Original Paper Neuroepidemiology 1992; 11:85-89
3 Department of Neurological Sciences, University of Rome, and b Department of Experimental Medicine, ‘Cattedra di Genetica Medica’, University of Rome, Italy
KeyWords Multiple sclerosis Families HLA
HLA Determinants in Familial Multiple Sclerosis
Abstract
HLA-A, -B, -C, -DR. -DQ antigens were studied in 11 multi plex MS families, 11 single-case MS families and 100 healthy subjects. The HLA DR4 was the most frequent antigen in all MS patients (p = 0.015). When the antigenic frequency in index familial cases was compared with that in single cases, the DR4 antigen was found to be more frequent (p = 0.01) in familial cases only. Furthermore, when the DR4 antigen was excluded from the analysis, we observed an increase in DR2 (p= 0.11) only in the familial MS cases. These results can be compatible with a multifactorial hypothesis according to which the HLA genes have an important role in MS suscepti bility in familial cases.
Introduction
Since the 1960s the epidemiology of multi ple sclerosis (MS) has been extensively inves tigated in Italy. The steadily increasing preva lence figures have raised the possibility of a real increase in the incidence of the disease [1]. In addition the uneven geographical dis tribution confirmed by these studies has pointed out the possible significance of ge netic factors in the occurrence of MS.
Thus the epidemiology of the disease is consistent with a polygenic disorder and a number of genes have been postulated as pos sible contributors to disease susceptibility [24], Particular attention has been paid to genes related to the immune function, as the pre vailing view is that an immunological process is pathogenically relevant [5]. It has been recognized that some cases of MS show familial aggregation, with a familial frequency ranging from 7 to 20% [6]. The risk
Maria Grazia Grasso, MD Dcpartmenl oCNcurological Sciences III Cattedra di Clinica Neurologica Viale dell'Universita 30 1-00185 Rome (Italy)
© 1992 S. Karger AG, Basel 0251-5350/92/ 0112-008552.75/0
Downloaded by: Access provided by the University of Michigan Library 141.216.78.40 - 1/11/2019 2:50:30 AM
M.G. Grosso* F. Cutrupih S. Bernardia S. Trabaceh C. Pozzilli* S. Cappellaccih C. Fieschi*
Patients and Method Patients from central and southern Italy were sur veyed in order to find families in which 2 or more firstdegree relatives had symptoms of MS. The diagnosis of MS conformed to the criteria of Schumacher ct al. [ 12] and Poser [ 13], and only individuals who had clinically definite MS were considered in the analysis. We studied 11 families with 2 affected members with definite MS (7 families with 2 siblings and 4 with a parent and a child affected) and 11 families with a single case of MS. matched according to their regions of origin. The familial and single cases did not differ in age at onset of disease, type of disease and disability, whereas the duration of disease was greater in familial than in single cases. Of the 94 individuals investigated, there were 33 MS patients and 61 healthy relatives. Furthermore a total of 100 healthy random subjects was considered as controls. Tissue-typing was performed using the stan dard complement-dependent microlymphocytotoxicity technique according to Tcrasaki et al. [ 14], The typ ing sera used defined 16 HLA-A specificities, 32 HLAB, 7 HLA-C, 10 HLA-DR and 3 HI.A-DQ specificities. Two patients were not analyzed for HLA-DR and DQ. All sera were validated in the previous histocompati bility workshop. Analysis Pedigrees of each family were inspected for ‘shar ing’ HLA haplotypes among family members affected by MS. The degree of association was evaluated by comparing the frequency of haplotype sharing among MS sib-pairs with the expected rate by Mendelian
86
segregation. In addition the frequency of haplotype sharing in MS pairs was compared with the frequency in unaffected family members. Finally the antigenic frequencies in single, in index familial cases and in both cases together were compared with the controls, according to Fisher’s exact test and y} test.
Results The 4 families whose affected members were a parent and a child were excluded from the analysis of ‘sharing’ HLA haplotypes be cause by definition they have a common haplotype. Two HLA haplotypes were shared in 4 sib-pairs, 1 haplotype in 2 and 1 sib-pair was completely different (table 1). Analysis of the antigenic frequencies in MS showed that no differences were found among the A, B, C and DQ antigenic frequency between the 2 groups of patients and controls. The HLA DR4 was the most frequent antigen in all MS patients (p = 0.015). When the anti genic frequency in familial index and single cases was separately compared with the con trols, the DR4 antigen was found to be more frequent (p = 0.01) in familial cases only (ta ble 2). Furthermore, when the DR4 antigen was excluded from the analysis, we observed an increase in DR2 (p = 0.011) only in the MS familial cases (table 3). The MS familial pa tients showed HLA DR4 or DR2 in 90% of the cases (p = 0.05).
