). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. Cycloheximide treatment increased the levels of both transcripts. CONCLUSIONS--The G319S variant results in the production of two abnormal transcripts and an alteration in the relative balance of normal splicing products. This is predicted to lead to a reduction in total HNF1A transcript levels, but residual hepatocyte nuclear factor-1α protein activity in G319S homozygotes may still reach up to 66% of normal levels. A combination of abnormal splicing and reduced activity of the G319S protein may explain the diabetes susceptibility., The Oji-Cree are an isolated population from North Central Canada who are among the most diabetes-prone subpopulations in the world; almost 40% of adults (1) and a high proportion of [...]