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The genetics of human systemic lupus erythematosus
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The genetics of human systemic lupus erythematosus John B Harley*, Kathy L Moser*, Patrick M Gaffney and Timothy W Behrens§ Major advances in understanding the genetic foundation of systemic lupus erythematosus are in the offing. Genetic association studies suggest multiple effects that include those encoded by the HLA region, the genes for Fcy receptors and other genes such as that for the mannosebinding protein. Genome scan studies suggest many (at least twelve) genetic linkages with lupus. Identifying the genes linked with lupus is likely to require many years of concerted effort, as well as the availability and evaluation of much larger pedigree collections.
Addresses *Oklahoma City US Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, Oklahoma 73 t 04, USA; e-mail: [email protected] *tOklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, Oklahoma 73104, USA; *e-mail: [email protected] :~Department of Medicine, Universityof Minnesota Medical School, Box 334 Mayo, 312 Church Street, S.E., Minneapolis, MN 55455, USA ~e-mail: gaffn001 @maroon.tc.umn.edu ~e-mail: behre001 @maroon.tc.umn.edu Correspondence: John B Harley or Kathy L Moser Current Opinion in Immunology 1998, 10:690-696 http://biomednet.com/elecref/0952791501000690 © Current Biology Ltd ISSN 0952-7915
Abbreviations FcTR Fc~ receptor Iod logarithm of odds TNF-~, tumor necrosis factor c~
Introduction Systemic lupus erythematosus is the prototype systemic autoimmune disease. There are many well described animal models of lupus which provide extraordinary opportunities to explain the complicated immunology of lupus autoimmunity and accompanying organ injury. Indeed, with immune and genetic manipulation of mice in ways never before possible, new animal models of lupus [1,2,3",4,5"] are now available. Concurrently, new technical capabilities in man promise to identify presently unknown human lupus susceptibility genes by providing the capacity to evaluate the entire human genome for the genetic risk factors in human lupus. Here we will largely ignore the work being done in experimental animal models and, instead, concentrate upon recent progress in explaining the genetics of lupus in man. Human lupus is a naturally arising, profound derangement of particular immune responses that are specific for self antigens. T h e extent of immune dysregulation is reflected
in the extraordinary quantities of autoantibodies that are often found against some self antigens, such as the antiSm autoantibody [6]. Systemic lupus erythematosus in man is an especially enigmatic disorder. Disease definition is dependent both upon satisfying a complicated formula derived from a smorgasbord of clinical and laboratory findings [7,8] and upon the basis of clinical 'experience'. These criteria for classifying lupus [7,8] are a true measure of our current state of ignorance. For example, they make no mention of the causes or etiologies of lupus. Not surprisingly, no cause of lupus is accepted by the community of scholars who study this problem and virtually all scholars of lupus would now contend that the etiology of lupus is n o t known, though evidence consistent with a viral etiology has been recently presented [9"]. It is generally agreed, however, that the origin of lupus must reside in contribt,tions both from the environment and from the genetic composition of the individual, which together generate the illness we recognize. Genes important in human lupus are being recognized in two basic ways: association and linkage. Association is the traditional approach and many susceptibility genes are known from this approach. Linkage has only been rarely attempted, which is not surprising given the complexities involved. H u m a n lupus would appear to involve many genes interacting in a myriad of complicated ways. Under these conditions, the power to reveal linkage is relatively small; nevertheless, linkage studies are underway and their initial successes promise to fundamentally change our understanding of lupus. Association studies The HLA region
Genetic association studies in lupus have been underway since before 1971, when HLA-B8 was shown to be associated with the disease [10]. T h e haplotype containing B8 and HLA-DR3 has been enriched in many populations of Northern European extraction and most of the data support the association actually being closer with I)R3 than it is with B8. Whether the true susceptibility gene is at H L A - D R , -DQ or some other nearby gene in the H L A region (e.g. the genes for the peptide transporter [TAP] or T N F - 0 0 has not been decisively determined in any population. T h e effects of many genes, apart from the B8-DR3 haplotype, are described in more than 100 publications (see [11]) though most are not sufficiently consistent between studies to be convincing. T h e hope of being able to describe the precise origin of the HLA genetic effect in lupus has been complicated
The genetics of human systemic lupus erythematosus Harley et aL
both by the multitude of effects encoded by the HLA region and the failure to find convincing HLA associations in many studies (see [11]). Perhaps the most consistent association apart from B8-DR3 is with HLA-DR2. HI,A alleles have also been examined at the level of discase expression and autoantibody production. Again, the literature is extensive (see [11]): however, the H L A associations with autoantibodies arc more consistently present than are many of the reported associations with lupus or its particular clinical manifestations. Anti-Ro and anti-l,a are associated with I)R3 or DR2; this may be more a reflection of an effect from DR3/DR2 hcterozygores and the most powerful association may' be at the I)Q alleles, which tend to be on haplotypes with I)R2 and DR3. Anti-Sin and anti-nRNP tend to be associated with alleles on a haplotype containing DR4 or a I)Q3 allele. T h e H L A associations with antibodies against D N A or lipid (anti-cardiolipin, anti-phospholipid, lupus anticoagulant or a biological false-positive screening test for syphilis) appear to be less consistent though many studies report associations between anti-lipid antibodies and DRT, DR4 or DQ7 [11,12]. A different perspective of these H I , A studies, offering much specifically detailed attribution of the observed effects and a less sceptical interpretation of the available results, has been presented by Arnett [13].
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same polymorphisnt (a G to A point mutation) of the TNF-0~ promoter at nucleotide position 308 (relative to the transcriptional start site) is associated in AfricanAmericans with lupus but, in this group, the association is independent of BS-I)R3 1191. Complement genes
Deficiency of any of the early complement components of the classical complement system has been consistently associated with lupus, especially the complement components Clq, C4 or C2. Complete dcficiency of C l q has been associated with lupus in ()vet 90% of the known instances of this deficiency [20]. C l q is encoded by three genes in tandem on chromosome 1. Defects in each of the three C l q peptide chains have been described in the affected lupus patients. Deficiencies in Clr and Cls, which are closely linked and usually deficient together, have also been found in lupus patients [21]. Complete deficiency of C4 is also associated with a very. high rate of lupus, affecting about 75% of deficient individuals. There arc two C4 genes. C4A and C4B, which have different biochemical specificities. While deficiency of any of the four alleles is associated with hlpus, the deficiency of C4A appears to be the most closely associated with lupus [22]. T h e rare patients with the absence of both alleles of both genes clearly appear to be at the greatest risk.
Despite the variation between studies (see [11]), the tendency for HLA associations with autoantibodies to be more reproducible than they are with particular clinical manifestations is consistent with a previously proposed model of lupus pathogenesis [14]. Here the genetic effects arc more directly associated with autoantibody production; the autoantibodies then interact to make complicated contributions to the clinical expressions of disease.
Absence of (]2 is relatively common in the population, with an allele frequency of 1%; thus a complete absence is predicted in 1 in 10,000 Europeans. Deficiency of C2 is also associated with lupus. About 33% of patients of European extraction who have (]2 defciency develop lupus [23]; this should account for about 3% of all lupus patients, ifa disease frequency of 1 in 1000 is asstmmd. These patients may also tend to have the anti-Ro autoantibody more commonly than would be expected otherwise [24].
