Systemic lupus erythematosus and rheumatoid arthritis

18. Paper V: Evaluation of three different polymorphisms of 
PTPN22
 in 
rheumatoid arthritis. 
A study of patients diagnosed early with RA showed the 
PTPN22
1858T allele 
to be highly associated with RA 
per se
.
205
The association was confined to 
ACPA and RF positive individuals. Patients carrying the risk allele and patients 
positive for ACPAs had an earlier disease onset. The age of disease onset was 
even earlier for patients carrying both the risk allele and having ACPAs. 
Smoking, independent of the 1858T variant and ACPAs, was also identified as a 
risk factor for RA.
205
To further investigate the 
PTPN22
gene two new SNPs were analysed based 
upon their physical location and their relevance according to the literature.
206-209
The rs3811021 polymorphism is located in the 3’ untranslated region (UTR), 
the rs2476601 (+1858C/T) polymorphism in exon 14 and the rs2488457 (-
1123G/C) polymorphism in the promoter region (5’-UTR). The patient material 
was extended from 505 patients to 669 patients and the control material from 
970 controls to 1054 controls, compared with the previous study.
205
There were strong associations with RA for the well-known 
PTPN22
1858T 
allele, the -1123C allele, but only a modest association with the rs3811021 
polymorphism (Table 16). All three SNPs were in high LD as measured by the 
- 50 -

---

D’ values but the r
2
values were substantially lower. The r
2
values indicated that 
the 1858C/T and -1123G/C polymorphisms were in the same haplotype block, 
whereas the rs3811021 SNP was not (Figure 14). Permutation testing was 
performed on markers and haplotypes simultaneously. After the permutation 
test both the 1858T and -1123C alleles remained significantly associated with 
RA, as well as a haplotype (TTC) of the two risk alleles (Table 16). The 
rs3811021 SNP failed to reach significance in the permutation test (Table 16). 
There was no association with the TCC haplotype, indicating that the 
association with RA was primarily owing to the risk conferred by carriage of 
the 1858T allele. The independent/dependent relationship between the 1858C/T 
SNP and other SNPs of the 
PTPN22
gene, also associated with RA, has been 
widely discussed.
206-208
Table 16.
Association analyses using conventional 
χ
2
-tests and permutation tests. Permutation 
testing was performed for single markers and haplotypes simultaneously. The haplotypes are in 
the following order; rs3811021, rs2476601 and rs2488457.