European Journal of lmmunogenetics (1994). 21, 457-460

THE ASSOCIATION BETWEEN COELIAC DISEASE, DERMATITIS HERPETIFORMIS AND CERTAIN

HLA-ANTIGENS I N ICELANDERS

A . ARNASON,* I . SKAFTAD6TTIR,* J . SIGMUNDSSON,t E. MOONEY,' J . BJORNSSON,' N. CARICLIA,' G. PALSSON** & H. GUDJ6NSSONt

*Department of Pathology, Immunogenetics Unit and 'Department of Pathology, University of Iceland. 'Department of Medicine and **Department of Paediatrics, University Hospital Iceland,

'Lreknastodin. Uppsolum, Rekjavik and 'District Hospital. Akureyri, Iceland

(Received 27 April 1994; revised 28 Julv 1994; accepted 6 August 1994)

S U M M A R Y

Twenty-eight cases of coeliac disease (CD) and seven of dermatitis herpetiformis (DH) have been verified in Iceland. Standard serological techniques were used for HLA typing. Twenty-five individuals with CD were typed, 21 (84%) of whom carried DR3,DQ2. Twelve of these 25 (48%) had DR3,DR7, DQ2, which makes them possibly homozygous for DQ2, and suggests that homozygosity of DQ2 increases the risk for CD. The four DH patients that were typed all had HLA-B8,DR3,DQ2. It is concluded that CD and DH are associated with DR3, DQZ in Icelanders.

INTRODUCTION

The association of certain HLA antigens with coeliac disease (CD) and dermatitis herpetiformis (DH) has been known for a long time (Tiwari & Terasaki, 1985). Sollid et al. (1989). demonstrated that the primary association was with a particular HLA-DQ cc/p heterodimer in coeliac disease. Both diseases are precipitated by gluten ingestion (Fry et al., 1973; Katz et al., 1980; Trier, 1991). In CD this results in atrophy of the intestinal villi and formation of antigliadin antibodies (Volta et al., 1988). Family studies have shown that a first degree relative of a CD patient has a 10% chance of having the disease also (Trier, 1993).

DH is a skin disease with a chronic, pruritic papulovesicular eruption that is usually symmetrically distributed on the extensor surfaces, upper back and buttocks. Ig A deposits are most commonly found in a granular pattern in the dermal papillae although other patterns have been described using immunohistological methods. The granular deposits most frequently are found in 85-95% of patients and are associated with certain HLA antigens. Gluten sensitive enteropathy is found to occur in DH patients (Katz et al., 1980; Hall, 1987). In Western and Northern Europe gluten intolerance is not uncommon, but the prevalence rates of CD vary considerably. In Western Ireland it is 1:300 (Mylotte

Correspondence: Dr Alfred Arnason, Department of Pathology, lmmunogenetics Unit, University Hospital, Reykjavik, Iceland.

451

458 A. Arnason et al. et al., 1973) and in other Northern European regions i t is 1:1000-1:2OoO (Tighe et al., 1992; Trier, 1991). The prevalence in Iceland is much lower at 1:10000 (Sigmundsson et al., 1992) than in other Nordic countries (Midhagen etal. , 1988). In Northern Europe CD is mainly associated with the HLA- B8, DR3, DQ2 haplotype, but in Southern Europe there is also an association with DR5,DQ7/DR7,DQ2 heterozygotes (Sollid & Thorsby, 1990; Trier, 1991; Tighe et al., 1992). In view of this we decided to investigate the association of HLA with CD and DH in Iceland.

M A T E R I A L S A N D M E T H O D S

At the time of study there were 28 CD patients known in Iceland of whom 24 adults and one child were available for HLA typing ( 18 females and 7 males).

The diagnostic criteria for adult CD were: ( I ) subjective and/or objective evidence of intestinal malabsorbtion; (2) biopsy of the small intestine showing total or subtotal villous atrophy; and (3) unequivocal clinical improvement after gluten withdrawal.

The diagnostic criteria for CD in children were the original criteria of the European Society for Pediatric Gasteroenterology and Nutrition (Meeuwisse, 1970). Only seven patients who had DH con- firmed by clinical, histological and immunohistological methods were known to be alive at that time. Four were available for investigation. All were female. The control group comprised 165 unrelated individuals. Tissue typing was carried out using the lymphocytoxity test. Only antisera to three DQ specificities, DQ I , DQ2 and DQ3, were available to us at the time of study. Haldane's modified ver- sion of Woolf s formula was used to calculate the relative risk (Woolf, 1955; Haldane, 1956; Tiwari & Terasaki, 1985). Probability ( P ) values were corrected by multiplying by the number of antigens tested.