T h e H L A region is clearly important. Indeed there may be too many genes, acting on lupus at multiple levels and with extremely variable impact in the groups studied, to demonstrate their respective contributions using the currently applied approaches. Dissecting these will be very difficult and would seem to require both that family-based controls be used (e.g. transmission discquilibrium testing) and that sophisticated mathentatical modeling methods be applied. Trying to locate the major effects, even with respect to the B8-DR3 haplotype, is likely to produce a multitude of apparently acceptable answers. Studies have been reported showing alleles in disequilibrium with B8-DR3; for example, the gene for Hsp70-2 in African-Americans [15] and the prolactin gene in the British [16] seem to be more closely related to the risk of lupus than DR3. Meanwhile, association at the promoter polymorphism for TNF-{x in British lupus patients appears to be dependent upon, and derivative of, an effect from elsewhere on the BS-DR3 haplotype [17,18]. In contradistinction, the
Since the M H C genes (HI,A-A, -B, -C, -DR, -DQ and -DP) and the genes for the complement components C2 and (;4 are linked and in disequilibrium with one another, the most simple apparent explanation would be that the observed association is mediated by a single effect. On the contrary, there is evidence that though the effects are linked, they make independent contributions to lupus susceptibility through C4A*Q(t and DQA*0501 [25]. Both of these alleles are on the extended B8-DR3 haplotype and, consequently, are in linkage disequilibrium with DRB*0301 (previonsly known as DR3). Mannose-binding protein
This polymorphic protein is an opsinin, directly binding to the surface of bacteria and activating complement by both the alternative and classical pathways [26-28]. Two studies of separate racial groups both show marginal statistical effects for an association of lupus with aspartic acid at amino-acid position 54 [29,30]. In studies of African-American [29] and Spanish lupus patients [31], alleles or haplotypes producing
699 Autoirnmunity
lower levels of serum mannose-binding protein were associated with increased lupus risk.
Fcy receptors Many members of the family of Fc? receptors (FcyRs) appear to be involved in the genetics of lupus. Alleles that fail to express a cell-surface product of FcyRIIIB have been fotmd in a few lupus patients [32,33]. T h e presumed rarity of this allele in the population [32-34] hints that this gene may be important for pathogenesis. FcyRIIA association with lupus has been directly demonstrated [35]. T h e two common alleles vary at the receptor's amino-acid position 131, where a histidine or an arginine is found - - referred to as H131 and R131, respectively. T h e affinity of IgG2 for FcyRIIA is reduced for the RI31 allele relative to the H131 allele; the latter is associated with lupus in both African-Americans and Koreans [36]. T h e relationship of this polymorphism to lupus susceptibility in Europeans (or European-Americans) is controversial, with some groups finding a relationship [37] and others failing to find association [35,38]. T h e H131/R131 FcyRIIA polymorphism is an example of a situation where the genotype informs us about the phenotype. In the association studies showing a relationship, the association is more powerful in lupus patients with nephritis [35,37] but the influence upon the phenotype does not end there. One study has found that lupus patients who are R131 homozygotes tend to have anti-spliceosomal antibodies, proteinuria or immune hemolytic anemia; the H131 homozygotes tend to have livedo [39]. Finally, lupus patients who are R131 homozygotes are at increased risk of invasive pneumococcal infections [40]. Recently, the distribution of alleles at a polymorphism of FcyRIIIA has been found to differ in SLE patients from that in normals [41]. When alanine is encoded at amino acid position 176 instead of phenylalanine, this natural killer (NK) cell receptor has higher apparent binding affinity for IgG1 and IgG3.
Other genes Many abnormalities have been described in lupus patients. T h e vast majority of these are a consequence of the disease process rather than the primary genetic foundation from which the other abnormalities derive. Other genes that appear to be associated with lupus include those encoding II,-10 [42,43] and the Gm allotypes of lgG (summarized by Schur [111). While not associated with lupus in all populations tested [44], IL-10 is interesting not only because alleles for it have been associated with lupus but also because elevated levels of IL-10 have been found in both patients and unaffected family members [45]. Also, a recent study has shown an interaction at the level of association
between IL-10 and/):'/-2 [46]. Finally, a haplotype of the IL-10 gcne has been associated with anti-Ro production [47], suggesting that IL-10 may also influence disease expression. Much interest has been focused upon apoptosis in recent years. T h e relevance of apoptosis to lt~pus has been clearly established, with a variety of the associated gene products being involved in apoptosis. In the first and most dramatic example, the fas gene, is responsible for the defect in the M R I , /pr//pr mouse model of lupus. Screening of 75 lupus patients for defects infas and its ligand produced only one patient with a defect in the Fas ligand, which has lead to the conclusion that defects in/?is and its ligand are associated with lupus in only a small proportion of affected patients [48]. Finally, genes modify disease e x p r e s s i o n - - a s shown for thrombosis in lupus. A polymorphism of coagulation factor V, referred to as factor V Leiden or as factor \::Q50¢,, is a relatively common polymorphism and is a risk factor for thrombosis in the general population. Though variably associated with venous thrombosis in patients with antiphospholipid autoantibodies [49-51], the most sophisticated analysis suggests that the risk of thrombosis in lupus is independently influenced by anti-lipid antibodies and by factor V:Qs°~ [52]. T h e HLA associations with the autoantibodies that tend to be tbund in the anti-phospholipid syndrome were discussed above. Meanwhile the immunochemistry of prothrombotic anti-lipid antibodies is becoming much more sophisticated, particularly with the appreciation of the importance of 132-glycoprotcin-I as an autoantigen in this system. A better tmderstanding of the various roles for the mtdtiple risk factors for thrombosis in lupus is likely to emerge.
Linkage studies An enlarging number of groups is attempting to define the linkages in human lupus. T h e first human linkage studies in lupus were done by Bias eta/. [53] who used clinical and laboratory manifestations of autoimmunity as an intermediate phenotype. Their segregation data best fit a model of at,tosomal dominant inheritance; however the poorly informative markers used, the paucity of pedigree material available to study and the probable complexity of the underlying genetics conspired against producing significant linkage results. More recent approaches that examined candidate genes have identified possible linkages on chromosome 1, with a probability level of<0.01 [54,55"]. A legion of potential candidate genes is available from association studies, from the present knowledge of the pathophysiology of lupns and from linkages in animal models which provide syntenic regions to explore in man. T h e linkage reported at Dls229 [55"] was sought in a region suspected to be syntenic with linkages reported
The genetics of human systemic lupus erythematosus Harley et aL
to fuel suspicion that the observed relationships may originate from a common genetic effect.
