Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population.
Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population.
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DOI：
10.1371/journal.pgen.1000038
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发表时间：
2008-03-21
期刊：
影响因子：
4.5
通讯作者：
Zhang XJ
中科院分区：
文献类型：
--
作者：
Fan X;Yang S;Huang W;Wang ZM;Sun LD;Liang YH;Gao M;Ren YQ;Zhang KY;Du WH;Shen YJ;Liu JJ;Zhang XJ
PSORS 1（psoriasis susceptibility gene 1）是银屑病的主要易感基因。一些精细定位研究已经强调了PSORS 1的300 kb候选区域，其中提出了多个生物学上合理的候选基因。最近的研究表明，HLA-Cw 6作为主要的PSORS 1风险等位基因的候选区域内的高加索人口。本研究对163个银屑病家系进行了PSORS 1基因座多态性微卫星标记及HLA-B、HLA-C和CDSN位点的关联分析。5个标记位点显示了强证据（P<10−3），1个标记位点显示了弱证据（P = 0.04）。 单倍型聚类分析显示，所有的危险单倍型都是Cw 6阳性，并且共有一个369-kb的同源标记等位基因区域，该区域携带本研究中鉴定的所有危险等位基因，包括HLA-Cw 6和CDSN*TTC。对228个中国家系的HLA-Cw 6和CDSN*TTC等位基因的重组单倍型分析显示，在中国人群中，HLA-Cw 6 −/CDSN*TTC +重组单倍型显然与银屑病风险无关（T∶NT = 29：57，p = 0.0025），这表明在没有HLA-Cw 6等位基因存在的情况下，CDSN*TTC等位基因本身不会带来风险。 对具有共同重组断点的非风险HLA-Cw 6 −/CDSN*TTC +重组单倍型的进一步排除分析使我们能够将PSORS 1的位置精确到一个小的候选区域。最后，我们进行了条件连锁分析，并表明HLA-Cw 6是一个主要的风险等位基因，但不能解释在中国人群中的PSORS 1基因座的全部连锁证据。通过进行一系列基于家族的关联分析的单倍型以及排除分析的重组单倍型，我们能够细化PSORS 1基因的一个小的关键区域，HLA-C是一个强有力的候选人是PSORS 1易感基因。牛皮癣是一种常见的皮肤病，具有很强的遗传风险。对具有多个受影响个体的银屑病家族的分析已经确定了与银屑病发展相关的几个基因组区域（显示连锁证据）。其中，6p21.3区域（PSORS 1）是一个得到充分证实的主要风险位点。然而，在PSOR 1基因座内的疾病风险基因的鉴定一直是困难的，这主要是由于几个基因显示出与疾病发展相关的证据，并且这些证据高度相关并且难以彼此分离。在这项研究中，我们进行了一个精细的定位研究PSORS 1基因座在中国家庭与银屑病。通过分析在不同基因中携带不同风险相关遗传变异的重组单倍型，我们能够分离在多个基因中观察到的遗传效应，并确定HLA-C是PSORS 1位点主要风险基因的有力支持证据。我们进一步证明了HLA-C基因内的遗传变异不能解释PSORS 1位点的全部连锁证据，这表明该区域内可能存在其他风险基因和/或等位基因。我们的发现提高了我们对PSORS 1基因座遗传复杂性的理解。
PSORS1 (psoriasis susceptibility gene 1) is a major susceptibility locus for psoriasis. Several fine-mapping studies have highlighted a 300-kb candidate region of PSORS1 where multiple biologically plausible candidate genes were suggested. The most recent study has indicated HLA-Cw6 as the primary PSORS1 risk allele within the candidate region in a Caucasian population. In this study, a family-based association analysis of the PSORS1 locus was performed by analyzing 10 polymorphic microsatellite markers from the PSORS1 region as well as HLA-B, HLA-C and CDSN loci in 163 Chinese families of psoriasis. Five marker loci show strong evidence (P<10−3), and one marker locus shows weak evidence (P = 0.04) for association. The haplotype cluster analysis showed that all the risk haplotypes are Cw6 positive and share a 369-kb region of homologous marker alleles which carries all the risk alleles, including HLA-Cw6 and CDSN*TTC, identified in this study. The recombinant haplotype analysis of the HLA-Cw6 and CDSN*TTC alleles in 228 Chinese families showed that the HLA-Cw6 −/CDSN*TTC + recombinant haplotype is clearly not associated with risk for psoriasis (T∶NT = 29:57, p = 0.0025) in a Chinese population, suggesting that the CDSN*TTC allele itself does not confer risk without the presence of the HLA-Cw6 allele. The further exclusion analysis of the non-risk HLA-Cw6 −/CDSN*TTC + recombinant haplotypes with common recombination breakpoints has allowed us to refine the location of PSORS1 to a small candidate region. Finally, we performed a conditional linkage analysis and showed that the HLA-Cw6 is a major risk allele but does not explain the full linkage evidence of the PSORS1 locus in a Chinese population. By performing a series of family-based association analyses of haplotypes as well as an exclusion analysis of recombinant haplotypes, we were able to refine the PSORS1 gene to a small critical region where HLA-C is a strong candidate to be the PSORS1 susceptibility gene. Psoriasis is a common skin disease with strong genetic risk. The analysis of psoriatic families with multiple affected individuals has identified several genomic regions that are linked (showing linkage evidence) to the development of psoriasis. Of them, the region on 6p21.3 (PSORS1) is a well-confirmed major risk locus. The identification of the disease risk gene within the PSOR1 locus, however, has been difficult, largely due to the fact that several genes show evidence for association with the disease development and the evidences are highly correlated and hard to be separated from each other. In this study, we performed a fine mapping study of the PSORS1 locus in Chinese families with psoriasis. By analyzing recombinant haplotypes that carry different risk-associated genetic variants within different genes, we were able to separate the genetic effects observed within multiple genes and identify strong supporting evidence for HLA-C to be the primary risk gene of the PSORS1 locus. We have further demonstrated that the genetic variation within the HLA-C gene does not explain the full linkage evidence at the PSORS1 locus, suggesting that there might be other risk genes and/or alleles within the region. Our findings have improved our understanding about the genetic complexity of the PSORS1 locus.
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