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author:("nadir, away")
1.  Sex-specific differences in the relationship between genetic susceptibility, T cell DNA demethylation and lupus flare severity 
Journal of Autoimmunity  2012;38(2-3):J216-J222.
Lupus is less common in men than women, and the reason is incompletely understood. Current evidence indicates that lupus flares when genetically predisposed individuals encounter environmental agents that trigger the disease, and that the environmental contribution is mediated at least in part by T cell DNA demethylation. We hypothesized that lupus disease activity is directly related to total genetic risk and inversely related to T cell DNA methylation levels in each patient. Since women are predisposed to lupus in part because of their second X chromosome, we also hypothesized that men would require a greater genetic risk, a greater degree of autosomal T cell DNA demethylation, or both, to achieve a lupus flare equal in severity to women. Genetic risk was determined by genotyping men and women with lupus across 32 confirmed lupus susceptibility loci. The methylation status of two T cell autosomal genes known to demethylate in proportion to disease activity, KIR2DL4 (KIR) and PRF1, was measured by bisulfite sequencing. Lupus disease activity was determined by the SLEDAI. Interactions between genetic score, T cell DNA demethylation, and the SLEDAI score were compared between the men and women by regression analysis. Combining the degree of DNA demethylation with the genetic risk score for each patient demonstrated that the (genetic risk)/(DNA methylation) ratio increased directly with disease activity in both men and women with lupus. Importantly, men required a greater (genetic risk)/(DNA methylation) ratio to achieve a SLEDAI score equivalent to women (p=0.010 for KIR and p=0.0054 for PRF1). This difference was not explained by a difference in the genetic risk or T cell DNA demethylation alone, suggesting a genetic-epigenetic interaction. These results suggest that genetic risk and T cell DNA demethylation interact in lupus patients to influence the severity of lupus flares, and that men require a higher genetic risk and/or greater degree of T cell DNA demethylation to achieve a lupus flare equal in severity to women.
doi:10.1016/j.jaut.2011.11.008
PMCID: PMC3313010  PMID: 22305513
Genetic risk; epigenetics; DNA methylation; lupus; genetic-epigenetic interaction; sex-disparity
2.  A putative functional variant within the ubiquitin-associated domain-containing protein 2 gene (UBAC2) is associated with increased risk of Behçet’s disease 
Arthritis and rheumatism  2011;63(11):3607-3612.
Objectives
Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet’s disease. Herein, we establish the genetic effect within the UBAC2 gene, replicate this genetic association, and identify a functional variant within this locus.
Methods
A total of 676 Behçet’s disease patients and 1,096 controls were studied. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls, and 144 patients and 560 controls, from Turkey and Italy, respectively. Genotyping of 14 SNPs within and around UBAC2 was performed using TaqMan SNP genotyping assays.
Results
The genetic association between Behçet’s disease and UBAC2 was established, replicated and confirmed (Meta-analysis OR= 1.84, meta-analysis P= 1.69X10−7). Haplotype analysis identified both a disease risk and a protective haplotype (P= 0.00014 and 0.0075, respectively). Using conditional haplotype analysis we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrate that rs7999348 tags a functional variant associated with increased mRNA expression of a UBAC2 transcript variant in PBMCs of individuals homozygous for the Behçet’s disease-associated “G” allele. Further, our data suggest the possibility of multiple genetic effects that increase susceptibility to Behçet’s disease in the UBAC2 locus.
Conclusion
We established and confirmed the genetic association between UBAC2 and Behçet’s disease in three independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression.
doi:10.1002/art.30604
PMCID: PMC3205238  PMID: 21918955
3.  Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(10):1752-1757.
Objective
Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus.
Materials and methods
4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria.
Results
Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0×10−6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing.
Conclusion
Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.
doi:10.1136/ard.2011.154104
PMCID: PMC3232181  PMID: 21719445

Results 1-4 (4)