Table 1 Linkage with the Dls229 locus in lupus patients from California or Oklahoma. Area studied
California Oklahoma
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Number of Mean fraction informative of shared alleles sibling pairs 50 78
0.64 0.58
p-value*
Reference
0.0005 0.014
[55*] (a)
*Sum of Zs method for the combined probability (p-) value = 0.00005. (a) KL Moser et aL, unpublished data.
from three separate groups [56-58] working with backcrosses from, or derived from, the F1 of NZB x NZW murine model of lupus. Unfortunately, the map of synteny available led these investigators to explore a region telomeric to the human region syntenic to the murine linkage [55"]. Astonishingly, these investigators found linkage anyway, most powerfully with the D1s229 locus [59]. This result has been confirmed (KL Moser etaL, unpublished data; Table 1). Linkage of the region around Dls229 with lupus should now be accepted and, indeed, a possible candidate gent product that may potentially be responsible for the e f f e c t - - p o l y ( A D P - r i b o s y l ) t r a n s f e r a s e - - h a s been identified [60°']. Genome scan studies from Minnesota [61"] and Oklahoma [62"] have been completed. These two studies had quite different designs. The Minnesota study included a collection of 105 sibling pair families genotyped at 341 loci using the marker set prepared by Applied Biosystems and analyzed using a newly available muhipoint nonparametric algorithm. The Oklahoma study included 94 extended pedigrees evaluated at 324 loci, largely from the Weber Screening Set "Version 8, and analyzed using classic parametric linkage. The likelihoods were maximized for 16 loci where any of six screening models achieved logarithm of odds (lod) >1.5. Also, the Oklahoma pedigrees are about one third African-American while the Minnesota sibling pairs were 5% African-American. The two studies chose different thresholds for declaring possible linkage, with that of Oklahoma using Iod > 1.5 and that of Minnesota using lod > 1.00. T h e 16 and 12 possible linkages that were, respectively, identified are not directly comparable because of the different microsatellite markers evaluated and the different study designs employed. Since the same criteria were used for ascertaining affected subjects [7], however, we should eventually be focusing on the same underlying genetic effects. Not surprisingly, almost half (12 out of 26) of the putative linkages found in the two studies were apparently supported, at least to a modest extent (lod >0.5), in both studies; moreover, potential linkages at chromosomes lq41-42 and 20q13 were found in both studies. The putatively linked markers are sufficiently close to one another
In the Minnesota study [61"], markers near the HLA region gave the highest lod score at 6p11-21 (Table 2). Meanwhile, this region was not identified as a suspicious region in the Oklahoma study [62"] though there is some modest support for linkage. The possible explanations for this difference are legion. The most likely reason is that the heterogeneity of the genetic mechanisms leading to lupus influences the sensitivity of each collection to reveal different genes. As can be appreciated from q~able 2, there is reason to be encouraged bv the similarities between the two linkage studies as well as to be awed by the complexity of this problem. In the Oklahoma study [62°°], the most impressive effects were found in African-Americans on chromosome lq23. T h e most convincing linkage is at the Fc~'RIIA locus for the H131/R131 polymorphism with lod = 3.37 using a parametric model in extended families and increased allele sharing (p = 0.0003) among the 78 sibling pairs in this study. D1s3462 (with lod = 3.5) is telomeric to both D1s229 and the Fc'fRIIA locus and, at this point, appears to be a separate genetic effect. Perhaps the most consistent findings for linkage are found on chromosome 1. If we include Dls229 [54,55"], then there are at least five separable putative genetic linkages on chromosome 1 alone. T h e complexity of the numerous genetic effects on chromosome 1 may actually impede progress. Of these, the FcTRIIA locus is associated with lupus in other studies and is known to encode a polymorphism that changes the behavior of a protein product. Dls252 was one of the few markers used in both studies and produced lod >1.44 in both, suggesting that there may be a persistent weak effect at lp13. Both D1s3462 and the FcyRIlA locus have their greatest effects in the African-Americans (lod >3.35), of the pedigrees studied in Oklahoma. Dls3462 has nearby support for linkage at the closest marker used in the Minnesota pedigrees, DlsZ~5; however, this very marker (Dls235) was used also in the Oklahoma study and only achieved a maximum lod = 0.225 in the African-American pedigrees. Perhaps there is a major gene for lupus between Dls3462 and Dls235. T h e explanations for these findings should be forthcoming as part of the effort to reconcile the similarities and differences between the two studies. Other interesting effects are found on chromosomes 13, 14, 16 and 20 (Table 2); all have lod = 2.5 in one study or the other. The chromosome 16 effect is near linked regions in psoriasis, Blau syndrome and Crohn's disease. The chromosome 20 effect is near a linkage in psoriasis. No doubt many idiopathic inflammatory diseases, presumed to be autoimmune, will be shown to share etiologic origins and some of the same genes will participate in pathogenesis.
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Autoimmunity
Table 2 Comparison of putative linkages from the Oklahoma and Minnesota studies. (a) Putative linkages from the Oklahoma study that are supported by the Minnesota study (Iod _>0.5) OK marker D1s3462 D20s481 D4s403 D2s1391
OK group*
OK Iod
Region
MN marker
MN Iod
AA AA EA EA
3.50 2.49 2.18 2.09
lq41-42 20q13 4p15 2q21-33
D1s235 D20s119 D4s412 D2s151
1.51 1.67 0.53 1.12
(b) Additionalputativelinkagesfrom the Minnesota studythataresupported bythe Oklahomastudy(Iod 2 0.5) OK marker
OK group
OK Iod
Region
MN marker
MN Iod
D6s1053 D16s3253 D20s604 D1s252 D4s2431 D3s2406 D11s1984
AA EA EA EA EA EA AA
0.86 0.82 0.71 1.44 1.47 1.30 0.87
6p11-21 16q13 20p12 lp13 4q28 3cen-q11 11p15
D6s257 D16s415 D20s186 D1s252 D4s424 D3s1271 D11s922
3.90 3.64 2.62 1.53 1.46 1.24 1.19
(c) Putative linkages not apparently supported by the other study Region
OK group
OK marker
OK Iod
1q23
AA
FcyRIIA
3.37
13q32 14qll 11q25 11q14-23 19q13 6q26-27 lq31 12p12-11 21q21 11p13 3p21
All EA EA AA EA EA All EA EA AA AA
D13s779 D14s742 D11s912 Dlls2002 D19s246 D6s1027 ~mcl D12s1042 D21s1437 D11s1392 D3s1766
2.50 2.21 2.15 2.10 2.05 2.04 2.04 2.01 1.88 1.87 1.68
Region
MN marker
MN Iod
14q21-23
D14s276
2.81
2p15 15q26 lp36
D2s337 D15s127 D1s234
1.68 1.07 1.00
*Oklahoma pedigrees were analyzed in three groupings: African-American (AA), European-American (EA) and combined (All). Minnesota pedigrees were not subdivided for this analysis. MN, Minnesota Study [61 "°]; OK, Oklahoma study [62°°].
Indeed, the possibility that autoimmune diseases share genetic susceptibility genes is supported by a recent metaanalysis. A n u m b e r of putative genetic effects in the lupus g e n o m e scan studies are found in chromosomal regions which are possibly linked in other disorders [63]. How many genes are there likely to be in man that influence susceptibility to lupus? At this m o m e n t only a wild guess is possible and the answer is completely d e p e n d e n t upon the assumptions one chooses to make. If only the genomic regions with effects in both genome scan studies [61",62 "°] are considered, then there are at least 12 distinguishable genetic effects. At the opposite extreme, if we assume that each of the putative linkages in the two studies represents an effect of a lupus susceptibility gene, then there would be more than 100 susceptibility genes to identify for lupus. Perhaps the truth will eventually be shown to lie somewhere between 12 and over 100 genes. T h e answer to this
question will require an effort much greater than that which has brought the genetics of lupus to this point.
