We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).

Belimumab has therapeutic benefit in active systemic lupus erythematosus (SLE), especially in patients with high-titer anti-dsDNA antibodies. We asked whether the profound B cell loss in belimumab-treated SLE patients is accompanied by shifts in the immunoglobulin repertoire. We enrolled 15 patients who had been continuously treated with belimumab for more than 7 years, 17 matched controls, and 5 patients who were studied before and after drug initiation. VH genes of sort-purified mature B cells and plasmablasts were subjected to next-generation sequencing. We found that B cell-activating factor (BAFF) regulates the transitional B cell checkpoint, with conservation of transitional 1 (T1) cells and approximately 90% loss of T3 and naive B cells after chronic belimumab treatment. Class-switched memory B cells, B1 B cells, and plasmablasts were also substantially depleted. Next-generation sequencing revealed no redistribution of VH, DH, or JH family usage and no effect of belimumab on representation of the autoreactive VH4-34 gene or CDR3 composition in unmutated IgM sequences, suggesting a minimal effect on selection of the naive B cell repertoire. Interestingly, a significantly greater loss of VH4-34 was observed among mutated IgM and plasmablast sequences in chronic belimumab-treated subjects than in controls, suggesting that belimumab promotes negative selection of activated autoreactive B cells.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single-nucleotide polymorphisms (SNPs) in tumor necrosis factor (TNF) superfamily gene TNFSF4 have been shown to be associated with SLE in European and Hong Kong Chinese populations. But it is unknown whether it is also associated with the disease in Mainland Chinese Han population. We genotyped the SNPs rs1234315 near the TNFSF4 gene in 1,344 SLE patients and 4,315 controls of Chinese Han population and confirmed the association between the SNP and the SLE [odds ratios (ORs) of 1.45 and P values of 1.5 × 10(-16)]. The stratification analyses showed that rs1234315 was more strongly associated with SLE patients with arthritis. Our study not only suggested that the TNFSF4 gene was associated with SLE in Chinese Han population, but also implied that it might be a common genetic factor predisposing to the development of SLE in multiple populations.

Purpose: Autosomal dominant optic atrophy is a form of blindness, due in part to mutations affecting the mitochondrial-targeted OPA1 gene product. Both OPA1-positive and OPA1-negative families exhibit variable expressivity and incomplete penetrance. The purpose of this study was therefore to determine if the background mtDNA genotype acts as a genetic modifier for the expression of this disease. Methods: To find novel pathogenic OPA1 mutations, we performed complete OPA1 gene exon sequencing in 30 patients. To assess the possibility that mitochondrial DNA haplotype acts as a genetic modifier, we determined the mitochondrial DNA haplotype in 29Caucasian OPA1-positive and OPA1-negative patients. Deviations in haplotype distribution between patient and control groups were determined by statistical means. Results: Seven new pathogenic OPA1 mutations were found.Most were detected in the mitochondrial targeting N-terminus or in the coiled-coil domain at the C-terminus.Mitochondrial DNA haplotype analysis indicated that the European haplogroup distribution was different between Caucasian patients and controls. Further, haplogroup J was three-fold over-represented in OPA1-negative patients.Conclusions: Overall, our results support haploinsufficiency as a genetic mechanism in OPA1-positive cases and also suggest that mtDNA genetic background may influence disease expression in a subset of cases. Genet Med 2006:8(4):217-225.

According to the defects of classical k-means clustering algorithm such as sensitive to the initial clustering center selection, the poor global search ability, falling into the local optimal solution. A differential evolution algorithm which was a kind of a heuristic global optimization algorithm based on population was introduced in this article, then put forward an improved differential evolution algorithm combined with k-means clustering algorithm at the same time. The experiments showed that the method has solved initial centers optimization problem of k-means clustering algorithm well, had a better searching ability,and more effectively improved clustering quality and convergence speed