A total of 46 cases with SLE and 46 healthy controls were enrolled in this study. There were 44 (95.65%) female and 2 (4.35%) male in cases. Their mean age was 27.05 ± 8.17 years (mean ± SD), ranging from 12.5-45 years. In control group, there were 44 (95.65%) female and 2 (4.35%) male with a mean age of 26.91 ± 5.96 years (mean ± SD), ranging from 16-45 years. In both case and control group female: male ratio was 22: 1 in table I
first group less than 30 years and second group ≥30 years on the basis of their age of onset of disease. There were 36 (78%) cases in first group and 10 (22%) in second group in fig. 1
Out of 46 cases, the most frequently identified HLA-DR was DR2 (86.96%) followed by DR7 (43.48%), DR4 (17.39%), DR5 (17.39%), DR6 (13.04%), DR10 (13.04%), DR1 (4.35%) and DR3 (4.35%). HLA-DR8 and DR9 were not expressed by any cases. Out of 46 controls, the most frequently identified HLA-DR was DR2 (58.70%) followed by DR7 (41.30%), DR4 (21.72%), DR6 (19.57%), DR10 (19.57%), DR5 (10.87%), DR1 (8.70%), DR3 (8.70%), DR8 (8.70%) and DR9 (2.17%) fig 2.
Positive association with SLE was observed for HLA-DR2 (86.96% Vs. 58.70%,
c = 0.036, RR = 4.6914, 95% CI = 1.658 to 13.267) when compared with healthy controls. There were a weak increased of HLA-DR7 and HLA-DR5 in cases Vs. controls but it was not statistically significant at 5% signific-ance level. HLA-DR1, DR3, DR4, DR6, DR8, DR9 and DR10 were found to be slightly de-creased in cases as compared to controls. RR of these antigens was less than 1 but at 95% CI their association was not significant in table II
HLA-DR frequencies in cases that had disease onset less than 30 years of age were DR2 (86.11%), DR7 (44.44%), DR5 (19.44%), DR10 (13.89%), DR4 (16.67%), DR3 (2.78%), DR1 (5.56%) and DR6 (11.11%). In second group HLA-DR frequencies were DR2 (90%), DR7 (40%), DR4 (20%), DR6 (20%), DR3 (10%), DR5 (10%), and DR10 (10%). HLA-DR1 was not expressed by any cases in this group. In both groups no cases express DR8 and DR9 in table III
When comparison was made in these 2 groups, no positive association of HLA-DR with age of disease onset was found.
Systemic lupus erythematosus (SLE) is a geneti-cally complex disease. The course of this chronic multisystem inflammatory disease may range from benign to fatal like organ failure (e.g., kid-ney) or malignancy. In spite of lots of study it is difficult to say the exact etiological factors caus-ing this disease. The importance of genetic fac-tors for development of disease has been con-firmed. But it is still controversial the contribu-tion of immunogenetic factors causing the dis-ease. A lot of work has been done to find out the degree and nature of association of human leukocyte antigen (HLA) and SLE. Genome wide association studies and haplotype study persuasively demonstrated the presence of SLE susceptibility factors in HLA-DRB1 and DQB1 alleles. Due to high degree of polymorphism within the genes of HLA, the distribution of HLA antigen is different according to race. Due to this variation, degree of association between SLE and specific genes of the major histocompatibility complex (MHC) also varies from one population group to another. This is the first description of immunogenetics of SLE in Bangladesh.
A total 92 study population (46 cases & 46 con-trols) were enrolled in this study. Mean age of cases at study entry was 27.05 ± 8.17 years which is almost similar to the findings of other studies. Study by Sirikong et al.
, Hussain et al.
, Fouad et al. and Castano-Rodriguez et al.
aver-age age was stated as 30.1 ± 10.5, 30.35 ± 1.687, 28 years and 34.7 ± 12.9 years in their studies, respectively.5,15-17
These findings indicate that SLE develops predominantly at 3rd
decade of life. In this study, majority of the cases were female that was in agreement with other studies. Study among Pakistani population, Taiwan population, Northern Italian population, black South Africans and Malay people reported almost similar findings.16,18-21
All these studies indicate that SLE is more prevalent among fe-male. Higher prevalence of SLE in female could be due to direct effects of sex chromosomes or indirect effects of chromosomes such as those mediated by sex hormones.22
A recent study showed a 14 times higher incidence of SLE among Klinefelter’s, defined by 47, XXY karyo-types, than normal men. This risk (1: 900) is closer to the female risk of SLE (1: 1400 in Eu-ropean ancestry).23
The recent identification of IRAK1 gene supports direct effects of chromo-some X, possibly through gene dosage effects. In addition to IRAK1, a risk haplotype in the me-thyl-CpG-binding protein 2 gene (MECP2) has been associated with SLE and suggests a poten-tial role for DNA methylation in the pathogenesis of SLE. As with IRAK1, mapping of MECP2 on chromosome X raises the possibility of a gene dosage effect that may contribute to increased prevalence of SLE among women.22
Abnormal aestrogen metabolism has also been demonstrated in patients with SLE of both sexes. The con-centrations of androgens correlate inversely with disease activity. Excessive aestrogen causes pro-longed survival of autoimmune cells and increase Th2 cytokine production which in turn stimulates B cells to produce autoantibodies.12
In this study, the most frequent HLA-DR ob-served in cases was HLA-DR2. A positive asso-ciation of DR2 with SLE was observed when compared with controls. Similarly among Thais, Japanese, Malay, South Africans, Taiwanese and Kuwaiti populations with SLE, the frequency of expression of HLA-DR2 was more. In these stu-dies, positive association of HLA-DRB1*1502 (DR2) and DQB1*0501 among Thai population; HLA-DRB1*1501 (DR2), DRB5*0101 and DQB1*0602 among Japanese; HLA-DR2, DQB1*0501 and DQB1*0601 in Malay people; HLA-DR2 in black South Africans; HLA-DR2 among Kuwaiti population and Baltimore people; and HLA-DR2 among Chinese population have been reported.15, 17, 20, 21, 24-28
