Use of Tag single nucleotide polymorphisms (SNPs) to screen PTPN21: no association with Graves' disease
ABSTRACT The protein-tyrosine-phosphate nonreceptor 22 gene (PTPN22) has recently been identified as a susceptibility locus for a number of autoimmune diseases including Graves' disease (GD). PTPN21 is another member of the PTPN family and its gene PTPN21 maps to the first reported region of genetic linkage to GD, GD-1, on chromosome 14q31. The aim of this study was to determine whether PTPN21 is acting as a GD susceptibility locus in UK Caucasian subjects.
A case control association study of seven Tag single nucleotide polymorphisms (SNPs) (rs1469602, rs8007288, rs1998670, rs11622270, rs2274736, rs2295136 and rs366476) selected to predict 51 un-genotyped polymorphisms present within PTPN21.
Unrelated Caucasian patients of UK origin with GD and ethnically and gender matched control subjects with no family history of autoimmune disease were recruited. In total, DNA was obtained from 768 GD patients and 768 control subjects.
No association of any of the seven Tag SNPs was detected with GD. Preliminary evidence of association of rs2274736 was found with younger age of GD onset (0-30 years) (OR = 1. 48 [95% CI = 1.11-1.97]). No other correlations with clinical phenotype or previously established susceptibility loci were detected.
Using a Tag SNP approach we screened PTPN21 as a susceptibility locus for GD and found no evidence for association with disease. Preliminary evidence for association of rs2274736 with younger age of GD onset requires replication in similar sized data sets to exclude a false positive result. Methods such as the Tag SNP approach significantly reduce the amount of genotyping required when screening candidate loci, including those within regions of chromosomal linkage.
SourceAvailable from: Rafal Ploski[Show abstract] [Hide abstract]
ABSTRACT: The presented comprehensive review of current knowledge about genetic factors predisposing to Graves' disease (GD) put emphasis on functional significance of observed associations. In particular, we discuss recent efforts aimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLA-DPB1 loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which have been extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene for FC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as other unverified possible candidate genes for GD selected through their documented association with type 1 diabetes mellitus: Tenr-IL2-IL21, CAPSL (encoding calcyphosine-like protein), IFIH1(gene for interferon-induced helicase C domain 1), AFF3, CD226 and PTPN2. We also review reports on association of skewed X chromosome inactivation and fetal microchimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD.Current Genomics 12/2011; 12(8):542-63. DOI:10.2174/138920211798120772 · 2.87 Impact Factor
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ABSTRACT: We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r(2)>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10 × 10(-3) and rs2274736, P=1.21 × 10(-3)). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86-0.97, P=5.45 × 10(-3) and rs2401751, OR=0.92, 95% CI: 0.86-0.97, P=5.29 × 10(-3)). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR=1.08, 95% CI: 1.02-1.14, P=6.43 × 10(-3)). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.Schizophrenia Research 09/2011; 131(1-3):43-51. DOI:10.1016/j.schres.2011.06.023 · 4.43 Impact Factor