CONCISE COMMUNICATIONS

Table 1. Comparison of HLA class I phenotypes in spondylarthro- pathy (SpA) patients, control patients, and the general Lebanese population *

Lebanese population

SPA Serre et a1 Abdelnoor patients Controls (ref. 5 ) (ref. 6) Mansour

Locus (n = 65) (n = 139) (n = 315) (n = 416) (n = 130)t

A1 A2 A3 A1 1 A19 A23 A24 A26 A28 A29 A30 A3 1 A32 A33 BS B7 B8 B13 B14 B18 B27 B35 B37 B38 B4 1 B44 B45 B49 B50 B5 1 853 B55 BS8 861 B62 B70

21.5 41.5 18.5 7.7 3.1 9.2

21.5 4.6

15.4 7.7

12.3 6.1 7.7 6.1 1.5 7.7 3.1 9.2 7.7

13.8 13.8 32.3 3.1

13.8 7.7

12.3 1.5 6.1 3.1

18.5 10.8 1.5 1.5 1.5 1.5 1.5

16.4 40 12.9 13.6 0 8.5

18.6 12.1 13.6 4.3 9.3 1.4 9.3

10 0 5 5.7 1.4

13.6 17.9 1.4

29.3 2.1 6.4

13.6 10.7 2.9 4.3 7.4

14.3 0.7 3.6 0.7 1.4 1.4 2.9

15.1 21.2 11.9 4.2

NA NA NA NA 7.6 2.8

NA NA NA NA 9.8 3.5 1.8 6.1 2.7 8.1 1.7

26.4 NA 2.9

NA NA NA NA NA NA NA NA NA NA NA NA

27 40 21 5

NA NA NA NA 10 10 11 5 5 8

23 7 6 9 5 9 2

32 1.5

NA 1.5

NA NA NA NA NA NA NA NA NA NA NA

19.2 40 16.1 6.9

27.7 5.3

39.2 8.4 7.6 6.9

10 0

13 6.1

26.9 10.7 0.8 4.6

10 14.6 0.8

34.6 3 6.9

14 11.5 2.3 9.2 5.3

14.6 1 .s 3 2.3 1.5 2.3 1.7

* Values are the percentages of subjects with the different phenotypes identified. Some rare phenotypes found in the general population but not in our patients are not shown. NA = data not available. i Unpublished recent data from our blood bank, showing serotypes absent from previous studies.

negative patients, in contrast to what has recently been de- scribed (9). No other class I allele was significantly associated with SpA in our study, but HLA class I1 typing is in progress to better characterize our population. Our results indicate that non-B27 disease-predisposing factors play a much stronger role in the disease in this particular population than in others. This could be related to the peculiar history and population mixing in our country. Further studies are needed to confirm the weak link between HLA-B27 and SpA in other popula- tions of the Middle East, and to observe if B27-negative patients have milder clinical disease than those who are

389

B27-positive. Family studies are also needed to identify the gene(s) associated with SpA in Lebanon.

Supported by grants ji-om the National Scientific Research Council, Beirut, Lebanon, and from pfizer Lebanon. Drs. Awada and Tamouza contributed equally to this work.

1.

2.

3.

4.

5.

6.

7.

8.

9.

H. Awada, MD R. Baddoura, MD R. Naman, MD, FRCP S. Klayme, PhD I. Mansour, PhD H6tel Dieu de France Beirut, Lebanon R. Tamouza, MD F. Marzais C. Raffoux, MD A. Toubert, MD D. Charron, MD H6pital Saint Louis Paris, France

Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, Cats A, Dijkmans B, Olivieri I, Pasero G, Veys E, Zeidler H, the European Spondylarthropathy Study Group: The European Spondylarthropathy Study Group preliminary criteria for the clas- sification of spondylarthropathy. Arthritis Rheum 34:1218-1227, 1991 Khan MA: HLA-B27 and its subtypes in world populations. Curr Opin Rheumatol 7:263-269, 1995 Van der Linden S, Valkenburgh HA, Cats A: Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modi- fication of the New York criteria. Arthritis Rheum 27:361-368, 1984 Wilkens RF, Arnett FC, Bitter T, Calin A, Fisher L, Ford DK, Good AE, Masi AT: Reiter’s syndrome: evaluation of preliminary criteria for definite disease. Arthritis Rheum 242344-849, 1981 Serre JL, Lefranc G, Loiselet J, Jacquard A: HLA markers in six Lebanese religious subpopulations. Tissue Antigens 14:251-255, 1979 Abdelnoor M, Abdelnoor A: Comparative study of HLA-A, B and C frequencies in Christians and Moslems in Lebanon. Leb Science

Amor B, Dougados M, Listrat V, Menkes CJ, Dubost J, Roux H, Benhamou C, Blottman F, Pattin S, Paollogi JB: Evaluation des critkres des spondylarthropathies d’Amor et de 1’European Spond- ylarthropathy Study Group (ESSG). Ann Med Interne (Paris) 14235-89, 1991 Robinson WP, van der Linden SM, Khan MA, Rentsch H-U, Cats A, Russell A, Thomson G: HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum 32:1135-1141, 1989 Yamaguchi A, Tsuchiya N, Mitsui H, Shiota M, Ogawa A, Toku-

Bull 6167-71, 1993

naga K, Yoshinoya S,.Juji T, Ito K Association of HLA-B39 with HLA-B27-negative ankylosing spondylitis and pauciarticular juve- nile rheumatoid arthritis in Japanese patients: evidence for a role of the peptide-anchoring B pocket. Arthritis Rheum 38:1672-1677, 1995

Interleukin-1 receptor antagonist gene polymorphism in Japanese patients with systemic lupus erythematosus

Recently, associations of interleukin-1 receptor antag- onist (IL-1Ra) gene polymorphism with several inflammatory

390 CONCISE COMMUNICATIONS

Table 1. Frequency of each interleukin-1 receptor antagonist (IL- 1Ra) gene allele, expressed as a percentage of the total alleles in Japanese healthy controls and Japanese patients with systemic lupus erythematosus (SLE)

Healthy controls SLE patients Allele (n = 218)* (n = 196)* P t

ILlRN*l (4 repeats) 95.0 88.3 <0.05 IL1RN*2 (2 repeats) 4.1 9.7 <0.05 IL1RN*3 (5 repeats) 0.0 1.0 NSS ILlRN*4 (3 repeats) 0.9 1 .0 NSS

* Total number of alleles of the IL-1Ra gene. t By chi-square test. $, NS = not significant (also not significant by Fisher’s exact test).

diseases have been reported (1,2). There is a variable-length polymorphism (a variable-number tandem repeat of an 86- basepair sequence) in intron 2 of the IL-1Ra gene (1). Blakemore et al have reported an increase in both frequency and carriage rate of an allele (the 2-repeat allele, ILlRN*2) in white patients with systemic lupus erythematosus (SLE) (2). They have also found associations of the allele with severity of SLE and with the presence of photosensitivity and discoid skin lesions (2). We have recently reported a strong correlation between serum IL-1Ra concentration and SLE Disease Activ- ity Index (SLEDAI) score (3) in patients with SLE (4). Because the SLEDAI score is correlated with the severity of the disease, we studied the polymorphism of the IL-1Ra gene in Japanese patients with SLE and examined whether a particular allele may influence circulating IL-1Ra concentra- tions. We also wished to know whether the allele, ILlRN*2, is associated with SLE irrespective of race.

Table 1 shows the frequency of each allele of the IL-1Ra gene in control and SLE groups. Each allele was determined by polymerase chain reaction typing according to the method described by Blakemore and colleagues (2). In both groups of Japanese subjects, the frequency of ILlRN*2 was considerably lower than that reported in white subjects (24.1% in the white control group and 32.7% in the white SLE group) (2). However, the frequency of ILlRN*2 in Japanese patients with SLE was significantly higher than that in Japanese controls, as had been found in the study of white subjects (2).