Conclusions Association and linkage studies have produced interesting possibilities for the susceptibility genes involved in lupus. T h e HLA region continues to be a hot-bed of findings and activity; no doubt it contains multiple genetic effects. T h e Fc receptors also appear to be very important. Exploding onto this scene, the new genetic approaches are providing new and important data that will provide a more complete picture of the genetics of lupus in man. T h e linkage studies demonstrate that a relatively large number of linkages await substantiation alung with the identification of the polymorphisms r e s p o n s i b l e for them. T h o u g h this task p r o m i s e s to be very challenging, it is within reach of existing technologies-allowing that t h e r e s o u r c e s and i n v e s t i g a t o r
The genetics of human systemic lupus erythematosus Harley eta/.
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c o m m i t m e n t are s u s t a i n e d . Finally, t h e s e g e n e s m u s t be i m p o r t a n t to t h e p a t h o g e n e s i s of l u p u s in ways that cannot at p r e s e n t be i m a g i n e d ; t h e e l u c i d a t i o n of t h e s e will p r o v i d e o p p o r t u n i t i e s to i m p r o v e prognosis, t h e r a p e u t i c s and p r e v e n t i o n .
13. Arnett FC: The genetics of human lupus. In Dubois' Lupus Erythernatosus, edn 5. Edited by Wallace DJ, Hahn BH. Baltimore: Wilkins and Wilkins; 1997:77-117.
Acknowledgements
15. JarjourW, Reed AM, Gauthier J, Hunt S, Winfield JB: The 8.5-kb Pstl allele of the stress protein gene, Hsp70-2. An independent risk factor for systemic lupus erythematosus in African-Americans? Hum Immuno/1996, 45:59-63.
\\:e ~ratefulh acknewlcd~c the National Institutes of llealth, the [.upus
Multiplcx Registry and Repository, the [ !S [)cpartmcnt of \crcrans ..\t'l:airs,our institutions and their benefactors and our professional colleagues along with the host of patients, their families and ph?'sicians fi~rtheir support of these studies.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest • " of outstanding interest
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16. BrennanP, Haleer A, On 9 KR, Worthington J, John S, Thomson W, Silman A, Oilier B: Alleleic markers close to prolactin are associated with HLA-DRB1 susceptibility alleles among women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 1997, 40:1383-1386. 17. Rudwaleit M, Tikly M, Khamashta M, Gibson K, Klinke J, Hughes G, Wordsworth P: Interethnic differences in the association of tumor necrosis factor promoter polymorphisms with systemic lupus erythematosus. J Rheumato/1996, 23:1725-1728.
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30. SullivanKE, Wooten C, Goldman D, Petri M: Mannose-binding protein polymorphism in black patients with systemic lupus erythematosus. Arthritis Rheum 1996, 39:2046-2051.
12. Granados J, Vargas-Alarcon G, Drenkard C, Andrade F, Melin-Aldana H, Alcocer-varela J, Alarc6n-Segovia D: Relationship of anticardiolipin antibodies and anti-phospholipid syndrome to HLA-DR7 in Mexican patients with systemic lupus erythematosus. Lupus 1997, 6:57-62.
31. Davies EJ, The L-S, Ordi-Ros J, Snowden N, Hillarby MC, Hajeer A, Donn R, Pilar P-P, VilardelFTarresM, Oilier WER: A dysfunctional allele of the mannose binding protein gene associates with systemic lupus erythematosus in a Spanish population. J Rheumato/1997, 24:485-488.
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32. Clark MR, Liu L, Clarkson SB, Ory PA, Goldstein IM: An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus. J Clin Invest 1990, 86:341-346. 33. Enenkel B, Jung D, Frey J: Molecular basis of IgG Fc receptor III defect in a patient with systemic lupus erythematosus. Eur J Immunol 1991, 21:659-663. 34. Fromont P, Bettaieb A, Skouri H, Floch C, Poulet E, Duedari N, Bieding P: Frequency of the polymorphonuclear neutrophil Fc gamma receptor III deficiency in the French population and its involvement in the development of neonatal neutropenia. Blood
1992, 79:2131-2134. 35. Salmon JE, Miliard S, Schachter L, Arnett FC, Ginzler EM, Gourley MF, Ramsey-Goldman R, Peterson MGE, Kimberly RP: Fc~IIA alleles are heritable risk factors for lupus nephritis in African-Americans. J C/in Invest 1996, 97:1348-1354. 36. Song YW, Han C-W, Kang S-W, Baek H-J, Lee E-B, Shin C-H, Hahn BH, Tsao BP: Abnormal distribution of the Fcyreceptor type I la polymorphisms in Korean patients with systemic lupus erythematosus. Arthritis Rheum 1998, 41:412-426. 37.
Duits A J, Bootsma H, De&sen RHWM, Spronk PE, Kater L, Kallenberg CGM, Capel PJA, Westerdaal NAC, Spierenburg GT, Gmelig-Meyling FHJ, van de Winkle JGJ: Skewed distribution of the Fc receptor Ila (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum 1995, 39:1832-1836.
38. Botto M, Theodoritis E, Thompson EM, Beynon HL, Briggs D, Isenberg DA, Walport MJ, Davies KA: Fc'/Rlla polymorphism in systemic lupus erythematosus (SLE): no association with disease. C/in Exp Immuno/1996, 104:264-268. 39. Manger K, van de Winkel JG, Kalden JR, Manger B, Wentz B, Westerdaal NA, Wassmuth R, Geiger A, Rascu A, Spriewald BM, Repp R: Fc gamma receptor Ila polymorphism in Caucasian patients with systemic lupus erythematosus: association with clinical symptoms. Arthritis Rheum 1998, 41:1161-1189. 40. Yee AMF, Ng SC, Sobel RE, Salmon JE: Fc~RIIA polymorphism as a risk factor for invasive pneumococcal infections in systemic lupus erythematosus. Arthritis Rheum 1997, 40:1180-1182. 41. Wu J, Edberg JC, Redcha PB, Bansal V, Guyre PM, Coleman K, Salmon JE, Kimberly RP: A novel polymorphism of Fc3~llla (CD16) alters receptor function and predisposes to autoimmune disease. J C/in Invest 1997, 100:1059-1070. 42. EskdaleJ, Wordsworth P, Bowman S, Field M, Gallagher G: Association between polymorphisms at the human I1-10 locus and systemic lupus erythematosus. Tissue Antigen 1997, 49:635-639. 43. Truner DM, Williams DM, Sanakaran D, Lazarus M, Sinnott PJ, Hutchinsin IV: An investigation of the polymorphisms in the interleukin-10 gene promoter. Eur J Immunogenet 199"7, 24:1-8. 44. Mok CC, Lanchbury JS, Chan DW, Lau CS: Interleukin-10 promoter polymorphisms in southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum 1998, 41:1090-1095. 45. Llerente L, Richard-Patis Y, Couderc J, Alarcon-Segovia D, Ruiz-Soto R, Alcocer-Castillejos N, Alacocer-Valera J, Granados J, Bahena S, Galanuad P, Emilie D: Dysregulation of interleukin-10 production in relatives of patients with systemic lupus erythematosus. Arthritis Rheum 1997, 40:1429-1435.
