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RELATIONSHIP BETWEEN HLA AND SEIZURE DISORDERS

AMONG CHINESE CHILDREN IN SOUTHERN TAIWAN

Chi-Hsiun CHIANG

Department of Pediatrics, Kaohsiung Medical College, Taiwan, Republic of China

(Received June 22, 1993)

The purpose of this study was to investigate the occurrence of human leukocyte antigens (HLA antigens) and haplotypes in children with different types of seizure disorders and their families. The sample consisted of 169 unrelated mentally normal

Chinese children in Southern Taiwan with seizure disorders, and 284 of their parents. The types of seizures were divided into idiopathic generalized seizures (74 cases), simple partial seizures (33 cases) and febrile convulsions (62 cases). HLA-Cw7 (p<O.OOI) was found to be significantly more common in both patients and thelr parents with simple

partial seizures and febrile convulsions. The prevalence of the HLA-Bw6 (p<O.OOI)

antigen was higher, to a statistically significant degree, in parents of children with

idiopathic generalized seizures as was HLA-Bw22 (p<O.OOI) in patients with simple

partial seizures. Only HLA-Cw3 (p<O.OOI) appeared to be present at a significantly lower frequency in parents of children with idiopathic generalized seizures than in controls. The prevalence of the All; Bw6 haplotype (p<O.OO05) was significantly higher in both patients and parents of children with idiopathic generalized seizures, and the A9; Bw6 haplotype (p<O.OOI) in parents of children with simple partial seizures. Among those

with febrile convulsions, there were no statistically significant increases in the

frequencies of these haplotypes, but the frequency of haplotype All; B40 was relatively low in parents. Since the HLA A2'; B40 and All; B40 were the most common haplotypes in normal controls, the relatively low frequency of the All; B40 haplotype in parents of

children,with febrile convulsions may support the hypothesis of "protecting" genes

which'somehow counter the effects of certain noxious mechanisms, and the lack of such a haplotype may point to an inherited susceptibility to seizure disorder. However, an investigation with HLA typing in larger populations. of epileptic individuals and their

families may give a more reliable and conclusive answer regarding the genetic

characteristics of seizure disorders. Furthermore; the results must be interpreted very

cautiously.

Introduction

Epilepsy is probably an inherited disorder. The fact that seizures sometimes occur with increased

frequency among families of patients with

epi-lepsy has long been recognized by clinicians and the public alike.

Several recent studies have provided evidence, both direct and indirect, that epilepsy is inherited.

For instance, clinical studies of epileptic Probands and their relativesi)2), electroencephalogrqphic (EEG) studies3>N6), twin studies7)"9), and pedigree studiesiO}Ni2) have provided direct evidence, and

studies on non-specific familial EEG

pat-terns4}i3}Ni5}, the inheritance of epilepsy in

animalsi6)i7), hereditary diseases associated with epilepsyi8)N2i), and chromosomal abnormalities as-sociated with epilepsy22}23) have contributed

(2)

-direct evidence. However, some of these data are still not entirely convincing, and reliable scientific data either confirming or refuting this hypothesis have not been easy to obtain.

In the recent years, the relationship of human leukocyte antigens (HLA antigens) to certain dis-eases has attracted interest since the discovery of

the close linkage between histocompatibility genes and those of the immune response in

ex-perimental animals24)25), and similarly in man, a

relationship has been found between diseases

with alteration of the immune system and

markers in the major histocompatibility complex

(MHC) chromosomal region, serum-defined

human leukocyte antigens (SDHL-A),

lymphocyte-defined antigens, and mixed lymphocyte reaction antigens (LD MLR)26)N28). Therefore, it has been realized that MCH is not only intimately involved

in regulation of the immune system, but also

shows extreme polymorphism and is the most

reliable set of human genetic markers so far

found, and may thus be helpful for identifying

individuals at risk for epilepsy.

The purpose of this investigation was to study the distribution frequencies of HLA antigens and

haplotypes among Chinese children in Southern

Taiwan with seizure disorders and their families,

in hopes of identifying HLA correlations with

these disorders.

Subjects and Methods

The subjects comprised 169 unrelated, mentally

normal Chinese children in Southern Taiwan

with seizure disorders. A study of history, clinical

examination, routine laboratory investigations

and EEG were performed to exclude other causes.

No definite causes of seizures, inheritance of

known central nervous system (CNS) disorders, or

no chromosomal anomalies, were found and all parents were free of seizures. A total of 284

parents of the patients agreed to participate in the investigation, which was a prerequisite. All were enrolled consecutively at the Department of Pedi-atrics at Kaohsiung Medical College Hospital. Five hundred and eighty-four healthy, unrelated

indi-viduals were included as a control group for HLA

antigen analysis. They were selected randomly

from among persons who visited the hospital for minor surgical conditions (not of genetic origin)

and nonconsanguineous parents of children

ex-amined in the pediatric outpatient clinic for sim-ple nongenetic diseases. Among them, 584 volun-teers were tested for class I antigens and 134 of these 584 for class II antigens, in the latter period of this investigation, and haplotype frequencies were determined for 252 controls.

The types of seizures were classified in accord-ance with the International League Against Epi-lepsy (ILAE) recommendations29) into idiopathic generalized seizures (74 cases) and simple partial seizures (33 cases), and febrile convulsions (62

cases) were added to the study as a special

syndrome.

1) HLA-A, -B, -C, and -DR typing

HLA antigens were identified on lymphocytes separated from heparinized peripheral blood by means of the Ficoll-Hypaque density gradient

centrifugation technique30>, and the microcytoto-xicity test of Mittal et al.3i) and the Terasaki32)

panel plate method. DR typing was performed on

B cell-enriched peripheral mononuclear cells. The

B cell enrichment was accomplished by a method

based on the different mobilities of cells in a discontinuous density gradient of Percol133). The

microcytotoxicity test and the Terasaki-panel

plate method were also used.

The following HLA antigens were examined in

this investigation:

HLA-A

HLA-B

HLA-C

HLA-DR

The antisera

Corp, West Germany,

DR from C-six Diagnostics

1, 2, 3, 9, 10, 11, w19, w23, 24, 25, 26, 28, w32 w4, 5, w6, 7, 8, 12,-13, 14, 15, w16, 17, 18, w21, w22, 27, w35, 37, w38,

40, w44, w49, w51, w55, w56,

w60, w73

w2, w3, w4, w7 1, 2, 3, w4, 5, w6, 7, 2 + Qwl, MT2,

MT3

were purchased from Boehring

and the antisera for HLA

, Inc., USA.

