September 9th, Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Institute of Dermatology, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education and Inflammation and Immunology The team of Professor Liangdan Sun from Anhui Laboratory of Sexual Diseases published a research paper entitled "Three Novel Structural Variations at MHC and IL12B Predisposing to Psoriasis" in the internationally renowned academic journal British Journal of Dermatology (IF: 9.3). The Dermatology Department of the First Affiliated Hospital of Anhui Medical University is the first author and first correspondent of this article. The study constructed the most comprehensive psoriasis structural variation (SV) map so far. A total of 45,386 samples from 5 Chinese Han populations were tested for genome-wide SV, and 4,535 SVs were obtained, which enriched the genetic structure and genetic structure of psoriasis. The pathogenesis highlights the non-ignorable influence of SV in complex diseases.

Figure 1. Screenshot of the article

        Single nucleotide polymorphism (SNP)-based association studies have discovered hundreds of gene variants related to psoriasis. However, psoriasis still lacks heritability, and the pathogenesis is not yet clear. Structural variation (SV, defined as DNA variation ≥50 bp), including deletions, insertions, duplications, and reverse sequences, affects the most base pairs in the human genome, and may affect genes by destroying coding sequences, changing gene dosages, or changing regulatory elements Structure or gene expression. Some SVs, mainly copy number variants (CNVs), have been reported to play an important role in the etiology of psoriasis in multiple populations. However, related studies only cover a small part of the missing heritability, and the number of recruited samples is also limited.

Figure 2. Meta-analysis of 5 groups of Manhattan chart

In this study, we used thousands of human genome data as a reference database to perform SV inference on sequencing data or genotyping data from 5 populations. We found that 4 SVs in the three loci of MHC, IL12B, and LCE are associated with psoriasis. Among them, 3 SVs located in MHC and IL12B are reported for the first time, and 1 SV located in LCE verifies the results of the predecessors. In the one population with the largest sample size, the heritability explanation degree of these 4 SVs was 14.26%.

Figure 3. Step-by-step condition analysis of the MHC area revealed 2 SVs independently related to psoriasis

        Step-by-step conditional analysis showed that the two SVs in the MHC area were independently associated with psoriasis. Through genetic interaction analysis and RNA expression analysis, we speculate that the relationship between the two SVs in the MHC region and psoriasis may be related to their influence on HLA-C expression.

Figure 4. The two SVs in the MHC region are correlated with the RNA expression level of HLA-C

        It is reported that doctoral students Zhen Qi, Zhang Yuanwei, Yu Yafen, bioinformatics expert Yang Huanjie are the co-first authors, and Professor Sun Liangdan is the corresponding author. Professor Sun Liangdan’s team has long been committed to disease genetics and translational medicine research, analyzing disease genome variation maps, and successively discovered single nucleotide variations in psoriasis susceptibility genes (Nat Genet, 2009, 2010; Nat Commun, 2014), copy number variations (J Invest Dermatol, 2010), coding variants (Nat Genet, 2014; Nat Commun, 2015; J Invest Dermatol, 2014), HLA variants (Nat Genet, 2016), indel variants (J Invest Dermatol, 2019) and protein truncation Variation (Genome Res, 2021), systematically explains the genetic susceptibility mechanism and genetic causes of psoriasis, and provides a basis for disease precision medicine research. This study constructed the most complete psoriasis SV map so far, provided evidence that SV is independently related to psoriasis, and proposed its possible mechanism of action, which is a more comprehensive and refined genomics study related to psoriasis. Provides new ideas and directions.

Original link:

https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.20752