48. Wu J, Wilson J, He J, Xiang L, Schur PH, Mountz JD: Fes ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J C/in Invest 1996, 98:1107-1113. 49. Bengsten A, Z~ller B, de Frutos PG, Dahlb~ick B, Sturfelt G: Factor V: QS0S mutation and anticardiolipin antibodies in systemic lupus erythematosus. Lupus 1996, 5:598-601. 50. Montaruli B, Borchielli A, Tamponi G, Giorda L, Bessone P, van Mourik JA, Voorberg J, Schinco P: Factor V Arg s°s > Gin mutation in patients with antiphospholipid antibodies. Lupus 1996, 5:303-306. 51. Simantov R, Lo SK, Salmon JE, Sammaritano LR, Silverstein RL: Factor V Leiden increases the risk of thrombosis in patients with antiphospholipid antibodies. Thromb Res 1996, 84:361-365. 52. FijnheerR, Horbach DA, Donders RCJM, Vile H, Oort EV, Nieuenhuis HK, Gmelig-Meijling FHJ, de Groot PG, Derksen RHWM: Factor V Leiden, antiphospholipid antibodies and thrombosis in
systemic lupus erythematosus. Thromb Haemost 1996, 76:514-517. 53. Bias WB, Reveille JD, Beaty TLH, Meyers DA, Amett FC: Evidence that autoimmunity in man is a Mendelian dominant trait. Amer J Hum Genet 1986, 39:584-602.
54. Harley JB, Sheldon P, Neas B, Murphy S, Wallace DJ, Scofield RH, Shaver TS, Moser KL: Systemic lupus erythematosus: considerations for a genetic approach. J Invest Dermatol 1994, 103:144S-149S. 55. Tsao BP, Cantor RM, Kalunian KC, Chen C-J, Badsha H, Singh R, • Wallace DJ, Kitridou RC, Chen S-I, Shen Net aL: Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest 199"7, 99:725-731. In this study, evidence for linkage to D1s229 was found in a collection of 52 sibling pairs. 56. Kono DH, Burlingame RW, Owens D, Kuramoch{ A, Banders RS, Balomenos D, Theofilopoulos A: Lupus susceptibility loci in New Zealand mice. Proc NatlAcadSci USA 1994, 91:10168-10172. 57.
DrakeCG, Rozzo SJ, Hirschfeld HF, Smarnworawong NP, Palmer E, Kotzin BL: Analysis if the New Zealand Black contribution to lupus-like renal disease: multiple genes that operate in a threshold manner. J/mmuno/1995, 154:2441-2447.
58. Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK: Polygenic control of susceptibility to murine SLE. Immunity 1994, 1:219-229. 59. KotzinBL: Susceptibility loci for lupus: a guiding light from murine models? J C/in Invest 1997, 99:55?-558. 60. Tsao PB, Cantor RM, Grossman JM, Theophilov N, Wallace DJ, • - Arnett FC, Hartung K, Goldstein R, Kalunian KC, Hahn BH, Rotter Jl: ADPRTelleles from chromosome 1 q41-42 linked region are associated with SLE. Arthritis Rheum 1998, 41 :$80. The association described here may identify the gene responsible for the linkage at D1s229. Confirmation and fine mapping studies are needed. 61. Gaffney P, Kearns GM, Shark KB, Ortmann WA, Selby SA, • • MalgrenML, Rohlf KE, Ockenden TC, Messner RP, King RA et aL: A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 1998, in press. Here, the results of genotyping 105 sibling pairs are reported.
46. Mehrian R, Quismerio FP, Strassmann G, Stimmler MM, Horowitz DA, Kitridou RC, Gauderman WJ, Morrison J, Brautbar C, Jacob CO: Synergistic effect between IL-IO and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus. Arthritis Rheum 199'7, 41:596-602.
62. Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, Asundi N, • o Bruner G R, Fox J, Kelly J, Henshall S e t aL: Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome l q in African-American pedigrees. Proc Nat/Acad Sci USA 1998, in press. In this paper, putative linkages from 94 extended pedigrees are reported.
47. LazarusM, Hajeer AH, Turner D, Sinnott P, Werthighton J, Oilier WE, Hutchinson IV: Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumato/199"7, 24:2314-231 "~
63. Becker KG, Simon RM, Bailey-Wilson JE, Freidlin B, Biddison WE, McFarland HF, Trent JM: Clustering of non-major histocompatibility complex susceptibility loci in human autoimmune diseases. Proc Natl Acad Sci USA 1998, g5:9979-9984.
The genetics of human systemic lupus erythematosus John B Harley*, Kathy L Moser*, Patrick M Gaffney and Timothy W Behrens§ Major advances in understanding the genetic foundation of systemic lupus erythematosus are in the offing. Genetic association studies suggest multiple effects that include those encoded by the HLA region, the genes for Fcy receptors and other genes such as that for the mannosebinding protein. Genome scan studies suggest many (at least twelve) genetic linkages with lupus. Identifying the genes linked with lupus is likely to require many years of concerted effort, as well as the availability and evaluation of much larger pedigree collections.