(3)

-E189-2) Statisticalmethods

HLA antigen frequencies (ab were determined

by direct counting. The association of a particular disease with a particular HLA antigen was quan-titated by calculating the "relative risk". The relative risk (RR) values were calculated accord-ing to the followaccord-ing equation34).

RR =Pd (1 ff Pc)/Pe (1 - Pd)

where Pd is the frequency in patients and P, that

in controls. RR indicates how many times more

frequently the disease occurs in a group of indi-viduals carrying the antigen relative to a group lacking it.

Gene frequency was estimated according to the following equation:

g=1-Vi:f

where g is the gene frequency and fthe antigen

phenotype frequency in the population.

For estimation of the haplotype frequencies

from the phenotype data, the equation of Ceppel-lini et al.35) was used:

X,j==P,Pj + D,j

were PiPj is the product of the gene frequencies of'

the antigens forming the haplotype and Dij the gametic association of these antigens. Since a

crossover within the HLA region is relatively rare, the demonstration that 2 siblings share the same 2 haplotypes, as judged on typing for HLA-A and B alone, usually implies that they are also identical

as to HLA-C, D, DR, and other genes within the

same region. This is fortunate, since most histo-compatibility testing laboratories can reliably type only the HLA-A and B antigens at the present

time36). Therefore, only HLA-A and B were

con-sidered for haplotype analysis in this study.

Linkage disequilibria, D (delta values), were

computed by subtracting from the haplotype fre-quency the product of the gene frequencies of the antigens describing the haplotype. The statistical significance of the linkage disequilibrium

coeffi-cient, "delta", was evaluated by means of an

approximate Chi-square calculated as follows:

4n (h-ggb)2

H-ggb

X2=

[1+

]2

gagb(2-g.) (2-gb) 2 (1-g,) (1-gb)

where n is the number of subjects, h the estimated

haplotype frequency, and g, and gb the gene

･frequencies37}.

The Chi-square test with Yates' correction for

continuity was used throughout this

investiga-tion. Only values of p<O.OOI were considered

significant.

Results

HLA antigens in patients

The HLA antigen distribution, gene frequencies and RR values for all 169 patients, with 3 different

types of seizures disorders, were studied, as

shown in Tables 1, 2, 3 and 4.

The HLA antigen did not exhibit a statistically significant distribution, except for a relatively high frequency and deviating RR value (positive

association) of antigen HLA-Bw21 (x2=7.626,

p<O.Ol, RR=･ 12.30) in patients with idiopathic

generalized seizures, as compared with normal

controls (Tables 1 and 5).

In patients with simple partial seizures, there were statistically significant high frequencies and deviating RR values (positive association) of

HLA-Bw22 (x2=14.803, p<O.OOI, RR=7.84) and -Cw7

(x2 :35.602, p<O.OO05, RR==18.32), and a relatively high frequenc'y and deviating RR value (positive association) of -Cw3 (x2=7.457, p<O.Ol, RR=2.92),

as compared with normal controls (Tables 2 and

5).

In patients with febrile convulsions, there was a statistically significant high frequency and devi-ating RR value (positive association) of HLA-Cw7 (x2=10.997, p<O.OOI, RR=7.23), and a relatively high frequency and deviating RR value (positive association) of -A2 (x2=10.402, p<O.O05, RR =2.70), , as compared with normal controls.

HLA antigens in parents

There was a statistically significant high fre-quency and deviating RR value (positive associa-tion) of HLA-Bw6 (x2==23.563, p<O.OO05, RR=2.76)

and a low frequency and deviating RR value

(negative association) of HLA-Cw3 (x2=15.726,

p<O.OOI, RR :O.39) in parents of idiopathic gen-eralized seizure cases, as compared with normal controls. HLA-B5 was found to show a relatively

(4)

-Table 1 Distribution of HLA antigens, gene frequencies, and RR values in idiopathic generalized selzures

Patients(n =74) Parents(n =122) Controls(n =584)

HLA

n af(%) gf(O/o)

RR

X2 n af(%) gf(O/o)

RR

X2 n af(O/o) gf(%) Al I 1,4 O.7 0.99 O.235 2 1.6 O.8 1.20 O.053 8

_L4

O.7

A2 43 58.1 35.3 1.38 1.664 65 53,3 31.6 1.13 O.392 293 50.2 29.4

A3 2 2.7

_L4

1,22 O,065 3 2.5 1.2 1.11 O.025 13 2.2 1.1

A9 23 31.1 17.0 1,38 1,434 39 32,O 17.5 1.44 2,814 144 24,7 13.2

AIO 1 1,4 O.7 7.99 3.117 2 1.6 O.8 8.11 2.244 1 O,2 O.1

All 40 54,1 32,2 1.11 O.192 62 50.8 29.9 O.48 O.O17 300 51.4 30,3

Aw19 5 6.8 3.4 O.85 O.124 8 6.6 3.3 O.82 O.256 46 7,9 4.0

Aw23 A24 A25 oo1 N-1.4 -LO.7 ... O.254 -1.556 ooo 7r- --- --- 0.421 --2oo. O.3 -" O.2

--A26 6 8.1 4,1 1.11 O.055 6 4.9 2.5 O.65 O.934 43 7.4 3.8

A28 2 2,7

_L4

1.59 O.363 1 O.8 O.4 O.47 O.526 10

_L7

O.9

Aw32 2 2.7 1.4 2.29 1.107 1 O.8 O.4 O.68 O.I33 7

L2

O.6

Bw4 7 9.5 4.8 O.48 3.380 15 12.3 6.3 O.64 2.318 105 18.0 9,4

B5 18 24.3 13.0 1.84 3.691 31 25,4 13.6 1,95 7.276 87 14.9 7,7

Bw6 26 35,1 19.5 1.95 5.879 53 43.4 24.8 2.76 23.563 127 21.7 11,5

B7 o

m

-

.

