Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene
Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene
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DOI：
10.1086/503821
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发表时间：
2006-05-01
影响因子：
9.8
通讯作者：
Elder, JT
中科院分区：
文献类型：
--
作者：
Nair, RP;Stuart, PE;Elder, JT
先前的研究已经将包含PSORS 1（主要组织相容性复合体（MHC）中的银屑病易感性位点）的区间缩小到类似于包含HLA-C和至少10个其他基因的300 kb区域。为了鉴定PSORS 1基因，我们从5个个体的两条染色体上克隆并完全测序了该区域。测序的单倍型中有两个与银屑病相关（风险），其他八个明显无关（无风险）。两个风险单倍型的序列比较确定了一个298 kb的同源区域，从HLA-B的端粒延伸到HCG 22基因，其两侧是明显的非同源区域。从无关个体克隆的相似单倍型具有几乎相同的序列。候选区间已知基因外显子变异的组合分析显示，HCG 27、PSORS 1C 3、OTF 3、TCF 19、HCR、STG和HCG 22在10个测序的单倍型中没有携带风险单倍型特有的等位基因。SPR 1和SEEK 1都有特异于风险单倍型的信使RNA等位基因，但只有HLA-C和CDSN产生风险特有的蛋白质等位基因。在678个早发性银屑病家系中对HLA-C和CDSN的危险等位基因（HLA-Cw 6和CDSN*TTC）进行基因分型;其中620个家系还对跨越PSORS 1间隔的34个微卫星标记进行分型。保留HLA-Cw 6但缺乏CDSN*TTC的重组单倍型与银屑病显著相关，而保留CDSN*TTC但缺乏HLA-Cw 6的重组单倍型与银屑病不相关，尽管具有良好的统计功效。通过将具有相似断裂点的重组体分组，可以以高置信度排除298-kb候选区间的最端粒四分之一。这些结果强烈表明HLA-Cw 6是导致早发性银屑病易感性的PSORS 1风险等位基因。
Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an similar to 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.