Addresses *Oklahoma City US Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, Oklahoma 73 t 04, USA; e-mail: [email protected] *tOklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, Oklahoma 73104, USA; *e-mail: [email protected] :~Department of Medicine, Universityof Minnesota Medical School, Box 334 Mayo, 312 Church Street, S.E., Minneapolis, MN 55455, USA ~e-mail: gaffn001 @maroon.tc.umn.edu ~e-mail: behre001 @maroon.tc.umn.edu Correspondence: John B Harley or Kathy L Moser Current Opinion in Immunology 1998, 10:690-696 http://biomednet.com/elecref/0952791501000690 © Current Biology Ltd ISSN 0952-7915
Abbreviations FcTR Fc~ receptor Iod logarithm of odds TNF-~, tumor necrosis factor c~
Introduction Systemic lupus erythematosus is the prototype systemic autoimmune disease. There are many well described animal models of lupus which provide extraordinary opportunities to explain the complicated immunology of lupus autoimmunity and accompanying organ injury. Indeed, with immune and genetic manipulation of mice in ways never before possible, new animal models of lupus [1,2,3",4,5"] are now available. Concurrently, new technical capabilities in man promise to identify presently unknown human lupus susceptibility genes by providing the capacity to evaluate the entire human genome for the genetic risk factors in human lupus. Here we will largely ignore the work being done in experimental animal models and, instead, concentrate upon recent progress in explaining the genetics of lupus in man. Human lupus is a naturally arising, profound derangement of particular immune responses that are specific for self antigens. T h e extent of immune dysregulation is reflected
in the extraordinary quantities of autoantibodies that are often found against some self antigens, such as the antiSm autoantibody [6]. Systemic lupus erythematosus in man is an especially enigmatic disorder. Disease definition is dependent both upon satisfying a complicated formula derived from a smorgasbord of clinical and laboratory findings [7,8] and upon the basis of clinical 'experience'. These criteria for classifying lupus [7,8] are a true measure of our current state of ignorance. For example, they make no mention of the causes or etiologies of lupus. Not surprisingly, no cause of lupus is accepted by the community of scholars who study this problem and virtually all scholars of lupus would now contend that the etiology of lupus is n o t known, though evidence consistent with a viral etiology has been recently presented [9"]. It is generally agreed, however, that the origin of lupus must reside in contribt,tions both from the environment and from the genetic composition of the individual, which together generate the illness we recognize. Genes important in human lupus are being recognized in two basic ways: association and linkage. Association is the traditional approach and many susceptibility genes are known from this approach. Linkage has only been rarely attempted, which is not surprising given the complexities involved. H u m a n lupus would appear to involve many genes interacting in a myriad of complicated ways. Under these conditions, the power to reveal linkage is relatively small; nevertheless, linkage studies are underway and their initial successes promise to fundamentally change our understanding of lupus. Association studies The HLA region
Genetic association studies in lupus have been underway since before 1971, when HLA-B8 was shown to be associated with the disease [10]. T h e haplotype containing B8 and HLA-DR3 has been enriched in many populations of Northern European extraction and most of the data support the association actually being closer with I)R3 than it is with B8. Whether the true susceptibility gene is at H L A - D R , -DQ or some other nearby gene in the H L A region (e.g. the genes for the peptide transporter [TAP] or T N F - 0 0 has not been decisively determined in any population. T h e effects of many genes, apart from the B8-DR3 haplotype, are described in more than 100 publications (see [11]) though most are not sufficiently consistent between studies to be convincing. T h e hope of being able to describe the precise origin of the HLA genetic effect in lupus has been complicated
The genetics of human systemic lupus erythematosus Harley et aL
both by the multitude of effects encoded by the HLA region and the failure to find convincing HLA associations in many studies (see [11]). Perhaps the most consistent association apart from B8-DR3 is with HLA-DR2. HI,A alleles have also been examined at the level of discase expression and autoantibody production. Again, the literature is extensive (see [11]): however, the H L A associations with autoantibodies arc more consistently present than are many of the reported associations with lupus or its particular clinical manifestations. Anti-Ro and anti-l,a are associated with I)R3 or DR2; this may be more a reflection of an effect from DR3/DR2 hcterozygores and the most powerful association may' be at the I)Q alleles, which tend to be on haplotypes with I)R2 and DR3. Anti-Sin and anti-nRNP tend to be associated with alleles on a haplotype containing DR4 or a I)Q3 allele. T h e H L A associations with antibodies against D N A or lipid (anti-cardiolipin, anti-phospholipid, lupus anticoagulant or a biological false-positive screening test for syphilis) appear to be less consistent though many studies report associations between anti-lipid antibodies and DRT, DR4 or DQ7 [11,12]. A different perspective of these H I , A studies, offering much specifically detailed attribution of the observed effects and a less sceptical interpretation of the available results, has been presented by Arnett [13].
691
same polymorphisnt (a G to A point mutation) of the TNF-0~ promoter at nucleotide position 308 (relative to the transcriptional start site) is associated in AfricanAmericans with lupus but, in this group, the association is independent of BS-I)R3 1191. Complement genes
Deficiency of any of the early complement components of the classical complement system has been consistently associated with lupus, especially the complement components Clq, C4 or C2. Complete dcficiency of C l q has been associated with lupus in ()vet 90% of the known instances of this deficiency [20]. C l q is encoded by three genes in tandem on chromosome 1. Defects in each of the three C l q peptide chains have been described in the affected lupus patients. Deficiencies in Clr and Cls, which are closely linked and usually deficient together, have also been found in lupus patients [21]. Complete deficiency of C4 is also associated with a very. high rate of lupus, affecting about 75% of deficient individuals. There arc two C4 genes. C4A and C4B, which have different biochemical specificities. While deficiency of any of the four alleles is associated with hlpus, the deficiency of C4A appears to be the most closely associated with lupus [22]. T h e rare patients with the absence of both alleles of both genes clearly appear to be at the greatest risk.
Despite the variation between studies (see [11]), the tendency for HLA associations with autoantibodies to be more reproducible than they are with particular clinical manifestations is consistent with a previously proposed model of lupus pathogenesis [14]. Here the genetic effects arc more directly associated with autoantibody production; the autoantibodies then interact to make complicated contributions to the clinical expressions of disease.
Absence of (]2 is relatively common in the population, with an allele frequency of 1%; thus a complete absence is predicted in 1 in 10,000 Europeans. Deficiency of C2 is also associated with lupus. About 33% of patients of European extraction who have (]2 defciency develop lupus [23]; this should account for about 3% of all lupus patients, ifa disease frequency of 1 in 1000 is asstmmd. These patients may also tend to have the anti-Ro autoantibody more commonly than would be expected otherwise [24].
T h e H L A region is clearly important. Indeed there may be too many genes, acting on lupus at multiple levels and with extremely variable impact in the groups studied, to demonstrate their respective contributions using the currently applied approaches. Dissecting these will be very difficult and would seem to require both that family-based controls be used (e.g. transmission discquilibrium testing) and that sophisticated mathentatical modeling methods be applied. Trying to locate the major effects, even with respect to the B8-DR3 haplotype, is likely to produce a multitude of apparently acceptable answers. Studies have been reported showing alleles in disequilibrium with B8-DR3; for example, the gene for Hsp70-2 in African-Americans [15] and the prolactin gene in the British [16] seem to be more closely related to the risk of lupus than DR3. Meanwhile, association at the promoter polymorphism for TNF-{x in British lupus patients appears to be dependent upon, and derivative of, an effect from elsewhere on the BS-DR3 haplotype [17,18]. In contradistinction, the
Since the M H C genes (HI,A-A, -B, -C, -DR, -DQ and -DP) and the genes for the complement components C2 and (;4 are linked and in disequilibrium with one another, the most simple apparent explanation would be that the observed association is mediated by a single effect. On the contrary, there is evidence that though the effects are linked, they make independent contributions to lupus susceptibility through C4A*Q(t and DQA*0501 [25]. Both of these alleles are on the extended B8-DR3 haplotype and, consequently, are in linkage disequilibrium with DRB*0301 (previonsly known as DR3). Mannose-binding protein
This polymorphic protein is an opsinin, directly binding to the surface of bacteria and activating complement by both the alternative and classical pathways [26-28]. Two studies of separate racial groups both show marginal statistical effects for an association of lupus with aspartic acid at amino-acid position 54 [29,30]. In studies of African-American [29] and Spanish lupus patients [31], alleles or haplotypes producing
699 Autoirnmunity
lower levels of serum mannose-binding protein were associated with increased lupus risk.