The association of ILlRN*2 with particular clinical features of SLE (i.e., individual elements of the American College of Rheumatology criteria [5]) was examined in 83 Japanese patients (16 of whom had at least 1 copy of ILlRN*2 and 67 of whom had no ILlRN*2). We observed a significant increase in the frequency of photosensitivity among patients with ILlRN*2 (62.5% of patients with IL1RN*2 versus 31.3% of patients without the allele; P = 0.021) and a nonsignificant trend toward an increase in the frequency of discoid skin lesions (43.8% of patients with versus 20.9% of patients without ILlRN*2; P = 0.059). However, we did not detect an association of ILlRN*2 with severity of SLE in Japanese patients (i.e., no association with renal or neurologic involvements).

Because the variable-length polymorphism of the IL-

1Ra gene might influence the production of IL-1Ra invivo (6), we examined serum IL-1Ra concentrations in patients with active SLE with or without IL1RN*2, Serum IL-lRa concen- trations were determined by enzyme-linked immunosorbent assay (R & D Systems, Minneapolis, MN) in 8 patients with ILlRN*2 (3 with ILlRN*2,*2 and 5 with ILlRN*2,*1 [the 4-repeat allele]) and 26 patients with ILlRN*l,*l. There was no significant difference in mean serum IL-1Ra concentrations between the 2 groups (mean 2 SD 2.3 2 1.4 ng/ml in the patients with at least 1 copy of IL1RN*2 versus 2.6 2 1.5 ng/ml in those with ILlRN*1,*1). Because only a small number of serum samples from patients with ILlRN*2 were available for analysis, we cannot exclude the possibility that the lack of statistical significance may be due to sample size.

In this study, we observed an association between ILlRN*2 and SLE, and in particular photosensitive SLE, in Japanese patients similar to that reported for white patients. This finding indicates that IL-1Ra gene polymorphism may constitute a common genetic susceptibility factor for skin lesions such as SLE photosensitivity. Although the lack of a significant difference in circulating IL-1Ra concentrations between patients with and those without IL1RN*2 does not enable one to draw a definitive conclusion, our results suggest that the number of 86-bp repeats in intron 2 may not greatly influence IL-1Ra productipn by macrophages in pathologic lesions. Because ILlRN*2 is associated with skin lesions irrespective of race, we cannot exclude the possibility that the polymorphism may affect the intracellular synthesis of IL-1Ra by keratinocytes and may change the balance of IL-1Ra and IL-la! in these cells. Further study is needed to elucidate this.

Supported in part by grants from the University of Tsukuba Research Project and the Ministry of Health and Welfare, Japan.

Hiroshi Suzuki, MD Yoshiki Matsui, MD Heihachiro Kashiwagi, MD University of Tsukuba Tsukubashi, Japan

1. Clay FE, Cork MJ, Tarlow JK, Blakemore AIF, Harrington C, Lewis F, Duff G W Interleukin 1 receptor antagonist gene poly- morphism association with lichen sclerosis. Hum Genet 94:407-410, 1994

2. Blakemore AIF, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff G W Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arthritis Rheum 37:1380-1385, 1994

3. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH, and the Committee on Prognosis Studies in SLE: Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 35:630-640,1992

4. Suzuki H, Takemura H, Kashiwagi H: Interleukin-1 receptor an- tagonist in patients with active systemic lupus erythematosus: enhanced production by monocytes and correlation with disease activity. Arthritis Rheum 38:1055-1059, 1995

5. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Tala1 N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1272-1277, 1982

6. Danis VA, Milligton M, Hyland VJ, Grennan D: Cytokine produc- tion by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymor- phism. Clin Exp lmmunol99:303-310, 1995