3,851 4 3.3

_L7

O.65 O.645 29 5.0 2.5

B8 1 1.4 O,7 O.49 O.506 1 O.8 O.4 O.29 1:582 16 2.7

_L4

B12 1

L4

O.7 O.56 O.328 2 1.6 O.8 O.68 O.264 14 2.4 1.2

B13 10 13.5 7.0 O.73 O.792 16 13.1 6.8 O,70 1.473 103 17.6 9.2 B14 2 2.7 1.4 O.29 1.107 3 2,5 1.2 2.08 1.155 7

L2

O.6

Bl5 8 10.8 5.6 O.73 O,642 13 10.7 5.5 O.72 1.093 83 14.2 7.4

Bwl6 1 1,4 O.7 1.99 O.393 1 O.8 O.4 1.20 O.035 4 O.7 O.3

B17 15 20.3 10.7 1.03 O.O12 32 26.2 14.1 l.43 2.478 116 19.9 10.5

B18 1 1.4 O.7 1.59 O.187 1 O.8 O.4 O.96 O.OOI 5 O.9 O.4

Bw21 3 4.1 2.0 12.30 7.626 0

-m

-

O.421 2 O.3 O.2

Bw22 6 5.4 2.7 3.88 6.122 7 5,7 2.9 2.07 3.324 13 2.2

_Ll

B27 3 4,1 2.0 O.44 1.335 2

L6

O.8 O.17 6.329 51 8.7 4.5

Bw35 7 9.5 4.8 1.03 O,O03 11 9,O 4.6 O.97 O.O15 54 9.2 4.7

B37 1 1,4 O.7 3.99 1.471 1 O.8 O.4 2.40 O,542 2 e.3 O.2

Bw38 1

L4

O.7 1.99 O.393 1 O.8 O.4 1.20 O.033 4 O.68 O.3

B40 29 39.2 22.0 O.84 O.464 41 33.6 18.5 O,66 3.527 253 43.3 24.7 Bw44 o

_T

_-

_m

O.513 o

_-

_rm O.844 4 O.68 O.3

Bw49 o

_-

_L

_-

O.135 o

_-

--

O.213 1 O,17 O.1

Bw51 o

-

T

-

O.383' o

_-

_rm O.631 3 O.5 O.3

Bw55 2 2.7 1.4 16.19 4.484 1 O.8 O.4 4.82 O.078 1 O.17 O.1

Bw56 o

_-

_m

_-

1,326 o

_-

_rm 2.717 18 3.10

L6

Bw60 o

_-

O.641 1 O.8 O.4 O.96 O.OOI 5 O.90 O.4

Bw63 o _rr

-

L

O.135 o

-

O.213 1 e.17 O.1

Bw73 o

_m

-r

O.254 2

L6

O.8 4.85 3.014 2 O.34 O.2

Cw2 o

_-

_L

-

4,122 3 2.5 1.2 O.45 1.793 31 5.30 2.7

Cw3 23 31.1 17.e O.65 2.264 26 21.3 11.3 e.39 15.726 239 40,9 23.1

Cw4 11 14.9 7.7 !.10 O.071 12 4.8 5.0 O.69 1.231 80 13.7 7.1

Cw7 1

L4

O.7 1.13 O.O13 3 2,5 1.2 2.08 1.154 7 1.2 O.6

af: antigen frequency, gf: gene frequency, RR: relative risk,

high frequency (x2=7.276, p<O.Ol, RR=1.95) in the same seizure group (Tables 1 and 5).

There was a statistically significant high

fre-quency and deviating RR value (positive

associa-tion) of HLA-Cw7 (z2=33.133, p<O.OO05,

RR=13.46) in parents of simple partial seizure E191

(5)

-Table 2 Distribution of HLA antigens, gene frequencies, and RR values in simple partial seizures Patients (n=33) Parents (n=57) Controls(n =584)

HLA

n af(O/.) gf(%)

RR

X2 n af(%) gf(O/o)

RR

X2 n af(O/o) _gf(%) Al 2 6,1 3,1 4.65 4.376 2 3,5 l..8 2.62 1.552 8 1.4 O.7

A2 20 60.6 32.3 1.53 1.362 36 63,2 39.3 1.70 3.514 293 50.2 29.4

A3 1 3.0

L5

1.37 O.091 1

L8

O.9 e.78 O,051 13 2.2

Ll

A9 9 27.3 14.7 l.15 O,110 17 29.8 16.2 1.30 O.743 144 24.7 13.2

AIO 1 3.0 1,5 18.22 4.080 1 1.8 O.9 10.41 2.460 1 O.2 O.1

All 11 33.3 18.4 O.47 3.331 16 28,1 15,2 O.37 10.366 300 5L4 30.3

Aw19 1 3.0

L5

O.39 1.045 2 3,5

_L8

O.43 1.43e 46 7.9 4.0

Aw23 A24 oo T" -T L- O.113

m

oo -T -- -- 0.198

"

2o _O.3

-O,2

-A25 A26 o5 -15.2 -7.9 -2.25 -2.647 o10 -l7,5 m9.2 -2.68 =5.819 043 m7.4 -3.8

A28 1 3.0

_L5

1.79 O.315 2 3,5 1.8 2.09 O.916 10

L7

O.9

Aw32 1 3.0

_L5

2.58 e.822 1

L8

O.9 1,47 O.133 7

_L2

O.6

Bw4 1 3.0 1,5 O.14 O.912 6 10.5 5.4 O.54 2.012 105 18.0 9.4

B5 4 12.1 6.3 O,79 O,194 8 14.0 7.3 O.93 O.034 87 14.9 7.7

Bw6 7 21.2 11.2 O.97 O.O13 21 36.8 20.5 2.10 5.842 127 21.7 ll,5 B7 2 6.1 3.1 1.23 e.osl 6 10.5 5,4 2･.25 3.1!2 29 5,O 2.5 B8 o

--

-

O.164 3 5,3 2.7 1,97 1.157 16 2.7

_L4

B12 2 6.1 3.1 2.63 1,664 2 3.5

_L8

l.48 O.265 14 2.4

L2

B13 8 24.2 13.0 1.49 O.923 11 19.3 10.2 1.12 0.183 103 17.6 9.2 B14 o

--

-

O,409 o _-.

_L

_-

O,691 7

L2

O.6

B15 o

-

`

4.268 1

L8

O.9 O.11 6,697 83 14.2 7.4

Bw16 o

_-

O.233 o

-

T

pt .O.399 4 0.7 O.3

B17 8 24.2 13.0 l,29 O.374 16 28.1 15.2 1,57 2.142 116 19.9 10.5

B18 o

_-

_T

_-

O,284 o

_-

_r

_-

O.497 5 O.9 O.4

Bw21 o

_m

_-

_m

0.113 o

_.