Fcy receptors Many members of the family of Fc? receptors (FcyRs) appear to be involved in the genetics of lupus. Alleles that fail to express a cell-surface product of FcyRIIIB have been fotmd in a few lupus patients [32,33]. T h e presumed rarity of this allele in the population [32-34] hints that this gene may be important for pathogenesis. FcyRIIA association with lupus has been directly demonstrated [35]. T h e two common alleles vary at the receptor's amino-acid position 131, where a histidine or an arginine is found - - referred to as H131 and R131, respectively. T h e affinity of IgG2 for FcyRIIA is reduced for the RI31 allele relative to the H131 allele; the latter is associated with lupus in both African-Americans and Koreans [36]. T h e relationship of this polymorphism to lupus susceptibility in Europeans (or European-Americans) is controversial, with some groups finding a relationship [37] and others failing to find association [35,38]. T h e H131/R131 FcyRIIA polymorphism is an example of a situation where the genotype informs us about the phenotype. In the association studies showing a relationship, the association is more powerful in lupus patients with nephritis [35,37] but the influence upon the phenotype does not end there. One study has found that lupus patients who are R131 homozygotes tend to have anti-spliceosomal antibodies, proteinuria or immune hemolytic anemia; the H131 homozygotes tend to have livedo [39]. Finally, lupus patients who are R131 homozygotes are at increased risk of invasive pneumococcal infections [40]. Recently, the distribution of alleles at a polymorphism of FcyRIIIA has been found to differ in SLE patients from that in normals [41]. When alanine is encoded at amino acid position 176 instead of phenylalanine, this natural killer (NK) cell receptor has higher apparent binding affinity for IgG1 and IgG3.
Other genes Many abnormalities have been described in lupus patients. T h e vast majority of these are a consequence of the disease process rather than the primary genetic foundation from which the other abnormalities derive. Other genes that appear to be associated with lupus include those encoding II,-10 [42,43] and the Gm allotypes of lgG (summarized by Schur [111). While not associated with lupus in all populations tested [44], IL-10 is interesting not only because alleles for it have been associated with lupus but also because elevated levels of IL-10 have been found in both patients and unaffected family members [45]. Also, a recent study has shown an interaction at the level of association
between IL-10 and/):'/-2 [46]. Finally, a haplotype of the IL-10 gcne has been associated with anti-Ro production [47], suggesting that IL-10 may also influence disease expression. Much interest has been focused upon apoptosis in recent years. T h e relevance of apoptosis to lt~pus has been clearly established, with a variety of the associated gene products being involved in apoptosis. In the first and most dramatic example, the fas gene, is responsible for the defect in the M R I , /pr//pr mouse model of lupus. Screening of 75 lupus patients for defects infas and its ligand produced only one patient with a defect in the Fas ligand, which has lead to the conclusion that defects in/?is and its ligand are associated with lupus in only a small proportion of affected patients [48]. Finally, genes modify disease e x p r e s s i o n - - a s shown for thrombosis in lupus. A polymorphism of coagulation factor V, referred to as factor V Leiden or as factor \::Q50¢,, is a relatively common polymorphism and is a risk factor for thrombosis in the general population. Though variably associated with venous thrombosis in patients with antiphospholipid autoantibodies [49-51], the most sophisticated analysis suggests that the risk of thrombosis in lupus is independently influenced by anti-lipid antibodies and by factor V:Qs°~ [52]. T h e HLA associations with the autoantibodies that tend to be tbund in the anti-phospholipid syndrome were discussed above. Meanwhile the immunochemistry of prothrombotic anti-lipid antibodies is becoming much more sophisticated, particularly with the appreciation of the importance of 132-glycoprotcin-I as an autoantigen in this system. A better tmderstanding of the various roles for the mtdtiple risk factors for thrombosis in lupus is likely to emerge.
Linkage studies An enlarging number of groups is attempting to define the linkages in human lupus. T h e first human linkage studies in lupus were done by Bias eta/. [53] who used clinical and laboratory manifestations of autoimmunity as an intermediate phenotype. Their segregation data best fit a model of at,tosomal dominant inheritance; however the poorly informative markers used, the paucity of pedigree material available to study and the probable complexity of the underlying genetics conspired against producing significant linkage results. More recent approaches that examined candidate genes have identified possible linkages on chromosome 1, with a probability level of<0.01 [54,55"]. A legion of potential candidate genes is available from association studies, from the present knowledge of the pathophysiology of lupns and from linkages in animal models which provide syntenic regions to explore in man. T h e linkage reported at Dls229 [55"] was sought in a region suspected to be syntenic with linkages reported
The genetics of human systemic lupus erythematosus Harley et aL
to fuel suspicion that the observed relationships may originate from a common genetic effect.
Table 1 Linkage with the Dls229 locus in lupus patients from California or Oklahoma. Area studied
California Oklahoma
693
Number of Mean fraction informative of shared alleles sibling pairs 50 78
0.64 0.58
p-value*
Reference
0.0005 0.014
[55*] (a)
*Sum of Zs method for the combined probability (p-) value = 0.00005. (a) KL Moser et aL, unpublished data.
from three separate groups [56-58] working with backcrosses from, or derived from, the F1 of NZB x NZW murine model of lupus. Unfortunately, the map of synteny available led these investigators to explore a region telomeric to the human region syntenic to the murine linkage [55"]. Astonishingly, these investigators found linkage anyway, most powerfully with the D1s229 locus [59]. This result has been confirmed (KL Moser etaL, unpublished data; Table 1). Linkage of the region around Dls229 with lupus should now be accepted and, indeed, a possible candidate gent product that may potentially be responsible for the e f f e c t - - p o l y ( A D P - r i b o s y l ) t r a n s f e r a s e - - h a s been identified [60°']. Genome scan studies from Minnesota [61"] and Oklahoma [62"] have been completed. These two studies had quite different designs. The Minnesota study included a collection of 105 sibling pair families genotyped at 341 loci using the marker set prepared by Applied Biosystems and analyzed using a newly available muhipoint nonparametric algorithm. The Oklahoma study included 94 extended pedigrees evaluated at 324 loci, largely from the Weber Screening Set "Version 8, and analyzed using classic parametric linkage. The likelihoods were maximized for 16 loci where any of six screening models achieved logarithm of odds (lod) >1.5. Also, the Oklahoma pedigrees are about one third African-American while the Minnesota sibling pairs were 5% African-American. The two studies chose different thresholds for declaring possible linkage, with that of Oklahoma using Iod > 1.5 and that of Minnesota using lod > 1.00. T h e 16 and 12 possible linkages that were, respectively, identified are not directly comparable because of the different microsatellite markers evaluated and the different study designs employed. Since the same criteria were used for ascertaining affected subjects [7], however, we should eventually be focusing on the same underlying genetic effects. Not surprisingly, almost half (12 out of 26) of the putative linkages found in the two studies were apparently supported, at least to a modest extent (lod >0.5), in both studies; moreover, potential linkages at chromosomes lq41-42 and 20q13 were found in both studies. The putatively linked markers are sufficiently close to one another
In the Minnesota study [61"], markers near the HLA region gave the highest lod score at 6p11-21 (Table 2). Meanwhile, this region was not identified as a suspicious region in the Oklahoma study [62"] though there is some modest support for linkage. The possible explanations for this difference are legion. The most likely reason is that the heterogeneity of the genetic mechanisms leading to lupus influences the sensitivity of each collection to reveal different genes. As can be appreciated from q~able 2, there is reason to be encouraged bv the similarities between the two linkage studies as well as to be awed by the complexity of this problem. In the Oklahoma study [62°°], the most impressive effects were found in African-Americans on chromosome lq23. T h e most convincing linkage is at the Fc~'RIIA locus for the H131/R131 polymorphism with lod = 3.37 using a parametric model in extended families and increased allele sharing (p = 0.0003) among the 78 sibling pairs in this study. D1s3462 (with lod = 3.5) is telomeric to both D1s229 and the Fc'fRIIA locus and, at this point, appears to be a separate genetic effect. Perhaps the most consistent findings for linkage are found on chromosome 1. If we include Dls229 [54,55"], then there are at least five separable putative genetic linkages on chromosome 1 alone. T h e complexity of the numerous genetic effects on chromosome 1 may actually impede progress. Of these, the FcTRIIA locus is associated with lupus in other studies and is known to encode a polymorphism that changes the behavior of a protein product. Dls252 was one of the few markers used in both studies and produced lod >1.44 in both, suggesting that there may be a persistent weak effect at lp13. Both D1s3462 and the FcyRIlA locus have their greatest effects in the African-Americans (lod >3.35), of the pedigrees studied in Oklahoma. Dls3462 has nearby support for linkage at the closest marker used in the Minnesota pedigrees, DlsZ~5; however, this very marker (Dls235) was used also in the Oklahoma study and only achieved a maximum lod = 0.225 in the African-American pedigrees. Perhaps there is a major gene for lupus between Dls3462 and Dls235. T h e explanations for these findings should be forthcoming as part of the effort to reconcile the similarities and differences between the two studies. Other interesting effects are found on chromosomes 13, 14, 16 and 20 (Table 2); all have lod = 2.5 in one study or the other. The chromosome 16 effect is near linked regions in psoriasis, Blau syndrome and Crohn's disease. The chromosome 20 effect is near a linkage in psoriasis. No doubt many idiopathic inflammatory diseases, presumed to be autoimmune, will be shown to share etiologic origins and some of the same genes will participate in pathogenesis.
