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 ¼ 1.1 Â 10 À4 , odds ratio (OR) ¼ 0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5 0 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 EuropeanAmerican 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 ¼ 1.5 Â 10 À3 , OR ¼ 0.75 (95% CI: 0.62À0.89)). 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.
Sle3 is an NZM2410/NZW-derived lupus susceptibility interval on murine chromosome 7, that is associated with spontaneous lupus nephritis, and also anti-GBM induced glomerulonephritis. The tissue kallikrein gene cluster is located within the Sle3 interval and constitutes potential candidate genes for this locus. We have recently reported that renal kallikrein expression was up-regulated by anti-GBM antibody challenge in a strain-specific manner and that it was significantly under-expressed in the anti-GBM sensitive strains, including B6.Sle3. Further sequencing and functional studies reported previously provided evidence that kallikreins could constitute disease genes in lupus. In the present report, we have used an adenoviral vector to deliver the klk1 gene to B6.Sle3 congenics to directly test if kallikreins might have a protective effect against anti-GBM induced nephritis. Our data shows that klk1 gene delivery ameliorated anti-GBM induced nephritis in B6.Sle3 congenics. Taken together with previous studies, these findings indicate that kallikreins play an important protective role in autoantibody-initiated glomerulonephritis, and could constitute potential candidate genes for anti-GBM induced and spontaneous lupus nephritis.
ABSTRACT. We conducted a hospital-based case-control study to evaluate the relationship between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and type 2 diabetes mellitus risk in a Chinese population. Genotyping of TCF7L2 rs7903146 was carried out using the polymerase chain reaction-restriction fragment length polymorphism method. A chi-square test revealed a statistically significant difference between the distributions of rs7903146 genotypes in type 2 diabetes mellitus patient and control groups (chi-square = 10.49, P = 0.005). Using unconditional logistic regression analysis, we observed that the TT genotype of this polymorphism was significantly correlated with increased risk of developing type 2 diabetes mellitus compared to the CC genotype [odds ratio (OR) = 2.31, 95% confidence interval (CI) = 1.33-4.04]. Furthermore, we found that the rs7903146 sequence variation was also significantly associated with susceptibility to this disease under dominant (OR = 1.58, 95%CI = 1.09-2.28) and recessive models (OR = 2.11, 95%CI = 1.25-3.62). We conclude that the TCF7L2 rs7903146 genetic polymorphism is independently associated with the risk of developing type 2 diabetes mellitus under co-dominant, dominant, and recessive models.
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