_-

O.199 2 O.3 O.2

Bw22 5 15.2 7.9 7.84 14,803 4 7.0 3.6 3.31 2,957 13 2.2

_Ll

B27 4 12.1 6.3 1.44 O.441 5 8,8 4.5 1.00 O,O09 51 8.7 4,5

Bw35 4 12.1 6.3 1,35 O.307 6 10.5 5.4 1.15 O.099 54 9.2 4.7

B37 e

_r

_m

_-

O.!13 o

_d

_m

_-

G.I9g 2 O.3 O.2

Bw38 0

_-

_L

O.236 o

_T

_-

_r

e.399 4 O.7 O.3

B40 15 45.5 26.1 1.09 O,061 25 43.9 25.1 1.02 O.094 253 43.3 24.7

Bw44 o

_-

_m

_-

O.236 o

_L

_m

_-

O.392 4 O.7 O,3

Bw49 o _rm

_-

_"

O.068 o

_-

_r

O.102 1 O.2 O.1

Bw51 2 6.1 3.l .12.49 5.972 2 3.5 1.8 7.04 4,759 3 ,O,5 O.3

Bw55 o

_-

_m

_-

O,068 o

_-

O.102 1 O.2 O.1

Bw56 o _rm

_L

_m

1,052 o _ne

_-

1.813 18 3.1 ,1.6

Bw60 o

_-

_L

O.284 o

_-

O.497 5 O.9 O.4

Bw63 o

_-

O.068 o

-

m

-

O.102 l 0.2 O.1 Bw73 o

-

L

-

O.ll3 2 3.5 1.8 10.58 4.012 2 O.3 O.2

Cw2 o

-

1.843 0

L

`

-

3.186 31 5,3 2.7

Cw3 22 66.7 42.3 2.92 7.457 34 59.6 36.5 2.13 6,695 239 40,9 23.1

Cw4 3 9.1 4,7 O.63 O,575 8 14.0 7.3 1,03 O.OQ4 80 13.7 7.1

Cw7 6 18.2 9.5 18.32 35.602 8 14.0 7.3 13.46 33.133 7 1.2 O.6 af: antigen frequency, gf: gene frequency, RR : relative risk,

cases, which was similar to that of patients with simple partial seizures, as compared with normal

controls, and a relatively high frequency and

deviating RR value (positive association) of HLA-Cw3 (x2=6.695, p<O.Ol, R =2.13) or relatively low

frequencies and deviating RR values (negative

(6)

-E192-Table 3 Distribution of HLA antigens, gene frequencies, and RR values in febrile convulsions Patients(ni=62) Parents(n= 105) Coritrols(n=:584)

HLA

n af(%) gf(%)

RR

X2 _n af(%) gf(%)

_RR

X2 _n af(O/o) gf(%) Al A2 o45 m72.6 N47.6 -2.70 O.863 10.402 o62 -59,O -36.0 -1.43 O.541 2.465 8293 1,4 50.2 O.7 29.4 A3 2 3.2 l.6 l.46 O.256 4 3.8 1.9 1.73 2.463 13 2.2 1.1

A9 16 25.8 13.9 1.06 O.041 25 23,8 12.7 O.95 O.O04 144 24.7 13.2

AIO 1 1,6 O.8 9.56 O.561 3 2.9 1.4 17.15 6.950 1 O.2 O.1

All 23 37.1 20.7 O.56 O.214 36 34.3 18.9 O.49 O.633 300 51.4 30.3

Aw19 6 9.7 5.0 1,25 O.254 6 5.7 2.9 O.3! O.156 46 7,9 4.0

Aw23 A24 oo NN mm -m O.214

-oo 7m -- Lr O.132

m

2o _O.3

-O.2

-A25 A26 o11 -17.7 -9.3 N2.71 -6.594 o14 "13.3 rm 6.9 m1.94 m3.425 o43 rm 7.4 -3.8

A28 2 3.2

_L6

1.91 O.120 7 6.7 3.4 4.10 7.140 10

_L7

O.9

Aw32 o

_-

O.756 o

_-

O.475 7 1.2 O.6

Bw4 15 24.2 12.9 1.46 1,047 22 21.0 11.1 1.21 O.346 105 18.0 9.4

B5 3 4.8 2.4 O,29 3.928 9 8,6 4.4 O.54 O.OOI 87 14.9 7.7

Bw6 17 27.4 14.8 1.30 1.042 25 23,8 12.7 1.12 O.117 !27 21.7 11.5

B7 1

L6

O.8 O.3! 1.422 7 6.7 3.4 l.37 2.681 29 5.0 2.5

B8 o

_'

_m

1.741 2

L9

1.0 O.69 O.030 16 2.7

_L4

B12 1

_L6

O.8 O.67 O.155 2

_L9

_LO

O.79 O.101 14 2.4 1.2

B13 9 14.5 7.5 O.79 O,382 17 16.2 8.5 O.90 2.233 103 17.6 9.2･

B14 2 3.2

_L6

O.75 1.687 2 1.9

_LO

1.60 1.Q65 7 1.2 O.6

B15 3 4.8 2,4 O.31 3.489 5 4,8 2.4 O.30 1.136 83 14.2 7.4

Bw16 o

_-

--

O.433 2

_L9

LO

2.82 2.483 4 O,7 O.3

B17 13 21.0 11.1 1.07 O.041 19 17.1 9.0 O.89 2.481 116 19.9 10.5

B18 o

L

-

L

O.532 o

-

O.344 5 O.9 O.4

Bw21 o

_"

_'

O.214 o

"

-

e.139 2 O.3 O.2 Bw22 4 6.5 3,3 3.03 2.437 8 7,6 2.9 3.62 7.031 13 2.2

_Ll

B27 6 9.7 5.0 1.12 O.060 13 12.4 6.4 1.48 O.853 51 8.7 4.5 Bw35 1 1.6 O.8 O,16 4.191 3 2.9 1.4 e.29 O.852 54

92

4.7

B37 o

-

O.214 o _rm

_-

_m

O.132 2 O.3 O.2

Bw38 o o o

r

O.431 1

LO

O.5 1.39 O.403 4 O.7 O.3

B40 34 54.8 32.8 1.59 3.012 47 44.8 25.7 1.06 O.077 253 43.3 24.7

Bw44 1 1.6 O.8 2.38 O.631 1 1.0 O.5 1.39 O.401 4 O,7 O.3

Bw49 o o o

-

O.113 e

_L

_-

O.071 1 e.2 O.1

Bw51 1

_L6

O.8 3,l7 1.102 2

_L9

1.0 3.76 3.382 3 O.5 O.3

Bw55 o

_-

_m

_N

e.113 1

_LO

O.5 5.61 2.384 1 O.2 O.1 Bw56 o

--

-

1.971 o _rr

_'

_fi 1.242 18 3.1

_L6

Bw60 o

_-

O.531 1 _LO O.5 l,11 O.223 5 O.9 O.4

Bw63 o

_-

O.113 o

_-

O.071 1 O.2 O.1

Bw73 2 3,2 1.6 9.70 3.670 4 3.8

_L9

11.52 8.765 2 O.3 O.2

Cw2 1

L6

O.8 O.29 1.632 3 2.9 1.4 O,52 O.023 31 5.3 2.7

Cw3 32 51.6 30.4 1.54 2.634 50 47.6 27.6 1.31 1.639 239 40.9 23.1

Cw4 6 9,7 5.0 O.68 O,794 7 6,7 3.4 O.45 O.182 80 13.7 7.1

Cw7 5 8.1 4.1 7.23 10.997 11 10.5 5.4 9.65 26,618 7

_L2

O.6

af:antigen frequency, gf:gene frequency, RR:relative risk.

