ABSTRACT
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving genetic, epigenetic and environmental factors and has higher incidence in women. In this study, we explored the association of estrogen receptor 1 (ESR1) rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms with susceptibility to SLE. PCR-RFLP and ELISA were used for genetic analysis and determination of specific autoantibodies, respectively. The univariate analysis showed no independent association of rs2234693 (OR: 1.14, 95% CI: 0.87 - 1.49, p = 0.36) and rs9340799 (OR: 0.87, 95% CI: 0.66-1.14, p = 0.34). The haplotype analysis using SHEsis platform revealed strong linkage disequilibrium between these two polymorphisms (D': 0.81, r2: 0.55). Among the four haplotype groups, the C-A haplotype (rs2234693-rs9340799) was strongly associated with the risk for SLE (OR: 2.10, 95% CI: 1.32 - 3.34, p = 0.001). The homozygous variant genotype of rs2234693 exhibited elevated TNF-α and depleted IFN-α, while the effects of rs9340799 were contradictory. The wild genotype of rs2234693 exhibited lower levels of IL-12 with number of rs9340799 variant alleles pronouncing this effect. From this study, it is concluded that the ESR1 haplotypes may influence the Th2 cytokine profile and susceptibility to SLE among the South Indians.
ABSTRACT
Background: Hydroxychloroquine (HCQ) used for long-term management of rheumatic diseases. Prolonged use of antimalarials has been implicated in the development of conduction disorders particularly with chloroquine. Since limited data are available with HCQ, we studied electrocardiograms (ECG’s) of 122 patients with rheumatic diseases treated with HCQ. This is the first study with large cohort evaluating conduction disorders in those receiving HCQ. Methods: To evaluate cardiac conduction disorders in patients receiving HCQ as a part of their treatment, during 1-year follow-up and to note other related adverse reactions with a hypothesis to determine, how common are conduction disorders with HCQ. This is longitudinal prospective observational study over 1-year in the tertiary referral of south India. All patients who were started on HCQ (200-400 mg/day) as a part of their treatment were included. Patients with established cardiac diseases, electrolyte abnormalities and who were on drugs that cause conduction disorders were excluded. All ECG’s were cross-checked by a cardiologist. Results: A total of 276 patients were screened at baseline and 270 patients were enrolled in the study. Patients of rheumatoid arthritis, lupus, Sjogren’s syndrome, undifferentiated connective tissue disease, palindromic rheumatism were included after satisfying respective classification criteria. The mean age is 38.85 (standard deviation [SD] 8.34) years. Females are 82.8% (n=101) and males are 17.2% (n=21). The baseline mean heart rate is 81.4 beats/min (SD=11.04), PR interval is 141.5 ms (SD=13.90), QRS is 84.8 ms (SD=13.90), QTc is 421.5 ms (SD=35.65). At 6 months, mean heart rate is 80.4 beats/min (SD=9.99), PR interval is 141.9 ms (SD=16-37), QRS is 81.5 ms (SD=11.82), QTc is 427.4 ms (SD=34.56). At the end of study period, mean heart rate is 81.8 beats/min (SD=9.49), PR interval is 140 ms (SD=21.33), QRS is 84.6 ms (SD=15.72), QTc is 422.7 ms (SD=36.2). During study period four events occurred. A young girl with lupus developed ventricular ectopics on hiking dose of HCQ from 200 mg to 400 mg with a cumulative drug intake of 9.8 g, which has resolved completely on stopping drug without any other intervention. A lupus patient died at home and the cause was not known. A 36-year-old male with rheumatoid arthritis of 4 years duration developed prolonged PR interval with 6 months of drug intake with cumulative was drug intake of 30.6 g with no available follow-up data. A 30-year-old female with undifferentiated arthritis developed skin rash which is pruritic, exfoliative with tiny blisters, 3 days after starting drug. The incidence of cardiac conduction defects in 1-year of follow-up in patients started on HCQ is 0.84. Conclusion: This study highlights need for periodic cardiac evaluation of patients receiving long-term antimalarials. Reversibility of antimalarial toxicity is also highlighted in this study. Conduction disorders observed were similar to that expected in general population thus adding further evidence on safety of HCQ.
ABSTRACT
In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web-based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 m1, m2 and m4 variants (D’: 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 m1 variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L × GSTT1 null × GSTM1 null (p<0.0001) and also between the phase II and I variants i.e. COMT H108L × GSTT1 null × CYP1A1 m1 × CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77-5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to m1 and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE.