HLA AND DISEASE ASSOCIATIONS IN IRAQ

The HLA system is deeply involved in susceptibility to a variety of diseases. Relationships between HLA and diseases are of considerable interest and importance, as they provide new tools for studying the inheritance, classification, and pathogenesis of these diseases. Studies on the distribution of HLA antigens in different populations have revealed the existence of racial variation and are therefore a prerequisite for studying HLA and disease associations in different racial groups. This study reviews six articles concerning HLA and disease in the Iraqi population. A comparison of these associations and an analysis of overall antigen frequencies among other Arab population and different ethnic groups are included. Some of our HLA-disease associations confirm other studies reported in these racial groups, while other diseases showed different HLA antigen associations from those recorded in other racial groups.


INTRODUCTION
The first indication of MHC-disease association came with the discovery that susceptibility to virus-induced Leukaemia in mice was genetically determined, and that alleles of one of the loci responsible segregated with those of H-2 system (Lilly et aI, 1964).In man, the first suggestive evidence of such an association was found by Amiel, (1967) who studied Hodgkin's disease which is analogous to the mouse Leukaemia, and found an association between this disease and a group of HLA-B Lous antigens (4C) which were later found to be the B5, B35, B 15, and B 18 cluster.During the next 25 years, a progressively larger number of diseases has been reported to have susceptibility associated with or linked to the HLA system (for review see Dausset and Svejgaad, 1977;Tiwari and Terasaki, 1985).
Studies on the distribution of HLA antigens in different popUlations have revealed the existence of racial variations which have been attributed to gene drift, gene flow, or possibly to linkage of certain immune response genes in such a way that individuals with certain phenotypes have better survival, i.e. selective advantage (Forbes et aI, 1973, Hill et aI., 1992).Therefore this racial variation in the frequency of HLA antigens may be of importance for studying HLA and disease in different racial groups.Iraq is an Arab country with a population of 16 million.Up to the present, six studies concerning disease association with HLA antigens have been accumulated.

RESULTS AND DISCUSSION
Diseases for which HLA association have been tested in Iraq are ankylosing spondylitis, Graves' disease, diabetes mellitus, coeliac disease, Lymphomas, and recurrent herpes simplex virus infection (Table 1).HLA antigens and gene frequency in the Iraqi population are shown in Table 2.When we compare antigen frequencies of the Iraqi population with other ethnic groups (Terasaki, 1980) (Table 3) it appears that HLA-A9, HLA-B5, HLA-B35 show considerably elevated frequencies within class I HLA antigens.Table 4 shows similar comparisons for HLA-DR antigens.DR2 shows the highest frequency (56%), DR5 and DR8 the lowest (0.04% for DR5 and 0.02 % for DR8).Comparing t\:lese findings with the figures for HLA-DR antigens from other Arab populations, it appears that HLA-DR7 has a 46% frequency in Saudi Arabs (Oilier et aI., 1985), while it shows only 27% in this study and 25.7 % in Tunisians (Ayad et at., 1987).HLA-DR2 occurs in 19% of Saudi Arabs and 19.3 % of Tunisians.There are no significant differences in phenotype frequencies for the other HLA-DR antigens as sho',Vn in Table 5.The frequencies of DR antigens for the three Arab populations studied are-broadly similar to those reported for several other racial groups (Tables 5 and 6).

DISEASE ASSOCIA nONS
As shown in Table 1, some of the diseases studied showed different HLA-antigens association in Iraqi Arabs when compared with other ethnic groups or, when association was with the same antigen, different relative risk values were found.
In the Iraqi population ankylosing spondylitis was observed in 0.07% (Al-Rawi et al., 1978).HLA-B27 was found in 21 out of 25 patients included in this study (84%) but in only two out of95 normal controls (2.1 %) with a relative risk of244.In Britain Brewerton and colleagues (1973) found an incidence of 96% in patients and 4% in controls.Schlosstein et al. (1973) found the incidence ofHLA-B27 to be 88 % in patients and 8% in controls in the U.S.A.
Among the auto immune diseases studied, Graves disease has a positive association with HLA-B8 in Caucasians (Grumet et aI., 1974, Whittingham et aI., 1975) while it is associated with HLA-B55 in the Japanese (Grumet et aI., 1976).In the Iraqi population Graves disease patients have a significantly increased frequency of HLA-B40 (AI-Zubaidi, 1978).In this study the frequency of B40 in patients was 4S % with relative risk of 4.46.HLA-W 19 and HLA-B3S antigens show significantly decreased frequencies.In Graves disease, there has been no previous report of negative associations in Caucasians (Grumet et af., 1974;Whittingham et af. , 1975) nor in Japanese (Grumet et al., 1976) .
Analysis of HLA antigens among Iraqi children with coeliac disease showed a significant increase in frequencies of B8 and B 12, with a relative risk of 14.0S for B8 and 4 .S8 for B 12 (Dawood et af., 1981).In this study four families were included in which one child has the disease.Four offive siblings who inherited the HLA-B8 antigen have developed coeliac disease.In one of the families both siblings have HLA-B8 but only one of them contracted the disease.Robinson et al. (197 1) and Mylotte et af.(1972) have suggested that the inheritance of coeliac disease is polygenic.This was later supported by Demarchi et af.(1979) who found strong association with both DW3 and DW7.
A study by Yen den tweel et af.(1982) showed a significant association between HLA-w33 (a split of HLA-WI9) and B-celllymphoma in Caucasoids, and between HLA-A W24 and B40 and B-cell non-Hodgkins lymphoma in Negroid patients.In the Iraqi population one study on lymphomas (Jabbar and Yassin, 1984) examined the association of lymphomas with HLA-A and B locus antigens in fifty patients from the southern region .Forty-two of these lymphomas were of non-Hodgkins type and eight patients had Hodgkins disease .In our study Hodgkins disease was found to be associated with HLA-AI, BS and B IS. None of the patients carried HLA-B8.However the number of patients was very small.Increases of HLA-A29 were found in patients with non-Hodgkins lymphoma as compared with the control group.The relative risk was 4 .S2 for HLA-A29 and 9.93 for B IS.The increased frequency of HLA-W33 reported by Yen den tweel et af.( 1982) might be comparable to our finding of an increase in the frequency of HLA-A29 because both are regarded as splits of the compound antigen , A W 19. Apart from B IS, no significant association with other antigens of the 4C group were detected.
Behbehain et af (1987) have studied HLA-A, B, C , DR and DQ antigens frequencies in Arab patients with IDDM, and found a significant positive association with HLA-DR3 and DR4 and a negative association with DR2 and DRS .HLA-B8 and B 18 also showed increased frequencies in those patients, but with a variation between the two groups studied (Gulf and non Gulf residents in Kuwait).In the Iraqi population we found highly significant associations of HLA-A I, B8, DR3 and DR4 with lODM.
These results are in agreement with those found in Caucasoids except for the association with B IS which we could not detect.The association found for HLA-A I may be due to linkage disequilibrium with B8 .B7 and DR2 have been called protective genes since they are found with much lower frequency in diabetics than in the general population (Bhatia, 1985).In the present study we have found a significant negative association between HLA-BS (not B7) and HLA DR2 and lODM.As in all reported studies, there was no HLA relationship with non insulin dependent diabetes mellitus (NlODM).
Few studies of the association between HLA antigens and recurrent herpes simplex viral infections have been undertaken.Russel and Schlant (197S) reported a significant association between HLA and recurrent herpes labialis.Volker-Dieben (1984) found that HLA-A3 was significantly more frequent in patients with recurrent herpes keratitis.Zimmerman et af.(1977) reported in increased frequency of HLA-BS in that condition .In the Iraqi population analysis of HLA antigens in 150 patients with recurrent HSV labialis compared to 176 normal Iraqi controls showed a highly significant association with HLA-A I, B5 and DR I (Jabbar et ai. 1990).HLA-A23 was also significantly associated with disease.No differences in association with these HLA antigens were found when the patients were subdivided into groups according to rate of recurrence or ELISA reading of antibody titre .Several observations suggest that antibody is not primaril y important in preventing recurrence of herpes labialis (Overall, 1984).However, there is some evidence for defects in cell mediated immunity, in otherwise normal patients with recurrent herpes labialis (Kirchner, 1982).
Differences between populations in the pattern of HLA associations with the same diseases support the view that the findings are really due to association with alleles of immune response genes in the HLA region controlling susceptibility through differences in the ability to respond to various immune stimuli (Benaceraff and McDevitt, 1972).
Such comparisons between genetically disparate groups can therefore have considerable impact on our understanding of disease heterogeneity and the inheri tance of disease susceptibility, increasing our knowledge of the biological function of the HLA system.

Table 1 .
HLA antigens and diseases studied in Iraq.

Table 3 .
HLA gene frequency (%) in Iraqi population compared with other population.

Table 4 .
The absolute number, phenotype and gene frequency of HLA-Class II antigens (DR) among Iraqi individuals.

Table 6 .
HLA-DRW Locus frequencies in Iraqi population in comparison to other population.