'

association) of HLA-All (x2=10.366, p<O.O05, group(Table2).

RR=O.37) and HLA-B15 (x2 :6.697, p<O.Ol, RR= For febrile convulsions, HLA-Cw7 (x2==26.618,

O.11) were found in the simple partial seizure p<O.OO05,RR=9.65) was found to

(7)

-E193-cally significant high frequency among parents, as in patients, and the HLA-AIO (x2=:6.950, p<O,Ol,

RR==17.15), -A28 (x2=7.140, p<O.Ol, RR=4.10), -Bw22 (x2==7.031, p<O.Ol, RR=3.62), and -Bw73 (x2=8.765, p<O.Ol, RR=11.52) showed relatively

high frequencies among parents of febrile convul-sion cases, as compared with normal controls.

Haplotype frequency and linkage

disequi-librium

Haplotypes with significant linkage disequilib-rium in the different seizure disorders are listed in Tables 6, 7 and 8. A statisitcally significant high frequency and significant positive linkage disequi-librium of haplotype HLA AI1; Bw6 were noted in both patients (x2=18.906, p<O.OO05, D/1000==180) and parents ix2==21.737, p<O.OO05, d/1000==156),

Table 4 Distribution ･of HLA-DR antigens and gene frequencies in different types of seizure disorders Patients Controls

HLA

n af(O/o) f(%)

RR

X2 _n af(%) f(%) DRI 2 9.1 4.7 4.45 2.86 3 2,2

_Ll

DR2 4 18.2 '9.6 O.88 O.05 27 20.1 10,6 DR3 4 18.2 9.6 1.13 O.04 22 16,4 8.6

DRw4

3 13.6 7,O 1.35 O.20 14 10.4 5,3 DR5 le 45.5 26,2 O.53 1.93 82 61.2 37,7

DRw6

o

_T

_"

_m

O.50 3 2.2

Ll

DR7 l 4.5 2.3 .O,29 1.57 19 14.2 7.4

DR2+DQw1

o

_-

O.50 3 2.2

Ll

MT2

2 9.1 4.7 6.6 1,89 2 1.5 O.8

MT3

o･

rr

-

O.17 1 O.8 O.4

af1antigen frequency, gf:gene frequency,

RR : relative riskL

Table 5 Distribution and significance of HLA antigen frequencies and deviating RR values disorders in different seizure Significantly highfrequency (p<O.OOI)

RR

value Relatively highfrequency (p<O.Ol-O,O05)

RR･

value Significantly lowfrequency (p<O.OO1)

RR

value Relatively lowfrequency (p<O.Ol-O.O05)

RR

value IdiopathicPatients Bw21 12.30 generalized (x2=7.626) seizuresParents Bw6 2.76 B5 1.95

_Cw3

O.39 (x2==23.563) (x2==7.276) (x2=15.726)

SimplePatients.

Bw22 7,84 Cw3 2.92 partial.selzures _(x2:=14.803) Cw7 18.32 (x2=7.457) (x2=35.602)

Parents Cw7 13,46 _Cw3 2.13 All O.37

(x2==33.133) (x2=6.695) (x2-10.366) B15 O.ll (x2=6.697)

FebrilePatients

Cw7 7,23 A2 2.70 convulsions (x2=10.997) (x2=10.402) Parents Cw7 9,65 AIO 17.15 (x2=26.618) (x2=6.95) A28 4.10 ' (x2=7.140) Bw22 3.62 (x2=7.03!) Bw73 11.52 (x2=8.765) RR : relative risk.

and a relatively high frequency and significant

positive linkage disequilibrium of HLA A2;B5

(x2=7.736, p<O.Ol, D/1000=96) were found in

parents of idiopathic generalized seizure cases,

which were comparable to those of normal

con-trols (Tables 6 and 9).

' HLA A9; Bw6 w'as found to show a statistically significant high frequency with a significant

posi-tive linkage disequilibrium ix2=12.371, p<O.OOI, D/1000=74) in parents of simple partial seizure cases, and a relatively high frequency and signifi-cant positive linkage disequilibrium of HLA AI;

B17 (x2==9.991, p<O.O05, D/1000=57), A2; Bw22

(x2=6.808, p<O.Ol, D/1000==66) and A26; B35

(x2==7.348, p<O.Ol, D/1000=96) were found in

patients with simple partial seizures, as compared

(8)

-Table 6 Distribution of HLA-A B haplotype frequencies and linkage disequilibria in generalized seizures

idiopathic Patients(n=74) Parents (n=122) Controls(fi=314) Haplotypes

n hfllOOO DllOOO X2 _n hf/1000 D/1000 X2 _n hf/1000

AllBw4

o

_T

+

O.067 o

_-

_L

O.391 1 3

AliBw6

1 14 13 O.743 1 8 6 2.580 o

-AliB13

o

_L

_-

O.067 e

_-

O.390 1 3

Al;B17

0

_'

₊

_-

o

_L

_-

o

-AilB35

o

_-

O,067 1 8 8 O.481 1 3

Al;B40

o

_-

O.067 o

-

O.390 1 3

A2iBw4

5 68 51 1.487 8 66 46 O.428 21 67

A2;B5

8 108 62 2.800 17 139 96 7.736 17 54

A2IBw6

5 68 -1 1.043 18 148 70 4.206 24 76

A2:B7

o

_-

O.067 1 8 3 O.481 1 3

A2;B8

o

_-

O.067 o

_L

_-

O.390 1 3

A2iB12

1 14 12 O.991 1 8 6 O.041 2 6

A2lB13

2 27 2 O.035 3 25 4 2.578 22 7

A2iB14

1 14 9 1.914 2 16 12 2,242 1 3

A2IB15

6 81 61 O.744 6 49 32 O.038 15 48

A2;B17

7 95 57 O.142 13 107 62 1.293 23 73

A2;B21

o

_r

_-

o.e67 o

_L

_T

O.390 1 3

A2lBw22

o

n

-

O.179 o

_"

_rm 1.172 3 10

A2;B27

o

_r

_-

e.523 o

L

"

3.571 9 29

A2iB35

2 27 10 O.252 4 33 19 O.O14 11 35

A2]B37

o

_-

O,067 o

m

rm O.390 ! 3

A2:B40

11 l49 71 O.197 14 115 57 2.642 56 178

A2iBw51

o

_-

o

_-

_m

o

_m

A2;Bw56

o

r

v

O.112 o

_-

O.786 2 6

A2iBw63

o

r

-

O.067 o

L

-

O.390 1 3

A2lBw73

o

n

-

L

o

₊

_T

_-

o

-A3iB5

o

_n

_-

O.067 o

"