R E S U L T S

The four patients suffering from DH all had 98, DR3, DQ2. One of the patients was homozygous for the haplotype B8,DR3,DQ2 as judged from a family study. The results for the CD patients are pre- sented in Table 1 which shows that the haplotype found in Iceland is the Northern haplotype DR3- DQ2. It is noteworthy that 48% of subjects had DR3, DR7, DQ2, whilst only 1.8% of the control group had that combination giving a relative risk of 43 (Table I ). A brother and a sister both had CD and were HLA identical: HLA-A2, A9; B8.B 12; DR3,DR7; DQ2. Their paternal aunt also had CD and shared one haplotype with them: HLA-A2, A I I ; B8, B21; DR3; DQ2. No CD patient had the

TABLE. I . Association between HLA antigens and coeliac disease in Icelanders

Patients Control n = 2 5 n = 165 Significance

HLA-tyF (n, %) ( n . %) RR x 2 ( P )

B8 16(64.0) 31 (18.8) 7.42 20.33 <0.00 I DR3.DQ2 21 (84.0) 33 (20.0) 18.90 30.59 <0.00 I DR7.DQ2 I2 (48.0) 30 (I 8.0) 4.1 I 10.64 =o.o 12 DR3,DQ2/DR7,DQ2 12 (48.0) 3 (1.8) 43.00 35.00 <0.00 I

Association between CD, DH and HLA-antigens 459

southern European type DR5/DR7. The four CD patients not having DQ2 had the following HLA- types: A2,A23; B5,B7; Cw7; DR2,(DR6); DQ I .

A2,A23; B 14,B 19; Cw7; DR5; DR(9);DQ3. A2.(A28); B7,B62; Cw 1 ,Cw7; DR6,DR9; DQ I ,DQ3. A2,A3; B7,B40; Cw3,Cw7DR4,DR6; DQ I ,DQ3.

D I S C U S S I O N

The association between CD and DH and HLA-antigens has long since been established, first with HLA-B8. later with DR3 and then with DQ2 (Tiwari & Terasaki, 1985; Hall, 1987; Trier, 1991). Roep et al. (1988) demonstrated that a certain HLA-DQ a allele had a stronger association with CD than other alleles previously described. Evidence for primary association of CD to a particular HLA- DQ cdp heterodimer was given by Sollid et al. (1989). The haplotype DR3,DQ2 is found in strong association with CD in and the DQ2 is encoded by the DQAl*O501 and DQB1*0201 genes in the cis position. The DR5DQ7DR7DQ2 carry the same DQA I *0501 and DQB 1 *0201 genes in the trans position (Spurkland et al. 1990; Sollid & Thorsby, 1990). In both CD and DH the association is pri- marily with the DQ alleles, not the DP alleles (Hall et al., 1989; Spurkland e t a l . , 1990). The results of our study suggest that similar associations between HLA-haplotypes and CD occur in Iceland as in Norway (Sollid & Thorsby, 1990).

All four DH patients had HLA-B8,DR3,DQ2. One of these was homozygous for the haplotype in question (family study). None of the DH patients had DR7. Twenty-one of 25 CD patients (84%) had DR3.DQ2. Twelve of the 25 CD patients (48%) had DR7,DQ2. All that had DR7, DQ2 also had DR3.DQ2 i.e. they were presumably homozygous for DQ2, and probably carrying DQB I *0201 on both chromosomes. This was not verified at the time of study, as we could not type at molecular level.

The occurrence of DR3,DQ2/DR7,DQ2 is far higher than expected with a relative risk of 43, and possibly the homozygosity of the DQB 1 *0201 gene increases susceptibility for CD. No DH or CD patient had the DR5/R7 phenotypes found in southern European populations.

Clearly, the next step should be a study of these haplotypes at molecular level.

R E F E R E N C E S

FRY, F.. SEAH, P.P., RICHES, D.J. & HOFFBRAND, A.V. ( I 973) Clearance of skin lesions in dermatitis herpetiformis after gluten withdrawal. Lancet, 1,288.

HALDANE, J.B.S. (1956) The estimation and significance of the logarithm of a ratio of frequencies. Annals of Human Generics, 20,309.

