A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population

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Abstract
Objective In the era of postgenomic research, linkage‐ and association‐based strategies are beginning to reveal novel complex disease genes. Using such an approach, a functional haplotype of the peptidylarginine deiminase 4 gene (PADI4) has recently been identified as a gene conferring susceptibility to rheumatoid arthritis (RA) in a Japanese population. In the present study, we investigated the association of single‐nucleotide polymorphisms (SNPs) in the PADI4 gene with RA in a UK population. Methods Association with 4 exonic SNPs (padi4_89*G/A, padi4_90*T/C, padi4_92*G/C, and padi4_104*T/C), mapping to the PADI4 gene and defining a haplotype previously reported to be associated with RA, was investigated. Genotyping was performed using 5′ allelic discrimination assays. Estimated haplotypes were generated using the expectation‐maximization algorithm, and frequencies of the SNPs and haplotypes were compared between unrelated Caucasian RA patients from the UK (n = 839) and population controls (n = 481). Results Allele frequencies for the 4 SNPs in the UK population were similar to those reported in the Japanese control population, but none of these was associated with RA. As in the Japanese population, the SNPs in the UK population defined 2 major haplotypes, but neither was associated with RA (P = 0.79). Conclusion A PADI4 susceptibility haplotype associated with RA in a Japanese population is not associated with RA in a UK population. Other genes involved in the citrullinating pathway remain strong candidate RA‐susceptibility genes and require further investigation.