Discussion Analysis of the antigenic frequency in the overall population confirms the presence of a specific HLA pattern in MS patients from central and southern Italy. Previous work on MS populations from Sardinia and central Italy found an associa tion with DR4 [15, 16], while studies per-
Grasso/Cutrupi/Bcrnardi/T rabace/ Pozzili/Cappellacct/Fieschi
HLA and Familial MS
Downloaded by: Access provided by the University of Michigan Library 141.216.78.40 - 1/11/2019 2:50:30 AM
of acquiring the disease is reported to be 1520 times higher in first-degree relatives than in the general population [7, 8]. The evidence that affected members within families share HLA haplotypes more frequently than ex pected on the basis of random segregation is, however, less conclusive [9-11]. We have thus studied all available multi plex families, with well-documented cases of MS, from central and southern Italy to define the antigenic frequency, the haplotype distri bution and to identify an eventual responsible gene of single and familial cases.
Haplotypes shared
Affected siblings, °/o ( n - 7)
Expected sharing, %
2 i 0
57 28 15
25 50 25
Table 2. HLA antigens in MS
DR1 DR2 DR3 DR4 DR5 DRw6 DR7 DRw8 DRw9 DRwIO
Familial (n= 10)
Single (n = 11)
Controls ( n - 100)
P
1 (0.10) 4 (0.40) 1 (0.10) 5(0.50) 4 (0.40) 1 (0.10) 1 (0.10) 0 0 2 (0.20)
0
16(0.16) 22 (0.22) 12(0.12) 14(0.14) 51 (0.51) 23 (0.23) 28(0.28) 6 (0.06) 2 (0.02) 6 (0.06)
n.s. n.s. n.s.
3 (0.27) 3 (0.27) 3 (0.27) 5 (0.45) 2(0.18) 1 (0.09) 0 0
1 (0.09)
0.013
n.s. n.s. n.s. n.s. n.s. n.s.
3 Familial compared with controls.
Table 3. HLA antigens in MS excluding DR4 from the analysis
DRl DR2 DR3 DR5 DRw6 DR7 DRw8 DRw9 DRwIO
Familial ( n -5 )
Single (n -8 )
Controls (n = 86)
P
1 (0.20) 4 (0.80) 1 (0.20) 4 (0.80) 1 (0.20) 1 (0.20) 0 0 2 (0.40)
0 3 (0.38) 3 (0.38) 5 (0.63) 2 (0.25) 1 (0.12) 0 0 1 (0.12)
15(0.18) 22 (0.25) 12(0.13) 51 (0.59) 23(0.26) 28(0.32) 6 (0.07) 2 (0.02) 6 (0.07)
n.s.
3 Familial compared with controls.
0 .013
n.s. n.s. n.s. n.s. n.s. n.s. n.s.
formed in northern Italy showed an associa tion with DR2 [ 17, 18], In our study we found a significant increase in DR4 and DR2 fre quencies in the familial cases. We did not find a statistical difference between single and fa milial cases, but the number of the patients was too small to reveal differences. Govaerts et al. [ 19] in a French MS series found similar data reporting a greater increase in DR2 anti gen in the familial cases than in the single cases. Our findings support the possible existence of different genes of susceptibility for single and familial cases of MS. In this latter group the presence of various genes, such as the DR4 or DR2, might be necessary for the pre disposition to the disease. Although the series is too small to reveal inheritance, we observed that 6 sib-pairs share 1 or 2 haplotypes. The latter sib-pair was completely different, but DR2 was found in both patients suggesting a dominant model. Previous data did not reach conclusive re sults. Using segregation analysis, Haile et al. [20] demonstrated that the best fit is with the dominant model even if all the models have relatively similar likelihood values. By pool ing affected sib-pair data from reports in the literature, Bundey [9] found an appreciable excess of pairs in whom both members share 1 or 2 haplotypes. Bundey [9] suggests a domi nant inheritance of a susceptibility gene which is situated within the HLA region on chromosome 6, but which is not essential for the development of disease. On the contrary, both Ebers et al. [21] and Francis et al. [22] did not show a distribution of haplotypes in affected sibs, which was not expected. Fur thermore, Weitkamp [23] studied sib-pair data in relation to sex and found that a nonrandom distribution of haplotypes was marked only in the sister-sister pairs with a recessive model of inheritance.
