Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.

We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of Caucasians (65.2%) and AfricanAmericans (34.2%), was analyzed for CNVs in a single study using a uniform array platform and computational process. We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These nonunique CNVs mapped to 3272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications, and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics.

OBJECTIVE— Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject–parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals. RESEARCH DESIGN AND METHODS— From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects. RESULTS— Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 × 10 −8 ) and BACH2 (1.13; combined P = 1.25 × 10 −6 ). CONCLUSIONS— Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2 , are both biologically relevant to autoimmunity.

OBJECTIVE—In stage 1 of our genome-wide association (GWA) study for type 1 diabetes, one locus at 16p13 was detected (P = 1.03 × 10−10) and confirmed in two additional cohorts. Here we describe the results of testing, in these additional cohorts, 23 loci that were next in rank of statistical significance. RESEARCH DESIGN AND METHODS—Two independent cohorts were studied. The Type 1 Diabetes Genetics Consortium replication cohort consisted of 549 families with at least one child diagnosed with diabetes (946 total affected) and DNA from both parents. The Canadian replication cohort consisted of 364 nuclear family trios with one type 1 diabetes–affected offspring and two parents (1,092 individuals). RESULTS—One locus at 12q13, with the highest statistical significance among the 23, was confirmed. It involves type 1 diabetes association with the minor allele of rs1701704 (P = 9.13 × 10−10, OR 1.25 [95% CI 1.12–1.40]). CONCLUSIONS—We have discovered a type 1 diabetes locus at 12q13 that is replicated in an independent cohort of type 1 diabetic patients and confers a type 1 diabetes risk comparable with that of the 16p13 locus we recently reported. These two loci are identical to two loci identified by the whole-genome association study of the Wellcome Trust Case-Control Consortium, a parallel independent discovery that adds further support to the validity of the GWA approach.

increased to seven (5.6%) in group 1 and one (2.1%) in group 2 (p = 0.445) after applying the immunohistochemical staining for detection of Mallory hyaline bodies. Pericellular fibrosis was identified in all steatohepatitis sections, but neutrophil inflammatory reaction was only identified in three specimens. Necroinflammatory injury, as reflected by modified Histology Activity Index (HAI), was significantly higher in group 1 than in group 2 (6.7 (2.7) vs 4.8 (3.4), p = 0.01). The fibrosis score was significantly higher in group 1 than in group 2 (3.3 (1.9) vs 1.8 (1.7), p = 0.002). Overweight/obesity (>25 kg/m 2) was reported in 80.6% of patients in group 1 and 62.5% in group 2 (p = 0.097), type 2 diabetes mellitus (fasting blood sugar .126 mg/dl and postprandial blood sugar 200 mg/dl on more than one occasion) was encountered in 27.4% of group 1 and 12.5% in group 2 (p = 0.038), while hypertriglyceridaemia (.200 mg/dl) was found in 6.5% of group 1 and 8.3% of group 2 (p = 0.759, table 1). While steatosis was not associated with HCV (p = 0.555), it was significantly correlated with overweight/obesity (p = 0.001), diabetes mellitus (p = 0.001) and hypertriglyceridaemia (p = 0.019). By multivariate analysis, only overweight/ obesity and diabetes mellitus were found to be significantly associated with steatosis. Neither necroinflammation nor fibrosis was correlated with steatosis in patients with HCV genotype 4 (p = 0.953 and 0.463). This lack of correlation may be explained by the discrepancy between a high frequency of steatosis (40%) and a low frequency of steatohepatitis (5.6%) in group 1. We conclude that hepatic steatosis is prevalent in nearly 40% of patients infected with HCV genotype 4, which is more highly attributed to associated metabolic factors. It seems that there is no correlation between necroinflammation or fibrosis and steatosis in patients with HCV genotype 4.