ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

Abstract

We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)—rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher’s exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes (“VRNQE,” “MKDRQ,” “MRDRE,” and “MKDRE”) in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination (“*001/*005”) previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10–24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

“…Hap1/Hap2 are risk haplotypes for AS and psoriasis [8,12], while being protective for BD and Birdshot. Therefore, Hap10 and Hap2 of ERAP1 play a central role for patients within the MHC-I-opathy cluster: patients with psoriasis have an increased risk of uveitis [31].…”

“…Figure 10 | Non-random distribution of the ERAP2-protein coding haplotype across common ERAP1 haplotypes based on 5 SNPs. Five missense variants in ERAP1 encode four discrete and common (>1% freq) haplotypes [12], while ERAP2 encodes 1 common protein-coding haplotype (HapA tagged by the A allele of rs2248374) and non-coding haplotypes (tagged by the G allele). Each chromosome harbors 1 ERAP1 haplotype and 1 ERAP2 haplotype.…”

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…Several studies agree to indicate the high trimming Met349/Lys528/Asp575/Arg725/Gln730 haplotype as being associated most strongly with AS risk, while the low trimming Val349/Arg528/Asn575/Gln725/Glu730 haplotype as the most protective [2,78,88]. In contrast, a report has suggested that rare hyperactive or hypoactive allotype pair combinations found in AS patients could explain the involvement of ERAP1 in the disease [79].…”

Progress of genome‐wide association studies of ankylosing spondylitis

“…A recent study investigated haplotypes generated from five common ERAP1 SNPs—rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q) and rs27044 (Q730E), and further confirmed that the association of ERAP1 with AS is primarily contributed by individual common ERAP1 genotypes, rather than by haplotypes. 62 …”