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Genetic factors are likely to be important both in determining the overall susceptibility to systemic lupus erythematosus (SLE) and in influencing the remarkable clinical heterogeneity in disease expression found in affected subjects. The more common clinical features seen in patients with SLE include, skin and joint diseases, renal disease, neuropsychiatric complications, and also some haematological abnormalities. Genetic factors, together with environmental factors, strongly influence the development of SLE. Multiple loci within the major histocompatibility complex (MHC) have been implicated in susceptibility as have HLA class II alleles, complement components, and tumour necrosis factor (TNF) loci.
Currently it is believed that some HLA alleles are in genetic linkage disequilibrium with certain disease related genes and they regulate the immune responses. Since 1969, when the first case of SLE was reported from India, the disease has been extensively studied in different regions of the country—namely, Chennai, Calcutta, Mumbai, and New Delhi. A statistically significant clinical correlation comparing the clinical variables from other racial groups of the world has been reported in Indian patients with SLE.1 HLA association studies from Indian patients with SLE are considerably limited2 and, furthermore, varying interethnic differences in the associations have been reported from UK, South African and Icelandic populations.3
PATIENTS AND METHODS
We studied 53 patients with severe SLE exhibiting the clinical manifestations described by the 1982 revised American Rheumatism Association diagnostic criteria who had one or more organ affected, such as kidney, brain, heart, and lungs. One hundred and ten normal healthy subjects with the same economic status and ethnic background comprised the controls for this study over the same period. The autoantibody profiles among the patients with SLE were studied by immunofluorescence and enzyme linked immunosorbent assay (ELISA). HLA-A and B locus antigens were identified by a National Institute of Health two stage microlymphocytotoxicity assay using indigenous and commercial antisera. The HLA-DRB1 and HLA-DQB1 alleles were determined by a polymerase chain reaction with sequence-specific primers technique from the total genomic DNA extracted from the EDTA blood. The phenotype frequencies, odds ratio, probability value, and confidence intervals were estimated using our database and computer programs. The p value was corrected by the Bonferoni inequality method.
RESULTS AND DISCUSSION
A significant increase in the frequency of HLA-A1, A2, B27, DRB1*03, DQB1*0302, and DQB1*0601 was found among patients with SLE. HLA-A19, B15, DRB1*14(6), DRB1*1001, and DQB1*0203 were found to be decreased in the patient group compared with the controls (table 1). The high risk alleles DRB1*03 and DQB1*0302 were then compared with the findings for other populations of the world (table 2). The comparison strongly supported the importance of ethnic background and indicated that the relative importance of different genes may vary in different populations studied. One of the important observations was that the Indian patients with SLE with HLA-DRB1*03 association overlap with the Spanish, Canadian, white, and Mexican populations. However, the Malaysian and Taiwanese population, who are predominantly mongoloid race, showed a different HLA association. All the patients with severe SLE studied presented with a high titre of antinuclear factor, antihistone antibodies, and anti-Sm antibodies. Further, it was found that 54% of the patients were anti-dsDNA positive, 10% had anti- Ro/SS-A antibodies, 22% had anti-La/SS-B antibodies, 14% had both Ro SS-A and La SS-B antibodies.
In SLE multiple loci within the MHC have been implicated in susceptibility-like HLA class II alleles, complement components, and TNF loci.6–11 HLA-DR2 and DR3 are both known to be associated with SLE and inheritance of both DR2 and C4B null alleles confers a higher relative risk. HLA-DQ1 and DQ2 are also found to be associated with Ro, La, Sm, and dsDNA autoantibodies. The HLA-DR2, DQ1 haplotype associated with SLE has low TNF levels.4 A review based on the clinical and laboratory measurements in Indian patients with SLE showed a higher proportion of alopecia, renal lupus, oral ulcers, and neurological involvement, reaching statistically significant levels when compared with other racial groups.1 HLA studies from patients with SLE from northern India showed an appreciable risk of HLA-DR4 among the patients, and additionally, the haplotype B8-DR4 was often found in the patient group.2 However, HLA-DR3 and TNF promoter polymorphisms in the white patients with SLE were independently associated.5 Interethnic differences in the associations of TNF promoter polymorphism with SLE have also been reported from the UK, South Africa, and Iceland.5 One of the interesting observations12 was the increased incidence of renal side effects with disease modifying drug “auranofin” in patients with rheumatoid arthritis, who incidentally inherited DRB1*0301, an allele linked strongly with SLE in his study as well as in ours. It may be relevant to mention here that the DRB1*0301 allele is present in 6.7% of the normal population, hence they may also become susceptible to the nephrotoxic effect of these kind of drugs when they receive treatment for various disease conditions.
In conclusion our results show, firstly, a significant twofold increase in the odds ratio for the presence of HLA-DRB1*03, and DQB1*0302, alleles and, secondly, a significant twofold decrease in the odds ratio for the presence of HLA-A19, DRB1*14(6), DRB1*1001, and DQB1*0203 alleles among the western Indian patients with SLE. Finally, the association supports the importance of ethnic background and indicates that the relative importance of different genes may vary in different ethnic populations around the world.