Background/Purpose: It was reported that genetic variations in B cell signal transduction were associated with susceptibility to SLE. However, these studies were limited in number and were performed in only certain populations. In our study, we aimed to evaluate the relationship between some important genetic variations and expressions of these genes in our SLE population. We also determined their association with clinical parameters.  

Methods: 84 SLE patients (79F, 5M, mean age: 37.6) and 105 healthy controls (98F, 7M, mean age: 38.2) were included into the study. SLEDAI scores and flares according to SELENA-SLEDAI were also recorded. Genomic DNA and cDNA were obtained from peripheral venous blood. BLK (rs13277113 and rs2736340), LYN (rs7829816 and rs6983130), SYK (rs2613310), CD247 (rs704853) polymorphisms, gene expressions of SRC-B family kinases (BLK, HCK, LCK ve LYN) and SYK kinases (SYK, ZAP70)  which are important in B-cell signal transduction and were found to be important in whole genome analyses in various races were studied by Real-time PCR in the Genetics Department.

Results:

The heterozygous genotypic pattern (GA) for rs13277113 polymorphism was more frequent in patients with SLE when compared to controls (48.8% vs. 31.4%, p=0.015). Other genotype variants were similar in SLE patients and controls. In SLE group, the heterozygous genotype (GA) for rs13277113 was significantly less frequent in initially active SLE patients (41.2% vs. 73.3%) and more frequent in anti-Ribosomal-P positive (14.6% vs. 0%) SLE patients (p values for both=0.01).AA genotype for rs2613310 was significantly more frequent in patients with thrombocytopenia (16.9% vs. none, p=0.048), in patients with positive anti-dsDNA (59.3% vs. 32%, p=0.01), and those with anti-nucleosome antibodies (23.7% vs. 4%, p=0.004). SLE flares according to SELENA-SLEDAI flare index was significantly more frequent in GA (rs13277113) (70% vs. 37%) and CT (rs 2736340) genotypes (66.7% vs. 35.2%) than in other genotypes (p values, 0.004 and 0.006). In the group which had flares according to SELENA flare index, the average delta CT value for BLK gene expression tended to be higher than in the group without flares (12.2±2.6 vs. 10.8±1.6, p=0.08). Quantitative relative expression of Syk gene, as calculated by delta-delta-CT method, showed significant difference between the average delta CT value for SLE patients and controls (7.5±1.2 vs. 7.8±1, p=0.02). The relative expression of mRNA for Syk gene to β2 microglobulin was increased by 1.22 fold in patients with SLE as compared to controls.The statistically significant intergenotypic variation in the delta-CT values was found in patients with GG and GA genotypes for rs13277113 (BLK) (10.8±2.1 vs 11.7±2.2, p=0.019). GA genotype showed higher delta-CT value representing lower gene expression at mRNA level. AA genotype groups was very small. 

Conclusion: We observed more frequent heterozygous GA genotypic pattern (rs13277113) in our SLE patients compared to controls; and it was associated with BLK expression and disease flare. In spite of the fact that Syk genotype was not increased in SLE patients, Syk expression was seen to be more frequent.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/blk-pathway-associated-rs13277113-ga-genotype-is-more-frequent-in-systemic-lupus-erythematosus-patients-and-associated-with-low-gene-expression-and-increased-flares/