Roberts Amity R, Appleton Louise H, Cortes Adrian, Vecellio Matteo, Lau Jonathan, Watts Laura, Brown Matthew A, Wordsworth Paul
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.
National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford OX3 7LE, United Kingdom.
Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):558-561. doi: 10.1073/pnas.1618856114. Epub 2017 Jan 3.
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) 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.
我们研究了强直性脊柱炎（AS）与异常ERAP1基因型相关的这一假说。利用家系数据为213例AS患者和46例类风湿性关节炎对照构建了ERAP1单倍型。单倍型由五个常见的ERAP1单核苷酸多态性（SNP）生成——rs2287987（M349V）、rs30187（K528R）、rs10050860（D575N）、rs17482078（R725Q）和rs27044（Q730E）。使用Fisher精确检验比较单倍型频率。还研究了从国际强直性脊柱炎遗传学联盟（IGAS）免疫芯片研究中推断出的ERAP1单倍型。在家族研究中，除了两种罕见的（<0.5%）此前未报告的单倍型外，我们在AS患者和对照中仅鉴定出四种常见的ERAP1单倍型（“VRNQE”、“MKDRQ”、“MRDRE”和“MKDRE”）。在53%的AS患者中，没有出现其他人之前报告的异常ERAP1单倍型组合（“*001/*005”）。正如预期的那样，在AS家族研究中，携带K528的单倍型有所增加（AS为43%，对照为35%），这尤其归因于MKDRQ单倍型的增加（AS为35%，对照为25%，P = 0.01）。这一趋势在两种携带K528的单倍型MKDRQ（AS为33%，对照为27%，P = 1.2×10）和MKDRE（AS为8%，对照为7%，P = 0.004）的推断免疫芯片数据中得到了重现。因此，ERAP1与AS的关联主要归因于常见的ERAP1单倍型和单倍型组合。