Haplotype analysis showed that haplotype containing DRB1*1501 and DRB1*0801 showed risk allele for SLE susceptibility and similar association was also showed in another study.7,29
Haplotype study in Saudis also showed association of HLA-DRB1*15 and DQB1*06 with SLE.30 Several other studies also showed association of HLA-DR2 with SLE in other populations such as study in Californiaand Latin American populations HLA-DR2 and DR3 showed the strongest association for susceptibility to SLE.5,31
But there are several studies that did not have similar findings with present study. Study among Pakistani population, western Indian, Egypt people showed different types of association other than HLA-DR2.16,32,33
Other studies among Norwegians, Spanish, Oklahoma, Toronto, UK, Southern Sweden and Netherland patients with SLE also showed positive association of DR3 with SLE.11,34-39
Study in Canada reported that among SLE patients with French origin HLA-DQ6 was positively associated and among non French Canadian SLE cases HLA-B8, DR3, Dw24 and DQ2 were associated.40
In all these studies, predominant HLA-DR among SLE patients was DR3 where as in the present study association of HLA-DR3 with SLE was not significant. A large series study among European SLE patients both HLA-DR2 and DR3 were found to be positively associated with SLE.41
A wide variation of negative association of HLA-DR with SLE was reported in many studies. A study among Toronto people reported a negative association of HLA-DR1, DR6 and DR7 with SLE.37
Negative association of HLA-DR7 with SLE in UK and HLA-DRB1*04, DRB1*07, DRB1*08 and DRB1*15 in Pakistani patients have also been reported.16,38
Some other studies also reported that HLA-DR9 and DR13 (split antigen of DR6) alleles may be protective alleles for Portuguese, Gypsies and Japanese people against SLE.24,42,43
A large series study of HLA class II alleles among European SLE patients showed negative association of some HLA class II antigens with SLE.41
Similarly negative association of HLA-DR5 with SLE among Latin American people has also been found.5
But in this study no HLA-DR was found to be negatively associated with SLE. Although, frequency of HLA-DR1, DR3, DR4, DR6, DR8, DR9 and DR10 decreased in cases compared to controls and their RR is less than 1 but at 95% CI their association was not significant (Table II). In future, if another study will do with large sample size these alleles may turn into negatively associated with SLE.
Some studies did not find any HLA-DR associa-tion with SLE. Association of HLA-DR with SLE among Jamaican, Iceland, Northern Italian, American Blacks, Chinese and Bulgarians SLE patients could not.19,44-48
These variations in the expression of HLA-DR among SLE patients re-ported in different studies and present study may be due to differences in ethnic, environmental exposure among study populations and con-founding factors in the extended MHC (xMHC) due to strong linkage disequilibrium.49
Although few studies showed an independent association of HLA class I with SLE, but the association was not consistent with the findings of other studies. Moreover, increase frequency of HLA-DR2 (58.70%) among control population compared to other DR in this study also indicate that these people may be at risk of development of SLE in future life if they exposed to appropriate envi-ronmental stimuli.
So, from the findings of above studies it has been revealed that some HLA alleles are protective and some are associated with increased risk for development of SLE. Several studies have been carried out to understand the mechanisms underlying MHC association with SLE, but yet not clearly understood. But it has been hypothesized that physiochemical differences in the nature of critical amino acid side chains that shape the peptide-binding groove in the DRβ chain might be related to the risk or protection conferred by HLA-DRB1 alleles associated with SLE.5
In this study, it was already reported that, the cases were divided into 2 groups according to their age of onset of disease shown in fig. 1. When frequency of HLA-DR was compared among 2 groups, both groups have almost same frequency of HLA-DR irrespective of their age of onset of disease. Although frequency of HLA-DR2 was increased in second group but it was not statistically significant. Similarly, study in Malay people any HLA-DR association with age of onset of disease could not confirmed.21
But another study reported increased frequency of DR3 bearing haplotype in patients with disease onset before 30 years of age compared to those above 30 years of age.50
This could be explained by the difference in race/ ethnic of study popula-tions and small sample size. To get a better pic-ture regarding association of HLA with age of onset of disease large sample size from multicen-ter analysis is needed.
Thus, the ethnic difference among study popula-tions, sample size of different study and hetero-genecity of the HLA could explain the contradic-tory results found in different studies mentioned above.
Therefore, the results of this study further con-firmed that HLA-DR particularly DR2 has role in development of SLE, may be by influencing production of specific autoantibodies. But it also has been observed that onset of SLE is more likely the consequence of cooperation of many other genes including HLA-DR, interacting with appropriate external stimuli. Because of small sample size, the study population in this study may not represent the entire SLE cases in Bangladesh. This study only included certain serological types of HLA. As HLA-DR is in linkage disequilibrium with other HLA, study of other loci of HLA at allele level thus recommend for proper identification of HLA association with SLE.
Authors are thankful to Dept. of Rheumatology, BSMMU and Dept. of Micro-biology and Immunology for their support to conduct the study. Authors are also thankfulto the lupus patients and all the medical persons who were control population, for their coopera-tion and support that made this study possible.
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