87
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Table 1. Multiplex MS families: Haplotype sharing between proband and other affected and unaffected siblings
However, only about 1% of sibs develop MS although many of them share the same HLA-linked susceptibility genes [9]. In our series the healthy sibs share both haplotypes in about 40% of cases. On the other hand, it was found that the healthy relatives may present cerebrospinal fluid and MRI abnor malities suggesting a possible subclinical form of the disease [24, 25]. The presence of different genes, such as the DR4 or DR2 in our Italian MS population, might be necessary for the predisposition to the disease in familial cases. These results can be compatible with a multifactorial hypothe
sis according to the suggestion that a genetic factor, influencing susceptibility to familial MS, is HLA-linked in association with class-II antigens.
Acknowledgements This study was supported by a grant from the Ital ian Multiple Sclerosis Society and developed within the targeted project FATMA (prevention and control of risk factors), sub-project community medicine, of CNR (Italian National Research Council), 1990— 1995.
1 Rosati G, Aiello I, Mannu L, Pirastru MI, Agnetti V, Dau G, Garau M, Gioia R, Sanna G: Incidence of mul tiple sclerosis in the town of Sassari, Sardinia 1965 to 1985: Evidence for increasing occurrence of the disease. Neurology 1988;38:384-387. 2 BeiT C, Dugoujou MJ, Clanet M, Cambon-Thomson A, Alperovitch A: A possible new genetic marker associated with a severe course of multiple sclerosis, located on chro mosome 2: Km. N Engl J Med 1989; 320:467. 3 Seboun E, Robinson MA, Doolittle TH, Ciulla TA, Kindt TJ, Hauser SL: A susceptibility locus for MS is linked to the T cell receptor B chain complex. Cell 1989;57:1095-1100. 4 Spielman RS, Nathanson N: The ge netics of susceptibility to MS. Epidem Rev 1982;4:45-65. 5 McFarlin DE, LachmanPJ: Hopeful genes and immunology. Nature 1989;341:693-694. 6 Kinnunen E, Wilkstrom J, Porras J, Koskimies S, Lagerstedt A, Palo J: Prevalence, incidence and familial risk of MS. Acta Neurol Scand 1984;(suppl):378—380.
88
7 Baraitser H: Multiple sclerosis; in The genetics of Neurologic Disor ders. Oxford, Oxford University Press, 1981, pp 306-313. 8 Sadovnick AD, Baird PA: The fa milial nature of MS: Age corrected empiric recurrence risk for children and siblings of patients. Neurology 1988;38:990-991. 9 Bundey S: Genetics and Neurology. Edinburgh, London, Melbourne, New York, Churchill Livingstone, 1985, pp 276-283. 10 Risch N: Genetic analysis workshop IV: Summary of the multiple sclero sis workshop. Genet Epidemiol 1986; 1(suppl):371-380. 11 Tiwari JL, Hodge SE, Terasaki PI, Spence MI: HLA and the inheri tance of MS: Linkage analyses of 72 pedigrees. Am J Hum Genet 1980; 32:103-111. 12 Schumacher GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, MacDowell F, Nagler B, Sibley WA, Tourtelotte WW, Willmon TL: Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965;122:552-568.
13 Poser CM: The Diagnosis of Multi ple Sclerosis. Stuttgart, Thieme, 1984. 14 Terasaki PI, Bemaco D, Park MS, Ozturk G, Iwaki Y: Microdroplet testing for HLA A-B-C and D anti gens. Am J Clin Pathol 1978;69: 103-118. 15 La Mantia L, Uleni MT, Milanese C, Salmaggi A, Eoli M, Pellegris G, Nespolo A: HLA and multiple scle rosis in Italy: A review of the litera ture. J Neurol 1990;237:441-444. 16 Marrosu GM, Muntoni F, Murru MR, Spinicci G, Pischedda MP, Goddi F, Cossu P, Pirastru M: Sar dinian multiple sclerosis is associ ated with HLA-DR4: A serological and molecular analysis. Neurology 1988;38:1749-1753. 17 Casetta I, Granieri E, Conighi C, Tola R, Govoni V, Grappa MT, Paolino E: Antigeni HLA e sclerosi multipla nella provincia di Ferrara. XXVI Congresso Nazionale della Socicta Italiana di Neurologia. Fer rara, CS Congress Service, 1989, p 314.
