The PTPN22 Locus and Rheumatoid Arthritis: No Evidence for an Effect on Risk Independent of Arg620Trp

The Trp(620) allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype '5', haplotype group '6-10' and susceptibility haplotype '4', suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility.A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used.The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR = 0.85, P = 1.4×10(-5)). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85).We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.324

Simulation of the Corrosion Point and Repairing Technique at the Crane with Finite Element Analysis

This paper describes the stress analysis for the corrosion area at the hollow pipe crane structure. This crane is used for lifting the load. Finite element analysis was used to, investigate the stress concentration at the corrosion point. Three stages had been simulated; first stage simulates the structure without corrosion, second stage simulates the main chord with corrosion and third stage simulates the corrosion point with patch method and clamp shell repair method. The results show that the stress concentrations at the corrosion points were double from the normal point. Clamp shell method reduces the stresses by 28.6%. This technique saves the costs and time to repair the corrosion areas

<i>Rs2476601-rs12566340</i> haplotypic analysis.

<p>1. Within each cell in the RA half, NZ data are top, WTCCC data middle and combined bottom.</p

Analysis of association of <i>PTPN22</i> ‘haplotype 5’ (<i>rs3789607</i>: T&gt;C) with rheumatoid arthritis.

<p>1 Cases top line, controls bottom line. The Carlton Set 2 cases and controls, the combined other cases and total cases deviated mildly from HWE (<i>P</i> = 0.02, 0.03, 0.05 and 0.02, respectively).</p><p>2 Allele 2; number of chromosomes (frequency).</p><p>3 Genotype data from <i>rs17274634</i> were used (r² = 1 with <i>rs3789607</i> in CEPH CEU (<a href="http://www.hapmap.org" target="_blank">www.hapmap.org</a>)).</p><p>4 The Mantel-Haenszel pooled OR = 0.87 [0.82–0.93], <i>P</i> = 7.5×10⁻⁶; Breslow-Day test for heterogeneity <i>P</i> = 0.083. The Mantel-Haenszel pooled OR excluding Carlton et al data was 0.91 [0.85–0.98], <i>P</i> = 0.016; Breslow-Day <i>P</i> = 0.50.</p

Analysis of association of <i>PTPN22</i> ‘haplotype 4’ (<i>rs3811021</i>: A&gt;G) with rheumatoid arthritis.

<p>1 Cases top line, controls bottom line.</p><p>2 Imputed genotypes were taken from <a href="http://www.wtccc.org.uk" target="_blank">www.wtccc.org.uk</a>.</p><p>3 The Mantel-Haenszel combined OR  = 0.85 [0.72–1.01], <i>P</i> = 0.071. The Breslow-Day test for heterogeneity <i>P</i>&lt;0.001.</p