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Guthridge, Joel M.,Lu, R.,Sun, H.,Sun, C.,Wiley, Graham B.,Dominguez, N.,Macwana, Susan R.,Lessard, Christopher J.,Kim-Howard, X.,Cobb, Beth L.,Kaufman, Kenneth M.,Kelly, Jennifer A.,Langefeld, Carl D University of Chicago Press [etc.] 2014 American journal of human genetics Vol.94 No.4
Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.
Genetic associations of LYN with systemic lupus erythematosus
Lu, R,Vidal, G S,Kelly, J A,Delgado-Vega, A M,Howard, X K,Macwana, S R,Dominguez, N,Klein, W,Burrell, C,Harley, I T,Kaufman, K M,Bruner, G R,Moser, K L,Gaffney, P M,Gilkeson, G S,Wakeland, E K,Li, Q-Z Macmillan Publishers Limited 2009 GENES AND IMMUNITY Vol.10 No.5
We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case–control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 × 10<SUP>−4</SUP>, odds ratio (OR)=0.81 (95% confidence interval: 0.73–0.90)). This single nucleotide polymorphism (SNP) is located in the 5′ untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 × 10<SUP>−3</SUP>, OR=0.75 (95% CI: 0.62−0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.Genes and Immunity (2009) 10, 397–403; doi:10.1038/gene.2009.19; published online 16 April 2009