Grasso/Cutrupi/Bemardi/T rabace/ Pozzili/Cappellacci/Fieschi
HLA and Familial MS
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References
20 Haile RW, Iselius L, Hodge SE, Morton NE, Detels R: Segregation and linkage analysis of 40 multiplex multiple sclerosis families. Hum Hered 1981;31:252-258. 21 Ebers GC, Paty DW, Stiller CR, Nelson RF, Seland TP, Larsen B: HLA-typing in MS siblings pairs. Lancet 1982;ii:88—90. 22 Francis DA, Batchelor JR, McDon ald Wl, Dodi IA, Hing SN, Hem JEC, Downie AW: HLA genetic de terminants in familial MS. Tissue Antigens 1987;29:7-12.
23 Weitkamp LR: MS susceptibilty. Arch Neurol 1983;40:399-401. 24 Lynch SG, Rose J W, Smoker W, Petajan JH: MRI in familial multiple sclerosis. Neurology 1990;40:900903. 25 Xian-hao Xu, McFarlin DE: Oligoclortal bands in CSF: Twins with MS. Neurology 1984;34:769-774.
89
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18 Granieri E, Conighi C, Tola R, Car reras M, Rosati G, Paolino E, Vicentini V, Grappa MT, Maitiuz PL: HLA and multiple sclerosis in Italy. Two population studies in northern and insular Italy. Acta Neurol (Na poli) 1987;9:124-133. 19 Govaerts A, Gony J, Martin-Mondiere C, Poirier JC, Schmid M, Schuller E, Degos JD, Dausset J: HLA and multiple sclerosis: Popula tion and families study. Tissue Anti gens 1985;25:187-199.
3 Department of Neurological Sciences, University of Rome, and b Department of Experimental Medicine, ‘Cattedra di Genetica Medica’, University of Rome, Italy
KeyWords Multiple sclerosis Families HLA
HLA Determinants in Familial Multiple Sclerosis
Abstract
HLA-A, -B, -C, -DR. -DQ antigens were studied in 11 multi plex MS families, 11 single-case MS families and 100 healthy subjects. The HLA DR4 was the most frequent antigen in all MS patients (p = 0.015). When the antigenic frequency in index familial cases was compared with that in single cases, the DR4 antigen was found to be more frequent (p = 0.01) in familial cases only. Furthermore, when the DR4 antigen was excluded from the analysis, we observed an increase in DR2 (p= 0.11) only in the familial MS cases. These results can be compatible with a multifactorial hypothesis according to which the HLA genes have an important role in MS suscepti bility in familial cases.
Introduction
Since the 1960s the epidemiology of multi ple sclerosis (MS) has been extensively inves tigated in Italy. The steadily increasing preva lence figures have raised the possibility of a real increase in the incidence of the disease [1]. In addition the uneven geographical dis tribution confirmed by these studies has pointed out the possible significance of ge netic factors in the occurrence of MS.
