The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 × 10 -5 -5 × 10 -7 in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 × 10 -8 ) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-α-induced protein 3 (TNFAIP3).The WTCCC genome-wide association screen (GWA) of 1,860 rheumatoid arthritis cases and 2,938 healthy controls confirmed association with SNPs within the HLA region and the PTPN22 gene (P < 1 × 10 -7 ; ref. 1). Nine other loci showed strong evidence for association (P = 1 × 10 -5 -5 × 10 -7 ). SNPs at these loci were genotyped in an independent cohort of 5,063 rheumatoid arthritis cases and 3,849 healthy controls (Supplementary Methods and Supplementary Table 1 Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts www.sequenom.com), to establish whether they are genuinely associated with the disease. In this cohort, we had 80% power to detect most of the effect sizes reported in the initial study at P < 0.05 (Supplementary Table 2 online). We selected ten SNPs for genotyping; these included the known rheumatoid arthritis susceptibility variant rs2476601, mapping to the PTPN22 gene, and nine previously unknown SNPs identified by the WTCCC study1. A Bonferroni correction of 9 was applied to account for the previously unknown loci investigated, resulting in a P value threshold of P < 0.006 for claims of significance in this validation study. We regarded SNPs validated at P values between 0.05 and 0.006 as suggestive evidence.We detected strong association with the rheumatoid arthritis-causing SNP in the PTPN22 gene (rs2476601), as expected (odds ratio (OR) = 1.53, 95% CI = 1.39-1.68, trend P = 2.0 × 10 -18 ). This was not a completely independent replication, as association of rheumatoid arthritis with this locus has been reported in previous studies using some of the same samples included in the current study2-4. However, it confirmed the suitability of this cohort for validation studies. Of the nine newly identified SNPs tested, rs6920220 (G > A) showed association with rheumatoid arthritis in this cohort (OR for minor allele = 1.23, 95% CI = 1.15-1.33, trend P = 1.1 × 10 -8 ) (Table 1). For this SNP, the allele frequencies were similar across control groups tested in the WTCCC study and the healthy controls tested here (minor allele frequency (MAF) 0.22 and 0.21, respectively). We therefore undertook a combined analysis of the WTCCC data and the validation data, and we obtained strong statistical evidence for association between this SNP and rheumatoid arthritis (OR = 1.22, 95% CI = 1.15-1.29, trend P = 3.6 × 10 -12

SummaryFactor XIII when activated by thrombin, crosslinks fibrin, however its role in thrombotic disorders is unknown. A common point mutation (G T) in exon 2 of the A-subunit gene which codes for an amino acid change three amino acids from the thrombin activation site (Factor XIIIVal34Leu) is a candidate for a role in the pathogenesis of acute myocardial infarction. Factor XIII genotype frequencies were determined in a case-control study of 398 caucasian patients and 196 healthy controls. Patients had undergone angiography for investigation of coronary artery disease and were evaluated for a history of myocardial infarction. The prevalence of the mutation was lower in patients with myocardial infarction than without (32% vs. 50%), p = 0.0009 and than in controls (32% vs. 48%), p = 0.005. Patients possessing the mutation with a history of myocardial infarction had higher PAI-1 concentrations (mean, 27.9 vs. 16.7 ng/ml, p = 0.004) and the PAI-1 4G/4G genotype was commoner (43% vs. 26%, p = 0.03). There was no difference in PAI-1 4G/4G genotype (33% vs. 32%) and PAI-1 levels (mean, 21.0 vs. 20.9 ng/ml) in patients possessing wild type with MI compared to those without MI. These results indicate that the G T mutation coding for factor XIIIVal34Leu is protective against myocardial infarction and suggest a mechanism whereby elevated levels of PAI-1 may contribute to vascular risk.

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To determine the prevalence of the factor V Leiden gene mutation in relation to the phenotypes of cerebral infarction and cerebral hemorrhage, we studied 386 randomly selected cases of acute stroke and 247 control subjects. Factor V genotype was determined by amplification of a 267-bp sequence of exon/intron 10 of the factor V gene. Levels of prothrombin fragment F(1 + 2), a marker of thrombin generation, were determined in both acute and convalescent stroke and related to factor V genotype. Prothrombin fragment F(1 + 2) was assessed by using an enzyme-linked immunosorbent assay. Sixteen stroke cases (4.1%) were identified as having the mutation compared with 14 (5.6%) control subjects. Prothrombin fragment F(1 + 2) levels were estimated in 191 cases and found to be elevated both acutely and after 3 months, but they were not related to factor V genotype. Prothrombin fragment F(1 + 2) is elevated in acute stroke and requires further evaluation in relation to cerebrovascular disease. These results suggest that the factor V Leiden gene mutation is not a risk factor for arterial thrombosis causing stroke.