A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P ¼ 0.001, IL2RA (rs2104286) P ¼ 0.033, RPL5 (rs6604026) P ¼ 0.041 and CD58 (rs12044852) P ¼ 0.042. There was no association (P ¼ 0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P ¼ 3 Â 10 À8 ) evidence of an association between KIAA0350 and risk of disease.
This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.
Objectives: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first‐degree relatives of patients with type 1 diabetes mellitus.
Participants: 3315 first‐degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation.
Main outcome measures: Prevalence of islet cell antibodies (ICA) levels ≥20 JDFu, insulin autoantibodies (IAA) levels > 100nU/ml, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in cell function over time; and development of clinical diabetes.
Results: 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis.
Conclusions: Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.