Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
PLoS One. 2019 Feb 19;14(2):e0212043. doi: 10.1371/journal.pone.0212043. eCollection 2019.
Psoriasis and its associated inflammatory arthritis, psoriatic arthritis (PsA), have a clear heritable component, but a large proportion of the heritable risk remains unexplained by gene sequence variation. This study aimed to determine if epigenetic factors contribute to the missing heritability in psoriatic disease. DNA methylation profiling was performed on sperm cells from 23 probands with psoriasis without PsA (PsC), 13 PsA probands, and 18 unaffected controls. Differentially methylated CpGs and regions (DMRs) were identified and validated by pyrosequencing. Underlying AluY and copy number variation (CNV) in the HCG26 and IL22 genes, respectively, were assessed by genotyping. Array, subject's age, age of psoriasis onset, psoriasis severity, and medication usage were found to influence methylation at many genes and were included as covariates in the analysis. Between PsC probands vs. controls, 169 DMRs were found; 754 DMRs were found between PsA probands vs. controls, and 86 between PsA and PsC probands (adjusted p<0.05). Differences in methylation across DMRs were generally subtle (<10%) but correlated well with pyrosequencing. Biological inference prioritized notable DMRs associated with skin disease (SIGLEC14, JAM3, PCOLCE, RXRB), skin and/or joint disease (MBP, OSBPL5, SNORD115, HCG26), and joint disease (IL22, ELF5, PPP2R2D, PTPRN2, HCG26). Hypermethylation of the DMR within the first exon of arthritis-associated IL22 showed significant correlation (rho = 0.34, 95% CI 0.06-0.57, p = 0.01) between paired sperm and blood samples, independent of a CNV within the same region. Further studies are needed to rule out underlying genetic causes and determine if these represent heritable, constitutional epimutations, or are the result of exposure of germ cells to endogenous or exogenous environmental factors.
银屑病及其相关炎症性关节炎，即银屑病关节炎（PsA），具有明显的遗传成分，但基因序列变异无法解释的遗传风险仍有很大一部分。本研究旨在确定表观遗传因素是否会导致银屑病遗传缺失。对 23 名无银屑病关节炎（PsA）的银屑病先证者（PsC）、13 名 PsA 先证者和 18 名未受影响的对照者的精子细胞进行 DNA 甲基化谱分析。通过焦磷酸测序鉴定和验证差异甲基化 CpG 及其区域（DMR）。通过基因分型评估分别位于 HCG26 和 IL22 基因中的 AluY 和拷贝数变异（CNV）。发现阵列、个体年龄、银屑病发病年龄、银屑病严重程度和药物使用情况会影响许多基因的甲基化，并将其作为协变量纳入分析。在 PsC 先证者与对照组之间发现了 169 个 DMR；在 PsA 先证者与对照组之间发现了 754 个 DMR，在 PsA 与 PsC 先证者之间发现了 86 个 DMR（调整后 p<0.05）。DMR 之间的甲基化差异通常较小（<10%），但与焦磷酸测序相关性良好。生物学推断优先考虑与皮肤疾病（SIGLEC14、JAM3、PCOLCE、RXRB）、皮肤和/或关节疾病（MBP、OSBPL5、SNORD115、HCG26）和关节疾病（IL22、ELF5、PPP2R2D、PTPRN2、HCG26）相关的显著 DMR。关节炎相关 IL22 第一外显子内 DMR 的高甲基化与配对精子和血液样本之间存在显著相关性（rho = 0.34，95%CI 0.06-0.57，p = 0.01），与同一区域内的 CNV 无关。需要进一步的研究来排除潜在的遗传原因，并确定这些是否代表可遗传的、先天的表观突变，还是生殖细胞暴露于内源性或外源性环境因素的结果。