Thus the epidemiology of the disease is consistent with a polygenic disorder and a number of genes have been postulated as pos sible contributors to disease susceptibility [24], Particular attention has been paid to genes related to the immune function, as the pre vailing view is that an immunological process is pathogenically relevant [5]. It has been recognized that some cases of MS show familial aggregation, with a familial frequency ranging from 7 to 20% [6]. The risk
Maria Grazia Grasso, MD Dcpartmenl oCNcurological Sciences III Cattedra di Clinica Neurologica Viale dell'Universita 30 1-00185 Rome (Italy)
© 1992 S. Karger AG, Basel 0251-5350/92/ 0112-008552.75/0
Downloaded by: Access provided by the University of Michigan Library 141.216.78.40 - 1/11/2019 2:50:30 AM
M.G. Grosso* F. Cutrupih S. Bernardia S. Trabaceh C. Pozzilli* S. Cappellaccih C. Fieschi*
Patients and Method Patients from central and southern Italy were sur veyed in order to find families in which 2 or more firstdegree relatives had symptoms of MS. The diagnosis of MS conformed to the criteria of Schumacher ct al. [ 12] and Poser [ 13], and only individuals who had clinically definite MS were considered in the analysis. We studied 11 families with 2 affected members with definite MS (7 families with 2 siblings and 4 with a parent and a child affected) and 11 families with a single case of MS. matched according to their regions of origin. The familial and single cases did not differ in age at onset of disease, type of disease and disability, whereas the duration of disease was greater in familial than in single cases. Of the 94 individuals investigated, there were 33 MS patients and 61 healthy relatives. Furthermore a total of 100 healthy random subjects was considered as controls. Tissue-typing was performed using the stan dard complement-dependent microlymphocytotoxicity technique according to Tcrasaki et al. [ 14], The typ ing sera used defined 16 HLA-A specificities, 32 HLAB, 7 HLA-C, 10 HLA-DR and 3 HI.A-DQ specificities. Two patients were not analyzed for HLA-DR and DQ. All sera were validated in the previous histocompati bility workshop. Analysis Pedigrees of each family were inspected for ‘shar ing’ HLA haplotypes among family members affected by MS. The degree of association was evaluated by comparing the frequency of haplotype sharing among MS sib-pairs with the expected rate by Mendelian
86
segregation. In addition the frequency of haplotype sharing in MS pairs was compared with the frequency in unaffected family members. Finally the antigenic frequencies in single, in index familial cases and in both cases together were compared with the controls, according to Fisher’s exact test and y} test.
Results The 4 families whose affected members were a parent and a child were excluded from the analysis of ‘sharing’ HLA haplotypes be cause by definition they have a common haplotype. Two HLA haplotypes were shared in 4 sib-pairs, 1 haplotype in 2 and 1 sib-pair was completely different (table 1). Analysis of the antigenic frequencies in MS showed that no differences were found among the A, B, C and DQ antigenic frequency between the 2 groups of patients and controls. The HLA DR4 was the most frequent antigen in all MS patients (p = 0.015). When the anti genic frequency in familial index and single cases was separately compared with the con trols, the DR4 antigen was found to be more frequent (p = 0.01) in familial cases only (ta ble 2). Furthermore, when the DR4 antigen was excluded from the analysis, we observed an increase in DR2 (p = 0.011) only in the MS familial cases (table 3). The MS familial pa tients showed HLA DR4 or DR2 in 90% of the cases (p = 0.05).
Discussion Analysis of the antigenic frequency in the overall population confirms the presence of a specific HLA pattern in MS patients from central and southern Italy. Previous work on MS populations from Sardinia and central Italy found an associa tion with DR4 [15, 16], while studies per-
Grasso/Cutrupi/Bcrnardi/T rabace/ Pozzili/Cappellacct/Fieschi
HLA and Familial MS
Downloaded by: Access provided by the University of Michigan Library 141.216.78.40 - 1/11/2019 2:50:30 AM
of acquiring the disease is reported to be 1520 times higher in first-degree relatives than in the general population [7, 8]. The evidence that affected members within families share HLA haplotypes more frequently than ex pected on the basis of random segregation is, however, less conclusive [9-11]. We have thus studied all available multi plex families, with well-documented cases of MS, from central and southern Italy to define the antigenic frequency, the haplotype distri bution and to identify an eventual responsible gene of single and familial cases.
Haplotypes shared
Affected siblings, °/o ( n - 7)
Expected sharing, %
2 i 0
57 28 15
25 50 25
Table 2. HLA antigens in MS
DR1 DR2 DR3 DR4 DR5 DRw6 DR7 DRw8 DRw9 DRwIO
Familial (n= 10)
Single (n = 11)
Controls ( n - 100)
P
1 (0.10) 4 (0.40) 1 (0.10) 5(0.50) 4 (0.40) 1 (0.10) 1 (0.10) 0 0 2 (0.20)
0
16(0.16) 22 (0.22) 12(0.12) 14(0.14) 51 (0.51) 23 (0.23) 28(0.28) 6 (0.06) 2 (0.02) 6 (0.06)
n.s. n.s. n.s.
3 (0.27) 3 (0.27) 3 (0.27) 5 (0.45) 2(0.18) 1 (0.09) 0 0
1 (0.09)
0.013
n.s. n.s. n.s. n.s. n.s. n.s.