HALL, R.P. ( 1987) The pathogenesis of dermatitis herpetiformis: Recent advances. Journal of the American Academy ofDermatology. 16, I 129.

HALL, R.P., SANDERS, M.E., DUQUESNOY, R.J., KATZ, S.I. & SHAW, S. (1989) Alterations in HLA-DP and HLA- DQ antigen frequency in patients with dermatitis herpetiformis. Journal of Investigative Dermatology, 93,501.

KATZ, S.I.. HALL, R.P., LAWLEY, T.J. & STRORER. W. (1980) Dermatitis herpetiformis: The skin and the gut. Annals of Internal Medicine, 93,857.

MEEUWISSE, G.W. (1970) Diagnostic criteria in coeliac disease. Acta Paediafrica Scandinavica. 59,461. MIDHAGEN, G. , JARNEROT, G. & KRAAZ, W. (1988) Adult coeliac disease within a defined geographic area in

Sweden: a study of prevalence and associated diseases. Scandinavian Journal of Gastroenterology. 23, IOOO. MYLOTTE, M.. EGAN-MITCHELL. B., MCCARTY. C.F. & MCNICHOLL, B. (1973) Incidence of coeliac disease in the

West of Ireland. British Medical Journal. 1,703. POWIS, S.H.. ROSENBERG, W.M.C., HALL, M., MOCKRIDGE, I., TONKS, S., IVINSON, A,, CICLITIRA, P.J., JEWELL,

D.P.. LANCHBURY. J.S., BELL, J.I. & TROWSDALE. J. (1993) TAP1 and TAP2 polymorphism in coeliac disease. Immunogenetics, 38,345.

REIJONEN, H., ILONEN, J., KNIP, M. & REUNALA, T. ( 1991 ) Insulin-dependent diabetes mellitus associated with der- matitis herpetifomis: Evidence for heterogeneity of HLA-associated genes. Tissue Antigens, 37.94.

460 A. Amason et al. ROEP, B.O., BONTROP, R.E., PEW, AS., VAN EGGERMOND, M.C.J.A., VAN ROOD, J.J. & GIPHART. M.J. (1988) An

HLA-DQ a allele identified at DNA and protein level is strongly associated with celiac disease. Human Immunology. 23,27 I .

SIGMUNDSSON, J., BJORNSSON, J., CARIGLIA, N., PALSSON, G. & GUDJONSSON, H. (1992) Gluten6pol B islandi. Icelandic Medical Journal, 78 (suppl. 2 I ) , 67.

SOLLID, L.M., MARKUSSEN, G., EK, J., GJERDE, H., VARTDAL, F. & THORSBY, E. ( I 989) Evidence for a primary association of celiac disease to a particular HLA-DQ a l p heterodimer. Journal of Experimental Medicine. 169, 345.

SOLLID, L.M. & THORSBY, E. (1990) The primary association of celiac disease to a given HLA-DQ a l p het- erodimer explains the divergent HLA-DR associations observed in various Caucasian populations. Tissue Antigens, 36, 136.

SPURKLAND, A., SOLLID, L.M., R0NNINGEN. K.S., BOSNES, V., EK, J., VARTDAL, F. & THORSBY. E. (1990) Susceptibility to develop celiac disease is primarly associated with HLA-DQ alleles. Human Immunology, 29, 157.

TIGHE, M.R., HALL, M.A., BARBAW. M., CARDI, E., WELSH, K.I. & CICLITIRA, P.J. (1992) HLA class 11 alleles associated with celiac disease susceptibility in a Southern European population. Tissue Anrigesn. 40,90.

TIWARI, J.L. & TERASAKI P.I. (1985) HL4 and disease associations, p. 472. Springer-Verlag. New York. TRIER, J.S. (1991) Celiac sprue. New England Journal of Medicine. 325, 1709. TRIER, J.S. (1993) Celiac disease. In: Gastroinresrinal Disease (ed. by M.H. Sleisenger & J.S. Fordtran), p. 1079.

VOLTA, U., BONAZZI, C., BALWNI, A.M., LENZI, M., CASSANI, F. & PISI, E. (1988) Clinical presentation of adult

WOOLF, B. (1955) On estimating the relation between blood group and disease. Annals ofHuman Generics, 19,

WB Saunders Co., Philadelphia.

coeliac disease. Annales de Medecine Interne (Paris), 139, 123.

251.