-

O.390 1 3

A3;Bw6

o

_-

O,067 2 16 13 2.242 1 3

A3IBw22

2 27 27 4.096 2 16

_T

2.202 o

-A3;B40

o

_r

_-

_L

o

_-

16

_-

o

_T

A9lBw4

1 14 6 O.175 2 16 5 O.152 5 16

A9;B5

3 41 19 2.042 5 41 17 O,738 8 25

A9lBw6

1 14 -19 O.313 3 25 _-18 O.784 4 13

A9iB7

o

_'

_-

0.236 o

_-

1,575 4 13

A91B12･

o _em

-

O.236 1 8 7 O.163 4 13

A9lB13

4 54 42 O.810 4 33 21 O.182 8 25

A91B15

1 14 5 O.041 2 l6 6 O.153 7 22

A9lB17

1 i4 _-4 O.092 5 41 16 O.033 14 45

A9lBw22

1 14 9 l.914 o

_L

o.3ge 1 3

A9iB27

o

_-

_.

O.284 o

-

m

1.972 5 l6

A9:B35

2 27 19 O.819 3 25 17 2,574 2 6

A9iB40

6 81 44 1.672 10 82 50 O.125 26 83

A9;Bw44

o

_-

O.112 e

_N

_-

O,041 2 86

A9iBw56

o

_-

_m

O.236 o

_-

1.575 4 13

A9;Bw60

o

-

O.067 l 8 7 O.481 1 3

A9;Bw73

o

_-

_L

2 16 15 2.202 o

-AIOlBw6

o

_"

_-

O,067 o

_m

'

O.390 1 3 AIOiB13 o

_-

_L

_-

2 16 15 2.202 o

-AIO:B17 1 14 13 O.743 1 8 7 O.291 o ..."

AlliBw4

1 14 2 O.062 2 16

_-3

1.653 13 41

(9)

-AlliB5

5 68 26 3.231 10 82- 41 2.366 14 45

AlllBw6

18 243 180 18.906 28 230 l56 21.737 21 67

AllIB7

o

_m

_-

O.401 1 8 3 O.972 7 22

AllIB8

1 14 12 O.313 1 8 7 O.I63 4 13

AlliB12 o

-T

O.112 o

_-

O.786 2 6

A!1iB13 3 41 19 0.115 8 66 46 O.428 21 67

AlllB14 o

_-

O.067 1 8 4 O.481 1 3

AlllB15 1 14 _-4 O.635 4 33 17 3.433 26 83

All;B17 3 41 7 O.343 7 57 15 O.621 17 54

All;B18 1 14 12 O.914 1 8 7 O.481 1 3

AlliBw21

o

_-

O.067 o

m

-

O.390 1 3

All;Bw22

2 27 18 1,888 2 16 7 2.242 1 3

All1B27 2 27 21 O.O12 2 16 14 2.172 17 54

AlllB35 2 27 12 O.122 3 25. 11 O.130 6 19

AlliB40 10 135 64 O.551 16 131 76 3.586 68 217

AlliBw44

o

_-

O.067 o

_T

_-

O.390 1 3

AlliBw51

o

_-

rm.t.

-

o

-

o

-AlliBw56, o

_-

O.067 o

_m

₊

O.390 1 3

A19;Bw4

o

₊

_-

O.112 o

_"

_m

O.786 2 6

A19;B5

o

-

m

O.236 1 8 4 O.163 4 13

A19;Bw6

1 14 7 O.551 1 8 -O.2 O.024 3 10

A19;B7

o

_-

O.179 o

-

1.172 3 10

A19;B13 1 14 12 O.551 3 25 23 1.462 3 10

A19lB17 1 14 10 O.551 1 8 3 O.024 3 10

A19iBw22

o

_-

_rm

_T

o

-

o

_r

A19iB27 o

_-

O.067 o

_r

_-

O.390 1 3

A19iB40 3 41 34 1.734 3 25 19 1.467 3 10

A19lBw55

1 14 14 O.743 1 8 8 2.580 o _rm

A23;B17 o

_-

O.067 e _-- _in O.390 1 3

A24;B17 o

-

T

o

-

o _rr

A25iB5

1 14 13 1.914 o

T

nt O.390 4 13

A261Bw4

1 14 12 1.914 1 8 6 O,481 1 3

A26IB5

o

-

e.o67 o

-

O.390 1 3

A26iBw6

o

-

O.112 o

_-

O.786 2 6

A26iB7

o

_-

O.236 o

_-

1.575 4 13 A26iB13 o

-

o

-

o _wu A26iB17 2 27 23 1L992 3 25 22 O.783 1 3

A26lBw22

e

_"

_N

O.067 o

_m

_-

O.39e 1 3

A26iB27 o

_-

O.067 o

_-

O.390 1 3

A26lB35 1 14 12 O.551 2 16 15 O.362 3 10

A26lB40 o

_-

O.179 1 8 3 O.024 3 10

A26;Bw55

o

_-

_-. O.067 o _rm

_-

O.391 1 3

A26;Bw56

o _im

_-

O.067 o

_-

O.391 1 3

'

A26;Bw73

o

-

O.I12 o

-

m

O.786 2 6

A28;Bw6

o

m

-

o

-

o,

-A28iB7

o

-

o

-

o

-A281B13 o

-

O.067 o

-

O.390 I 3 A281B17 o

m

h

O,067 o

_-

O.390 1 3 A28lB40 o

-

um e.112 o

N

-

O.786 2 6･

A281Bw49

o

_-

O.067 o

_-

_m

O.390 1 3

A32lB40 1 14 IO.9 e.743 o

_-

_th

_m

o

-hf/1000 : haplotype frequencies per thousand, D/1000:delta values per thousand.

(10)

-E196-Table 7 Distribution of HLA-A-B haplotype frequencies and linkage disequilibria in simple partial selzures

Patients(n=33) Parents (n=57) Controls(n:=314)

Haplotypes n hf/1000 D!1000 X2 n hf/loee D/1000 X2 n hf!1000

Al1Bw4

o

.

-

e.113 o

_m

_L

O.182 ! 3

Al:Bw6

o

-

o

_-

_rm _rm o

_m

AllB13

o

-

L

O.113 o

_-

O.182 1 3

AliB17

2 61 57 9.991 2 36 33 5.435 o

-Al:B35

o

_.