3 Familial compared with controls.
Table 3. HLA antigens in MS excluding DR4 from the analysis
DRl DR2 DR3 DR5 DRw6 DR7 DRw8 DRw9 DRwIO
Familial ( n -5 )
Single (n -8 )
Controls (n = 86)
P
1 (0.20) 4 (0.80) 1 (0.20) 4 (0.80) 1 (0.20) 1 (0.20) 0 0 2 (0.40)
0 3 (0.38) 3 (0.38) 5 (0.63) 2 (0.25) 1 (0.12) 0 0 1 (0.12)
15(0.18) 22 (0.25) 12(0.13) 51 (0.59) 23(0.26) 28(0.32) 6 (0.07) 2 (0.02) 6 (0.07)
n.s.
3 Familial compared with controls.
0 .013
n.s. n.s. n.s. n.s. n.s. n.s. n.s.
formed in northern Italy showed an associa tion with DR2 [ 17, 18], In our study we found a significant increase in DR4 and DR2 fre quencies in the familial cases. We did not find a statistical difference between single and fa milial cases, but the number of the patients was too small to reveal differences. Govaerts et al. [ 19] in a French MS series found similar data reporting a greater increase in DR2 anti gen in the familial cases than in the single cases. Our findings support the possible existence of different genes of susceptibility for single and familial cases of MS. In this latter group the presence of various genes, such as the DR4 or DR2, might be necessary for the pre disposition to the disease. Although the series is too small to reveal inheritance, we observed that 6 sib-pairs share 1 or 2 haplotypes. The latter sib-pair was completely different, but DR2 was found in both patients suggesting a dominant model. Previous data did not reach conclusive re sults. Using segregation analysis, Haile et al. [20] demonstrated that the best fit is with the dominant model even if all the models have relatively similar likelihood values. By pool ing affected sib-pair data from reports in the literature, Bundey [9] found an appreciable excess of pairs in whom both members share 1 or 2 haplotypes. Bundey [9] suggests a domi nant inheritance of a susceptibility gene which is situated within the HLA region on chromosome 6, but which is not essential for the development of disease. On the contrary, both Ebers et al. [21] and Francis et al. [22] did not show a distribution of haplotypes in affected sibs, which was not expected. Fur thermore, Weitkamp [23] studied sib-pair data in relation to sex and found that a nonrandom distribution of haplotypes was marked only in the sister-sister pairs with a recessive model of inheritance.
87
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Table 1. Multiplex MS families: Haplotype sharing between proband and other affected and unaffected siblings
However, only about 1% of sibs develop MS although many of them share the same HLA-linked susceptibility genes [9]. In our series the healthy sibs share both haplotypes in about 40% of cases. On the other hand, it was found that the healthy relatives may present cerebrospinal fluid and MRI abnor malities suggesting a possible subclinical form of the disease [24, 25]. The presence of different genes, such as the DR4 or DR2 in our Italian MS population, might be necessary for the predisposition to the disease in familial cases. These results can be compatible with a multifactorial hypothe
sis according to the suggestion that a genetic factor, influencing susceptibility to familial MS, is HLA-linked in association with class-II antigens.
Acknowledgements This study was supported by a grant from the Ital ian Multiple Sclerosis Society and developed within the targeted project FATMA (prevention and control of risk factors), sub-project community medicine, of CNR (Italian National Research Council), 1990— 1995.
1 Rosati G, Aiello I, Mannu L, Pirastru MI, Agnetti V, Dau G, Garau M, Gioia R, Sanna G: Incidence of mul tiple sclerosis in the town of Sassari, Sardinia 1965 to 1985: Evidence for increasing occurrence of the disease. Neurology 1988;38:384-387. 2 BeiT C, Dugoujou MJ, Clanet M, Cambon-Thomson A, Alperovitch A: A possible new genetic marker associated with a severe course of multiple sclerosis, located on chro mosome 2: Km. N Engl J Med 1989; 320:467. 3 Seboun E, Robinson MA, Doolittle TH, Ciulla TA, Kindt TJ, Hauser SL: A susceptibility locus for MS is linked to the T cell receptor B chain complex. Cell 1989;57:1095-1100. 4 Spielman RS, Nathanson N: The ge netics of susceptibility to MS. Epidem Rev 1982;4:45-65. 5 McFarlin DE, LachmanPJ: Hopeful genes and immunology. Nature 1989;341:693-694. 6 Kinnunen E, Wilkstrom J, Porras J, Koskimies S, Lagerstedt A, Palo J: Prevalence, incidence and familial risk of MS. Acta Neurol Scand 1984;(suppl):378—380.
