Uebe Steffen, Ehrlicher Maria, Ekici Arif Bülent, Behrens Frank, Böhm Beate, Homuth Georg, Schurmann Claudia, Völker Uwe, Jünger Michael, Nauck Matthias, Völzke Henry, Traupe Heiko, Krawczak Michael, Burkhardt Harald, Reis André, Hüffmeier Ulrike
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, 91054, Erlangen, Germany.
Division of Rheumatology and IME Fraunhofer Project Group Translational Medicine & Pharmacology, Goethe University, Frankfurt/Main, Germany.
BMC Med Genet. 2017 Aug 23;18(1):92. doi: 10.1186/s12881-017-0447-y.
Psoriatic Arthritis (PsA) is a chronic inflammatory disease of the joints. PsA is etiologically complex, and 11 susceptibility loci have been identified so far. Most of these overlap with loci associated with psoriasis vulgaris (PsV), the most common psoriatic skin manifestation which is also frequently seen in PsA patients. In addition, two copy number variants (CNVs) are associated with PsV, one of which, located within the LCE3 gene cluster, is also associated with PsA. Finally, an intergenic deletion has been reported as a PsA-specific CNV.
We performed a genome-wide association study (GWAS) of CNVs in PsA and assessed the contribution to disease risk by CNVs at known psoriasis susceptibility loci.
After stringent quality assessment and validation of CNVs of the GWAS with an alternative quantitative method, two significantly associated CNVs remained, one near UXS1, the other one at the TRB locus. However, MLPA analysis did not confirm the CN state in ~1/3 of individuals, and an analysis of an independent case-control-study failed to confirm the initial associations. Furthermore, detailed PCR-based analysis of the sequence at TRB revealed the existence of a more complex genomic sequence most accurately represented by freeze hg18 which accordingly failed to confirm the hg19 sequence. Only rare CNVs were detected at psoriasis susceptibility loci. At three of 12 susceptibility loci with CNVs (CSMD1, IL12B, RYR2), CN variability was confirmed independently by MLPA. Overall, the rate of CNV confirmation by MLPA was strongly dependent upon CNV type, CNV size and the number of array markers involved in a CNV.
Although we identified PsA associations at several loci and confirmed that the common CNVs at these sites were real, ~1/3 of the common CNV states could not be reproduced. Furthermore, replication analysis failed to confirm the original association. Furthermore, SNP array-based analyses of CNVs were found to be more reliable for deletions than duplications, independent of the respective CNV allele frequency. CNVs are thus good candidate disease variants, while the methods to detect them should be applied cautiously and reproduced by an independent method.
银屑病关节炎（PsA）是一种关节慢性炎症性疾病。PsA病因复杂，目前已确定11个易感基因座。其中大多数与寻常型银屑病（PsV）相关的基因座重叠，PsV是最常见的银屑病皮肤表现，在PsA患者中也经常出现。此外，两个拷贝数变异（CNV）与PsV相关，其中一个位于LCE3基因簇内，也与PsA相关。最后，一个基因间缺失已被报道为PsA特异性CNV。
我们对PsA中的CNV进行了全基因组关联研究（GWAS），并评估了已知银屑病易感基因座处CNV对疾病风险的贡献。
在使用另一种定量方法对GWAS的CNV进行严格的质量评估和验证后，仍有两个显著相关的CNV，一个在UXS1附近，另一个在TRB基因座。然而，MLPA分析未能在约1/3的个体中确认CN状态，并且一项独立病例对照研究的分析未能确认最初的关联。此外，基于PCR对TRB序列进行的详细分析揭示了存在一个更复杂的基因组序列，最准确地由冻结的hg18表示，因此未能确认hg19序列。在银屑病易感基因座仅检测到罕见的CNV。在12个有CNV的易感基因座中的3个（CSMD1、IL12B、RYR2），MLPA独立确认了CN变异性。总体而言，MLPA对CNV的确认率强烈依赖于CNV类型、CNV大小以及参与CNV的阵列标记数量。
虽然我们在几个基因座发现了与PsA的关联，并确认这些位点的常见CNV是真实的，但约1/3的常见CNV状态无法重现。此外，重复分析未能确认最初的关联。此外，发现基于SNP阵列的CNV分析对于缺失比对重复更可靠，与各自的CNV等位基因频率无关。因此，CNV是良好的候选疾病变异体，而检测它们的方法应谨慎应用并通过独立方法进行重复验证。
