Genome-wide association study for systemic lupus erythematosus in an egyptian population.

Systemic lupus erythematosus (SLE) susceptibility has a strong genetic component. Genome-wide association studies (GWAS) across trans-ancestral populations show both common and distinct genetic variants of susceptibility across European and Asian ancestries, while many other ethnic populations remain underexplored. We conducted the first SLE GWAS on Egyptians-an admixed North African/Middle Eastern population-using 537 patients and 883 controls. To identify novel susceptibility loci and replicate previously known loci, we performed imputation-based association analysis with 6,382,276 SNPs while accounting for individual admixture. We validated the association analysis using adaptive permutation tests (n = 109). We identified a novel genome-wide significant locus near IRS1/miR-5702 (Pcorrected = 1.98 × 10-8) and eight novel suggestive loci (Pcorrected < 1.0 × 10-5). We also replicated (Pperm < 0.01) 97 previously known loci with at least one associated nearby SNP, with ITGAM, DEF6-PPARD and IRF5 the top three replicated loci. SNPs correlated (r 2 > 0.8) with lead SNPs from four suggestive loci (ARMC9, DIAPH3, IFLDT1, and ENTPD3) were associated with differential gene expression (3.5 × 10-95 < p < 1.0 × 10-2) across diverse tissues. These loci are involved in cellular proliferation and invasion-pathways prominent in lupus and nephritis. Our study highlights the utility of GWAS in an admixed Egyptian population for delineating new genetic associations and for understanding SLE pathogenesis.

Ischemic heart disease and rheumatoid arthritis: Do inflammatory cytokines have a role?

BACKGROUND: The increase in Rheumatoid arthritis (RA) associated mortality is predominantly due to accelerated coronary artery and cerebrovascular atherosclerosis with increased risk of ischemic heart disease about 50% in RA patients compared to controls. OBJECTIVE: To study the pathogenesis of ischemic heart disease in RA, role of inflammatory cytokine interplay, disease activity and rheumatoid factor positivity. METHODS: Eighty RA patients and 44 healthy controls were included. All subjects were younger than 45years for females and 55years for males with exclusion of all traditional risk factors for atherosclerosis. Interleukin (IL) 1, 6 and 18 were assessed in all subjects. RA patients fulfilled ACR/EULAR 2010 criteria and were subjected to Dobutaminestress-echocardiography, diseases activity assessed by DAS-28, X-ray hands for Larsen score and function assessment by HAQ. RESULTS: RA patients had significantly higher serum IL 1, 6 and 18 than controls (p=0.00 in all). Thirty four (42.5%) patients had hypertensive reaction on Dobutamine-stress-echocardiography, four of them had ischemic change, and 46 (57.5%) had normal reaction. All patients with hypertensive reaction had positive RF (p=0.00), 10 had DAS-28>5.1, 20 had DAS-28 from 3.2 to5.1 and 4 were in remission (p=0.001). CRP was higher in patients with hypertensive reaction (p=0.003) while serum levels of IL1, 6 and 18 showed no significant difference. In all patients, serum levels of IL1, 6 and 18 showed significant positive correlation with VAS, HAQ and DAS-28 (p<0.001 in all). Only IL18 showed significant positive correlation with X-ray score in all patients. CONCLUSION: Disease activity and RF positivity play an important risk factor for ischemic heart disease in RA. Serum levels of IL1, 6 and 18 did not help much in detecting patients at risk of ischemic heart disease. Better control of RA disease activity with early remission helps in preventing cardiac complications. More studies on larger number of patients are needed for better understanding of mechanism of ischemic heart disease in RA.

Insight on Bone Morphogenetic Protein 7 in Ankylosing Spondylitis and its association with disease activity and radiographic damage.

INTRODUCTION: Fusion of joints as well as intervertebral spaces by the formation of bony spurs appearing as syndesmophytes and osteophytes are the hallmark of spondyloarthropathies which accounts for disability. The aim of this study was to assess the serum level of bone morphogenetic protein (BMP)-7 in ankylosing spondylitis and its relationship with disease activity and the radiographic damage. METHODS: This longitudinal case control study was conducted in Ain Shams University Hospitals (Egypt). A total of 55 subjects were included in two case groups and one control group. Group I included 20 patients with Ankylosing Spondylitis (AS) assessed at baseline (defined as Ia and after 18 months defined as Ib). Group II included 20 patients with Rheumatoid Arthritis (RA) and Group III included 15 healthy subjects as controls. Patients with other forms of seronegative spondyloarthropathies, bone forming diseases were excluded from the study. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI) were used to assess disease activity in AS patients. RA disease activity was assessed using the disease activity score 28 (DAS28). Radiographic changes were assessed using the Bath AS Radiographic Index (BASRI) in AS and Larsen scores in RA. Laboratory investigations included: Complete blood picture (CBC), Erythrocyte sedimentation rate (ESR), quantitative CRP, serum calcium, phosphorus and alkaline phosphatase. Determination of serum bone morphogenetic protein-7 level (BMP-7) was done using enzyme linked immunosorbent assay (ELISA). Sample collections, clinical and radiological assessments were performed at baseline for all groups and after a mean follow-up of 18 months for Group I. Data were analyzed by SPSS 17, using t-test, Kruskal-Wallis, Mann-Whitney, Fischer exact test, Chi square, and Pearson Product-Moment Correlation Coefficient. RESULTS: There were statistically significant differences between the 3 groups as regard baseline BMP-7 levels; the mean BMP-7 level of AS patients was significantly higher than that of RA patients and controls and significantly higher in the RA group than that of controls. BMP-7 levels were not associated with any of the clinical or drug related variables either in AS or RA. In AS BMP-7 levels showed significant increase after follow up and significant positive correlation with serum alkaline phosphatase (both at baseline and after follow up) and BASDAI score (after follow up) respectively. Despite the parallel increase of BMP7 and BASRI score during the follow-up period no statistically significant correlation was detected. There were no significant correlations between BMP7 level and patient's age or any disease related characteristics in the RA group. CONCLUSION: A significant progressive increase in serum BMP-7 was noted in AS patients that correlated with serum markers of bone formation. Such a biomarker measurement may not only act as a surrogate marker for the disease but has the potential to contribute to the pathogenesis of AS that may provide a complementary or alternative therapeutic approach.