88
7 Baraitser H: Multiple sclerosis; in The genetics of Neurologic Disor ders. Oxford, Oxford University Press, 1981, pp 306-313. 8 Sadovnick AD, Baird PA: The fa milial nature of MS: Age corrected empiric recurrence risk for children and siblings of patients. Neurology 1988;38:990-991. 9 Bundey S: Genetics and Neurology. Edinburgh, London, Melbourne, New York, Churchill Livingstone, 1985, pp 276-283. 10 Risch N: Genetic analysis workshop IV: Summary of the multiple sclero sis workshop. Genet Epidemiol 1986; 1(suppl):371-380. 11 Tiwari JL, Hodge SE, Terasaki PI, Spence MI: HLA and the inheri tance of MS: Linkage analyses of 72 pedigrees. Am J Hum Genet 1980; 32:103-111. 12 Schumacher GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, MacDowell F, Nagler B, Sibley WA, Tourtelotte WW, Willmon TL: Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965;122:552-568.
13 Poser CM: The Diagnosis of Multi ple Sclerosis. Stuttgart, Thieme, 1984. 14 Terasaki PI, Bemaco D, Park MS, Ozturk G, Iwaki Y: Microdroplet testing for HLA A-B-C and D anti gens. Am J Clin Pathol 1978;69: 103-118. 15 La Mantia L, Uleni MT, Milanese C, Salmaggi A, Eoli M, Pellegris G, Nespolo A: HLA and multiple scle rosis in Italy: A review of the litera ture. J Neurol 1990;237:441-444. 16 Marrosu GM, Muntoni F, Murru MR, Spinicci G, Pischedda MP, Goddi F, Cossu P, Pirastru M: Sar dinian multiple sclerosis is associ ated with HLA-DR4: A serological and molecular analysis. Neurology 1988;38:1749-1753. 17 Casetta I, Granieri E, Conighi C, Tola R, Govoni V, Grappa MT, Paolino E: Antigeni HLA e sclerosi multipla nella provincia di Ferrara. XXVI Congresso Nazionale della Socicta Italiana di Neurologia. Fer rara, CS Congress Service, 1989, p 314.
Grasso/Cutrupi/Bemardi/T rabace/ Pozzili/Cappellacci/Fieschi
HLA and Familial MS
Downloaded by: Access provided by the University of Michigan Library 141.216.78.40 - 1/11/2019 2:50:30 AM
References
20 Haile RW, Iselius L, Hodge SE, Morton NE, Detels R: Segregation and linkage analysis of 40 multiplex multiple sclerosis families. Hum Hered 1981;31:252-258. 21 Ebers GC, Paty DW, Stiller CR, Nelson RF, Seland TP, Larsen B: HLA-typing in MS siblings pairs. Lancet 1982;ii:88—90. 22 Francis DA, Batchelor JR, McDon ald Wl, Dodi IA, Hing SN, Hem JEC, Downie AW: HLA genetic de terminants in familial MS. Tissue Antigens 1987;29:7-12.
23 Weitkamp LR: MS susceptibilty. Arch Neurol 1983;40:399-401. 24 Lynch SG, Rose J W, Smoker W, Petajan JH: MRI in familial multiple sclerosis. Neurology 1990;40:900903. 25 Xian-hao Xu, McFarlin DE: Oligoclortal bands in CSF: Twins with MS. Neurology 1984;34:769-774.
89
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18 Granieri E, Conighi C, Tola R, Car reras M, Rosati G, Paolino E, Vicentini V, Grappa MT, Maitiuz PL: HLA and multiple sclerosis in Italy. Two population studies in northern and insular Italy. Acta Neurol (Na poli) 1987;9:124-133. 19 Govaerts A, Gony J, Martin-Mondiere C, Poirier JC, Schmid M, Schuller E, Degos JD, Dausset J: HLA and multiple sclerosis: Popula tion and families study. Tissue Anti gens 1985;25:187-199.