_-

O.113 o

m

-

O.182 1 3

Al;B40

o

--

O.113 e

_m

_-

O.182 1 3

A2iBw4

1 30 25 O.675 2 36 15 O.844 21 67

A2lB5

3 91 71 O.743 4 71 42 O.236 17 54

A21Bw6

1 30 _-6 O.952 4 71 -10 O.031 24 76

A2iB7

1 30 20 O.562 2 36 15 2.780 1 3

A2lB8

o

_-

O.113 o

_-

_m

O.182 1 3

A21B12

1 30 o O.169 1 18 11 O.752 2 6

A2lB13

2 61 19 O.044 3 54 l4 O.233 22 70

A2;B14

o

_-

_rm O.562 o

_r

_-

O.182 1 3

A2lB15

o

_-

_m

1.653 o

m

n

2.840 15 48

A2iB17

2 61 19 O.075 2 36 -24 1.125 23 73

A2IB21

o _un

_-

O.113 o

-

T

O.182 1 3

A2lBw22

3 91 66 6.808 4 71 57 6.334 3 10

A2lB27

1 30 10 O.023 2 36 18 O.074 9 29

A2iB35

o

m

7

1.194 2 36 15 O.053 11 35

A2;B37

o

_-

O.I13 o

-

O.182 1 3

A2;B40

5 152 68 O.020 5 89 -10 2.884 56 178

A2lBw51

o

-

rm o

-

rm

L

o

-A2IBw56

o

-

O.215 o

-

O.372 2 6

A2lBw63

o

_-

O.113 o

-

O.182 1 3

A2iBw73

o

r

L

-

1 18 11 e.963 o

-A3;B5

o

_m

_-

O.113 o

_L

_-

e.182 1 3

A3lBw6

o

_"

_ne O.113 o

m

-

O.182 1 3

A3lBw22

o

--

rm o

-

o

-A3iB40

1 30 13 2.058 1 18 i6 O.963 o

_T

A9:Bw4

0

_T

T

O.OOI o

_-

O.923 5 16

A9lB5

o

_-

_"

O.531 1 18 6 O.134 8 25

A9iBw6

o

_-

O.028 6 107 74 12.371 4 13

A9iB7

o

_-

O.028 o

-

O.735 4 13

A91B12

o

-

O.028 1 18 15 O.083 4 13

A9lB13

o

_L

_-

o.Ieo o

-

1.480 8 25

A9IB15

o

L

-

O.752 o

--

1.301 7 22

A9:B17

2 61 42 e.173 1 18 _-7 O.912 14 45

A9lBw22

1 30 18 O.562 1 18 12 1.861 1 3

A9;B27

2 61 52 1.161 2 36 29 O.962 5 16

A9lB35

1 30 21 1.802 1 18 9 O.752 2 6

A9IB40

5 155 117 l.733 5 89 48 O.025 26 83

A9lBw44

o

-

O.215 o

-

m

O.372 2 6

A9lBw56

o _rm _rr O.028 o

_-

O.735 4 13

A9IBw60

o

-

O.113 e

T

-

O.!82 1 3

A9iBw73

o

-

m

1 18 15 O.963 o

_"

AIO;Bw6

1 30 28 e.562 1 18 16 1.861 1 3 AIO:B13 o

_-

o

-

m

-

o

-AIO1B17 o

_m

_r

_rm o

-

o

-All;Bw4

o

-

1.422 1 18 10 O.766 13 41

(11)

-E197-AlliB5

o 30 18 O.153 3 54 43 O.071 14 45

AlllBw6

1 121 100 1.322 4 71 40 O.O14 21 67

'All;B7 o _pt

_m

.O.752 1' 18 10 O.Q57 7 22

AllIB8

o

-

O.028 o

-

e.735 4 13 AlllB12 o

r

7

O.215 o _rr

-

O.372 2 6

AlliB13 1 61 37 O.029 2 36 20 O.844 21 67

AlliB!4 o

r

+

O.113 o

_n

-

O.182 1 3

AlliB15 o

-

2.950 1 18 17 1.405 26. 83.

All1B17 o 30 6 O.344 1 18 -5 O.186 17 54

AllIB18 o

"

-

O.113 o

m

-

O.182 1 3

All;Bw21

o

_-

O.113･ 0

L

-

O.182 1 3

AllIBw22

o

_-

_"

O,113 o.

_-

_m

O.182 1 3

AlliB27 o

_-

_r

1.887 1 l8 11 1.404 17 54

AlliB35 o _pt _un O.644 o

-

1.115 6 19

All･]B40 4 121 73 1.634 4 71 33 5.704 68 217

AlllBw44

o .tnff

-

O.113 o

-

O.182 1 3

AlllBw51

1 30 24 1.913 1 18 15 O.963 o

-AlllBw56

o

_-

O.113 o

_"

_-

O.182 1 3

A19lBw4

o

_-

_u

O.215 o

-

O.372 2 6

A19iB5

o

_'

_rm O.028 o

_L

_-

O.735 4 13

A19lBw6

o

_-

O.322 o

-

O.553 3 io

A19lB7

o

_-

O.322 1 18 17 O,297 3 10

A19lB13 1 30 28 1,135 1 18- 16 O,297 3 10 A19lB17 o

_-

_'

O.322 o

-

ua O.553 3 10

A19iBw22

o

_-

_L

o

_-

_ne

₌

o

-A19lB27 o

"

-

O,113 o

m

-

O.182 1 3

A19lB40 o

_'

_-

O.322 1 18 14 O,297 3 10

A19;Bw55

o

_-

_L

o

_-

_`

e

-A23lB17 o

_-

O,113 o

-

O.182 1 3

A24iB17 o

_-

_m

_-

o

_-

o

-A25IB5

o

_"

_-

O.113 o

_m

_-

O.182 1 3

A26lBw4

o

_-

O.113 1 18 13 1,865 1 3

A26IB5

o

_-

_T

0.113 o

-

rm O.182 1 3

A26lBw6

o

_-

_rm O.215 1 18 _-1 O.752 2 6

A26iB7

1 30 28 O.651 2 36 31 O.963 4 13

A26IB13 1 30 20 1.913 1 18 9 O.963 o

-A26lB17 o

-

L

O.028 1 18 4 O,083 4 13

A26iBw22

o

-

rm O,113 o

T

-

O.182 1 3 A26IB27 o

_v

_-

O.113 o

-

O.182 1 3 A261B35 3 91 96 7.348 3 54 49 3.257 3 10 A261B40 o

_-

O.322 o

-

T

O.553 3 10

A26iBw55

o

_-

O;113 o

T

-

O.182 1 3

A26iBw56

o

-

O.113 e

_-

_m

O.182 1 3

A26iBw73

o

_"

_-

O.215 o

m

-

O.372 2 6

A28:Bw6

o

_-

o

-

r

o

T

A281B7

o

_-

_m

o

-

r

-

o

-A28;B13 1 30 28 0.562 1 18 16 1.865 1 3 A28lB17 o

-

mt O.113 1 18 14 1.865 1 3 A28lB40 o

-

=

O.215 o

-

m

O.372 2 6

A28iBw49

o _an

_-

O.113 o _rm

_-

O.182 1 3

A32lB40 o

'

-

o _rm

-

m

o

m

hfllOOO:haplotype frequencies per thousand, D/1000:delta values per thousand.

