Evidence of a genetic background predisposing to Complex Regional Pain Syndrome type 1

Background Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling, and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared to those who do not have the condition. Methods Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a Discovery Cohort of well-characterised patients with chronic CRPS-1 (n=34) compared to population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a Replication Cohort (n=50). Gene expression of peripheral blood macrophages was assessed. Results In the Discovery Cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The Replication Cohort confirmed this finding. In a Chronic Pain Cohort these alleles were not overexpressed. In total 25/84 (29.8%) of patients with CRPS-1 expressed a rare allele. The SNPs were; rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1, and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8/14 (57.1%) versus 17/70 (24.3%), (Fischer’s p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. Conclusion A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1