| Background Psoriasis is a common chronic inflammatory skin disease. It affects a population of 0.1%-5% of the whole world. Its prevalence varies with the race. Patients with psoriasis are increasing year by year in our country. The patients suffer from the physical, psychological and social impact of this disease which bring poor quality of life for them.As is known, psoriasis is a complex disease with recognized hereditary basis. Genome-wide linkage analysis with psoriasis pedigrees have identified 12 chromosomal loci that associated with the risk of psoriasis. And more than 50% of the hereditary susceptibility are from PSORS1. However, psoriasis is different from Mendelian diseases. It is difficult to find the susceptibility genes for psoriasis using Genome-wide linkage analysis. With the completion of Hap Map Project and the growing and maturing of high-throughput genotyping technique, genome-wide association studies(GWASs) quickly develop worldwide. Samples of a cohort of cases and controls are used to perform GWASs. To date, many research teams including our team have performed several psoriasis GWASs in various populations. More than 40 novel psoriasis susceptibility genes/loci have been identified, which greatly promote the development of the study on psoriasis.However, most of these GWASs were conducted in Caucasian population. Besides the GWASs finished by our team, few large GWASs are performed in Chinese Hanpopulation. As is known, great difference in the genetic structure existed in between Chinese Han population and Caucasian population. So, are the established psoriasis susceptibility loci also associated with psoriasis in Chinese Han population? For the established susceptibility loci, what are the heterogeneities between Chinese Han population and Caucasian population? To date, there is not a study on these problems. If they are fully understood, it’s helpful to reveal the pathogenesis of psoriasis and then for drug research and development, psoriasis prevention and diagnosis, and individualized treatment. We have a large sample size and technical advantages on genetic research, which enable us to complete the study successfully.Objective To collect a large sample including psoriasis and healthy controls in Chinese Han population. To carry out a case-control study to confirm the association of the established psoriasis susceptibility loci with psoriasis of Chinese Han population. And to elucidate the genetic heterogeneity on psoriasis susceptibility loci between Chinese Han population and Caucasian population.Methods We collected a cohort of Chinese Han people including psoriasis and healthy controls. We retrieved the literature for the established psoriasis susceptibility loci for Caucasian population and included the related data for the heterogeneity analysis.We detected the SNPs genotype using the Illumina Human Exome Bead Chip and screened the SNPs data we needed.We genotyped the remaining SNPs using Sequenom Mass ARRAY method(Sequenom Platform).The statistical analysis was processed using Plink 1.07 software. All the P value obtained from the case-control study were adjusted by using Bonferroni Correction method. The heterogeneity for each SNP between Chinese Han population andCaucasian population was analyzed using Stata software.Results 1. In this study, 22,860 samples of Chinese Han were included. The age and life region between cases and controls were well matched. After retrieving literature, thirty-two psoriasis susceptibility varients(SNPs) for Caucasian population were included in this study.2. We obtained the data of 11 SNPs from the Illumina Human Exome Bead Chip study(11,610 psoriasis vs.11,250 controls). After quality control and statistical analysis, 6 SNPs which locate in 4 genes/loci reached the genome-wide significant level(P<5×10-08). They are IFNLR1(rs4649203, P=2.55×10-08, OR=0.86, 95%CI =0.82~0.91), LCE3D-LCE3E(rs4112788, 2.97×10-27, 0.76(0.72~0.80)), IL12B(rs2082412, 1.38×10-14, 0.82(0.78~0.86); rs2546890, 6.56×10-14, 1.21(1.15~1.27); rs6887695, 7.02×10-14, 0.82(0.78~0.87)) and HLA-B(rs3134792, 3.99×10-26, 0.54(0.49~0.61)). The other 5 SNPs lie in 5 different genes/loci, including B3GNT2(rs10865331), REL(rs702873), ERAP1(s27044), RPL3P2(rs12191877) and WASF5P(rs10484554), did not reach the genome-wide significant level(P >5×10-08).3. We obtained 21 SNPs data by using Sequenom platform(8,110 psoriasis vs.8,373 controls). After quality control, 2 SNPs including rs6677595 and rs963986 were removed. Nine SNPs which lie in 8 different genes/loci reached the significant level(P<2.38×10-03). They are IFNLR1(rs7552167, 6.14×10-13, 0.83(0.79~0.87)), RUNX3(rs7536201, 2.91×10-07, 0.88(0.84~0.92)), IL13(rs1295685, 3.46×10-05, 0.90(0.86~0.95)), TNIP1(rs2233278, 5.86×10-23, 1.46(1.36~1.58)), IL12B(rs3212227, 6.457×10-19, 0.82(0.79~0.86)), EXOC2(rs9504361, 1.40×10-06, 0.88(0.84~0.93)), POLI(rs545979, 1.41×10-03, 1.21(1.08~1.37)), SPATA2-RNF114(rs495337, 4.65×10-04, 0.92(0.88~0.97); rs1056198, 1.32×10-03, 0.93(0.89~0.97)). The remaining ten genes/loci, including IL23R(rs9988642), 1p36.23(rs11121129), 2p16.1(rs62149416), TRAF3IP2(rs13210247), TNFAIP3(rs582757), TAGAP(rs2451258), 9q31.2(rs10979182),ZC3H12C(rs4561177), ETS1(rs3802826) and NOS2(rs28998802), did not reach the significant level(P>2.38×10-03).4. The heterogeneity analysis revealed that 4 genes/loci, including IFNLR1(rs7552167) RUNX3(rs7536201), EXOC2(rs9504361) and POLI(rs545979), which were associated with psoriasis in Chinese Han population, had no obvious heterogeneity(I2≤50%, H<1.2). For another eight SNPs in 5 genes/loci, including IFNLR1(rs4649203), IL13(rs1295685), TNIP1(rs2233278), IL12B(rs2082412, rs6887695 and rs3212227), SPATA2-RNF114(rs495337 and rs1056198), which also reached the significant level in Chinese Han population, they had obvious heterogeneity(I2>50%, H>1.5) between the two populations. More interestingly, an allele rs2546890-A, a varient in the gene IL12, is a protective factor for caucasian population(OR=0.65, P=1.29×10-20), but a risk factor for Chinese Han population(OR=1.21, P=6.56×10-14). In addition, the remaining genes/loci, including IL23R(rs9988642), TAGAP(rs2451258), NOS2(rs28998802), 1p36.23(rs11121129), B3GNT2(rs10865331), REL(rs702873), 2p16.1(rs62149416), RPL3P2(rs12191877), WASF5P(rs10484554), TRAF3IP2(rs13210247), TNFAIP3(rs582757), 9q31.2(rs10979182), ZC3H12C(rs4561177) and ETS1(rs3802826), were not associated with psoriasis in Chinese Han population in this study. But the heterogeneity existed for them between the two populations. So, it still needs more multicentric and large sample studies to validate these results.Conclusions In this study, we validate 15 SNPs associated with the risk of psoriasis in Chinese Han population, which lie in 10 genes/loci(IFNLR1, LCE3D-LCE3 E, HLA-B, RUNX3, IL13, TNIP1, IL12 B, EXOC2, POLI and SPATA2-RNF114). The heterogeneity analysis indicated that the 13 psoriasis susceptibility SNPs for both Chinese Han population and Caucasian population, which locate in 8 genes/loci, including IFNLR1, RUNX3, IL13, TNIP1, IL12 B, EXOC2, POLI and SPATA2-RNF114, have various genetic heterogeneity between these two populations. In addition, an allelers2546890-A, was found to be a protective factor for Caucasian population, but a risk factor for Chinese Han population. Besides, this study also detected 14 genes/loci, including IL23R、TAGAP、NOS2、1p36.23、B3GNT2、REL、2p16.1、RPL3P2、WASF5P、TRAF3IP2、TNFAIP3、RPL31P43、ZC3H12C and ETS1, which were not associated with psoriasis in Chinese Han population. As the heterogeneity across these two populations existed for these 14 genes/loci, more studies are needed to confirm our results. It brings opportunites and challenges for the subsequent studies. |
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