694
Autoimmunity
Table 2 Comparison of putative linkages from the Oklahoma and Minnesota studies. (a) Putative linkages from the Oklahoma study that are supported by the Minnesota study (Iod _>0.5) OK marker D1s3462 D20s481 D4s403 D2s1391
OK group*
OK Iod
Region
MN marker
MN Iod
AA AA EA EA
3.50 2.49 2.18 2.09
lq41-42 20q13 4p15 2q21-33
D1s235 D20s119 D4s412 D2s151
1.51 1.67 0.53 1.12
(b) Additionalputativelinkagesfrom the Minnesota studythataresupported bythe Oklahomastudy(Iod 2 0.5) OK marker
OK group
OK Iod
Region
MN marker
MN Iod
D6s1053 D16s3253 D20s604 D1s252 D4s2431 D3s2406 D11s1984
AA EA EA EA EA EA AA
0.86 0.82 0.71 1.44 1.47 1.30 0.87
6p11-21 16q13 20p12 lp13 4q28 3cen-q11 11p15
D6s257 D16s415 D20s186 D1s252 D4s424 D3s1271 D11s922
3.90 3.64 2.62 1.53 1.46 1.24 1.19
(c) Putative linkages not apparently supported by the other study Region
OK group
OK marker
OK Iod
1q23
AA
FcyRIIA
3.37
13q32 14qll 11q25 11q14-23 19q13 6q26-27 lq31 12p12-11 21q21 11p13 3p21
All EA EA AA EA EA All EA EA AA AA
D13s779 D14s742 D11s912 Dlls2002 D19s246 D6s1027 ~mcl D12s1042 D21s1437 D11s1392 D3s1766
2.50 2.21 2.15 2.10 2.05 2.04 2.04 2.01 1.88 1.87 1.68
Region
MN marker
MN Iod
14q21-23
D14s276
2.81
2p15 15q26 lp36
D2s337 D15s127 D1s234
1.68 1.07 1.00
*Oklahoma pedigrees were analyzed in three groupings: African-American (AA), European-American (EA) and combined (All). Minnesota pedigrees were not subdivided for this analysis. MN, Minnesota Study [61 "°]; OK, Oklahoma study [62°°].
Indeed, the possibility that autoimmune diseases share genetic susceptibility genes is supported by a recent metaanalysis. A n u m b e r of putative genetic effects in the lupus g e n o m e scan studies are found in chromosomal regions which are possibly linked in other disorders [63]. How many genes are there likely to be in man that influence susceptibility to lupus? At this m o m e n t only a wild guess is possible and the answer is completely d e p e n d e n t upon the assumptions one chooses to make. If only the genomic regions with effects in both genome scan studies [61",62 "°] are considered, then there are at least 12 distinguishable genetic effects. At the opposite extreme, if we assume that each of the putative linkages in the two studies represents an effect of a lupus susceptibility gene, then there would be more than 100 susceptibility genes to identify for lupus. Perhaps the truth will eventually be shown to lie somewhere between 12 and over 100 genes. T h e answer to this
question will require an effort much greater than that which has brought the genetics of lupus to this point.
Conclusions Association and linkage studies have produced interesting possibilities for the susceptibility genes involved in lupus. T h e HLA region continues to be a hot-bed of findings and activity; no doubt it contains multiple genetic effects. T h e Fc receptors also appear to be very important. Exploding onto this scene, the new genetic approaches are providing new and important data that will provide a more complete picture of the genetics of lupus in man. T h e linkage studies demonstrate that a relatively large number of linkages await substantiation alung with the identification of the polymorphisms r e s p o n s i b l e for them. T h o u g h this task p r o m i s e s to be very challenging, it is within reach of existing technologies-allowing that t h e r e s o u r c e s and i n v e s t i g a t o r
The genetics of human systemic lupus erythematosus Harley eta/.
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c o m m i t m e n t are s u s t a i n e d . Finally, t h e s e g e n e s m u s t be i m p o r t a n t to t h e p a t h o g e n e s i s of l u p u s in ways that cannot at p r e s e n t be i m a g i n e d ; t h e e l u c i d a t i o n of t h e s e will p r o v i d e o p p o r t u n i t i e s to i m p r o v e prognosis, t h e r a p e u t i c s and p r e v e n t i o n .
13. Arnett FC: The genetics of human lupus. In Dubois' Lupus Erythernatosus, edn 5. Edited by Wallace DJ, Hahn BH. Baltimore: Wilkins and Wilkins; 1997:77-117.
Acknowledgements
15. JarjourW, Reed AM, Gauthier J, Hunt S, Winfield JB: The 8.5-kb Pstl allele of the stress protein gene, Hsp70-2. An independent risk factor for systemic lupus erythematosus in African-Americans? Hum Immuno/1996, 45:59-63.
\\:e ~ratefulh acknewlcd~c the National Institutes of llealth, the [.upus
Multiplcx Registry and Repository, the [ !S [)cpartmcnt of \crcrans ..\t'l:airs,our institutions and their benefactors and our professional colleagues along with the host of patients, their families and ph?'sicians fi~rtheir support of these studies.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest • " of outstanding interest
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