Fine Mapping Psoriasis Susceptibility Genes In Chinese Han Population

Background Psoriasis (OMIM #177900) is a common inflammation cutaneous disorder characterized by red scaly patches and abnormal epidermal proliferation with a prevalence of 1-5% in genereal population and 0.123% in Chinese population. So far there are more than 3.5 million psoriasis patients and the net increasing number of the patients is 100 thousands annually. The pathogenesis of psoriasis remains unclear. Now most people tend to think it as a genetic and autoimmune skin disorder and caused by the interaction between genetics, immunity and enviornmental factors. In 2002, our group performed a genome-wide linkage scan in 61 Chinese Han families with psoriasis vulgaris and found two major susceptibility loci at 6p21 and 4q31 and suggestive evidence for linkage on several other regions including 2p,9q and 13q. In 2003, another group from China carried out a linkage study in 38 Chinese Han families with psoriasis vulgaris and confirmed the suggestive evidence for linkage to 6p21 and 17q25(PSORS2), which was the second major psoriasis locus except PSORS1.However we could not find suggestive evidence for linkage to this locus in our original genome-wide scan.Objective To perfect the psoriasis mapping study in Chinese Hans and confirm whether they are psoriasis susceptibility loci in Chinese Hans and then narrow down the candidate region, lay solid foundation for the susceptibility gene identification and cloning of these genes. Methods To perform the fine mapping studies on 2p22-11,9q33-34,13q21-32,17q22-25 by a larger sample size and a more dense genetic markers;to genotype automatically and process the data primarily by ABI3730 and GeneMapper(4.0 Version).To transform the data by linkage software and perform the parametric and nonparametric linkage analysis by GENEHUNTER (2.0 Version) and define the susceptibility region according to Lander and Kruglyak critera(p<0.000022).Results 1. 9q33-34 The multipoint nonparametric analysis of the 160 families revealed significant linkage evidence throughout the region D9S1682 and D9S164 with NPL scores >3 and a maximum multipoint NPL score of 4.64(p=0.0000003) between D9S1881 and D9S290 .The multipoint parametric analysis of the 160 families revaled significant linkage evidence between D9S1881 and D9S164 with HLOD scores >3 and a maximum multipoint HLOD score of 5.03 (α=46%) between D9S1881 and D9S290. The analysis of the 99 new families yielded multipoint NPL scores >3 between D9S1682 and D9S1847 and a maximum multipoint NPL score 3.67 (p=0.000003) and a maximum multipoint HLOD score 4.49 (α=64%) between D9S1682 and D9S1847. The linkage analysis of the 130 early-onset families gave multipotint NPL scores >4 between D9S1682 and D9S1847 and a maximum multipoint NPL score of 4.69(p=0.0000001) between D9S1881 and D9S290 and a maximum multipoint HLOD scores of 6.48 (α=58%) at the same region.2. 2p22-11 The multipoint parametric and nonparametric linkage analyses using the whole 180 revealed significant linkage evidence between D2S391and D2S2109 with NPL scores>3 and a maximum NPL score of 4.11 (p=0.000003) between D2S2153 and D2S2368 and with multipoint HLOD >3 between D2S391 and D2S2368 and a maximum multipoint HLOD value of 4.93 (α=54%) between D2S2153 and D2S337. The analysis of the 119 new families yielded a maximum multipoint HLOD 4.87 (α=78%), a maximum multipoint NPL score 3.60(p=0.00001) at the same locus. 3. 13q21-32 and 17q22-25 Multipoint parametric and nonparametric linkage analyses of either the whole 180 families or the 119 new families did not provide supporting evidence for the suggested linkage loci at 13q21-32 and 17q22-25. At the region 13q21-32, the analysis of the 180 families identified a maximum multipoint HLOD score of 0.10 (α=7%) and NPL score of 0.95 (p=0.14) at locus D13S1315. At the region 17q22-25, the analysis of the 180 families identified a maximum multipoint HLOD score of 0.08 (α=6%) and NPL value of 0.94(p=0.14) at locus D17S802. All the lod scores from the 180 families as well as the 119 new families (not shown) are much smaller than the ones obtained from the original 61 families.Conclusions There are suscetptibility loci on chromosomes2p22-11 and 9q33-34 in Chines Hans especially for the early-oneset psororiasis and narrow down the candidate region, which lay a solid foundation for susceptibilty gene cloning. There are no psoriasis susceptibility loci on chromosome 13q21-32 and 17q22-25 in Chinese Hans.