Genetic factors play a major role in the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). We have previously identified three loci on chro Show more
Genetic factors play a major role in the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). We have previously identified three loci on chromosomes 10q, 12q, and 14q that showed strong linkage with AITD, HT, and GD, respectively. The objective of the study was to identify the AITD susceptibility genes at the 10q, 12q, and 14q loci. Three hundred forty North American Caucasian AITD patients and 183 healthy controls were studied. The 10q, 12q, and 14q loci were fine mapped by genotyping densely spaced single-nucleotide polymorphisms (SNPs) using the Illumina GoldenGate genotyping platform. Case control association analyses were performed using the UNPHASED computer package. Associated SNPs were reanalyzed in a replication set consisting of 238 AITD patients and 276 controls. Fine mapping of the AITD locus, 10q, showed replicated association of the AITD phenotype (both GD and HT) with SNP rs6479778. This SNP was located within the ARID5B gene recently reported to be associated with rheumatoid arthritis and GD in Japanese. Fine mapping of the GD locus, 14q, revealed replicated association of the GD phenotype with two markers, rs12147587 and rs2284720, located within the NRXN3 and TSHR genes, respectively. Fine mapping of three linked loci identified novel susceptibility genes for AITD. The discoveries of new AITD susceptibility genes will engender a new understanding of AITD etiology. Show less
In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. Show more
In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10(-6) ) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10(-8) ], rs12411988 [OR 1.57, P = 1.16 × 10(-7) ], and rs10995450 [OR 1.31, P = 6.74 × 10(-5) ]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10(-7) for rs4688011, P = 4.33 × 10(-5) for rs6479891, P = 2.71 × 10(-5) for rs12411988, and P = 5.39 × 10(-5) for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology. Show less