(12)

-El98-Table 8 Distribution of HLA-A-B haplotype frequencies and linkage convulsions

disequilibria in febrile

Patients(n=62) Parents (n=105) Controls (n=314) Haplotypes

n hf/IOOO D/1000 X2 n hf/1000 D/1000 X2 n hf/1000

Al;Bw4

o

_-

O.862 o

_L

_"

O.341 1 3

AliBw6

o

_-

_r

_-

o

N

-

o

-Al;B13

0

_-

_m

O.862 o

-

O,341 1 3

AllB17

o

_"

_-

o

-

N

o

T

AllB35

o

m

L

O.862 o

-

O.341 1 3

AliB40

o

_-

_L

O.862 o

-

r

O.341 1 3

A21Bw4

11 177 116 O.131 13 124 8 3.423 21 67

A2iB5

o

-

L

2.369 3 29 13 1.135 17 54

A2iBw6

6 97 27 O.292 10 95 49 O.372 24 76

A2iB7

o

_-

_L

O.862 1 10 _-2 O.677 1 3

A2lB8

o

_-

O.862 o

m

-

O.341 1 3

A2lB12

o

_-

_T

O,106 1 10 6 O.115 2 6

A2lB13

4 65 29 O.022 5 48 16 O.663 22 7

A2;B14

1 16 8 1.644 1 10 6 O,677 1 3

A2;B15

1 16 5 1.273 2 19 IO 1.673 15 48

A2:BI7

4 65 12 O,431 5 48 16 O,832 23 73

A2;B21

o

-T

O.862 o

_m

_-

O.341 1 3

A2lBw22

1 16 O.3 O.215 o

_-

1.015 3 10

A2iB27

2 32 8 O.022 10 95 72 6.597 9 29

A2iB35

1 16 12 O.602 1 10 5 1.846 11 35

A2iB37

o

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_-

O.862 o

-

O,341 1 3

A2iB4e

14 226 70 O.773 19 181 89 O.025 56 178

A2iBw51

1 16

_-

O,862 2 19 15 2.673 o

-A2lBw56

o

_-

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O.106 o

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O.671 2 6

A2iBw63

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O.862 o _rm

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O.341 1 3

A2lBw73

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A31B5

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O.341 1 3

A3lBw6

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O.862 o

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O,341 1 3

A31Bw22

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A3lB40

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-A9iBw4

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A9iB5

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1.611 o

T

n

O.733 8 25

A9iBw6

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A9:B7

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O.823 1 10 6 O.076 4 13

A9;B12

o

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O.823 o

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1.351 4 13

A9lB13

2 32 22 O.092 2 19 8 O.144 8 25

A9iB15

2 32 29 O.225 2 19 16 O.043 7 22

A9iB17

4 65 50 O.451 4 38 27 O,082 14 45

A9iBw22

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O.862 o

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O.341 1 3

A9]B27

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A91B35

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A91B40

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-AIOlBw6

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-

o

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-

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-AIOlB17 1 16 16 Or862 2 19 18 2.673 o

-AlliBw4

3 48 21 O,066 3 29 8 O.352 l3 41

(13)

-E199-AlllB5

o _nt _-･ 2.873 5 48 40 O.022 14 45

All;Bw6

7 113 84 1.592 11 105 81 1.654 21 67

AlliB7

1 1･6 14 O.092 2 19 13 O.045 7 22

All;B8

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O.823 o

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1.351 4 13 All;B12 o

-

O.453 1 10 8 O.115 2 6 All1B13 2 32 17 1.085 5 48 32 O.502 21 17 AllIB14 1 16 13 1.644 1 10 8 O.677 1 3 AlllB15 2 32 27 1.922 2 19 15 5.133 26 83 All;B17 ･1 16 -7 O.915 2 19 2 2.242 l7 54 All;B18 o

-

1 O.862 o

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O.341 1 3

AlliBw21

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O.341 1 3

AlliBw22

1 16 9 1.644 1 10 5 O.677 l 3

AlllB27 2 32 22 O.526 3 29 27 1.133 17 54

All;B35 1 16 14 O.031 1 10 7 O.447 6 19

All;B40 7 113 45 2.868 10 95 46 6.870 68 217

AlliBw44

'1 16 14 1.644 1 10 9 O.670 1 3

AlliBw51

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_-

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"

-

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o

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O.862 o

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O.341 1 3

A19lBw4

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A19iB5

1 16 15 O,052 1 10 9 O.077 4 13

A19lBw6

o

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O.603 o

-

1.015 3 10

A191B7

o

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O.603 1 10 9 O.333 3 IO

A19iB13 2 32 29 2.o3e 5 48 46 4.247 3 le

A19lB17 1 16 10 O.215 1 10 7 O.333 3 le

A19;Bw22

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r

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O.341 1 3

A19lB40 o

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O,603 o

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1.015 3 10

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O.341 1 3

A26IBw4

1 16 4 1.644 2 19 11 1.007 1 3

A26iB5

1 l6 14 1,644 1 10 7 O.671 1 3

A26;Bw6

o

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A26iB7

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O.823 o

_T

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1.350 4 13 A26lB13 o

_-

o

-

0

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_-

O.823 1 10 8 O.076 4 l3

A26lBw22

o

_m

_-

O.862 o

-

m

O.341 1 3 A26iB27 3 48 43 6.209 3 29 25 3,028 1 3 A26iB35 o

_-

O.603 o

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1.015 3 10 A26lB40 3 48 18 2,803 3 29 11 2.025 3 10

A26iBw55

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O.341 1 3

A26lBw56

o _rm

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e.862 o

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A26iBw73

1 16 15 O.622 1 10 9 O.115 2 6

A28iBw6

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-A28lB7

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A28;B13 o _un _nt O,862 o

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O.341 1 3

A28iB17 o

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O.862 o

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O.341 1 3

A28lB40 2 32 27 3.303 1 19 10 e.I15 2 6

A28;Bw49

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-

.-

O.341 1 3 A32iB40 o

_-

o

-

o

-hfllOOO : haplotype frequencies per thousand, D/1000:delta values per thousand.

(14)

-E200-Table 9 Distribution and significance of haplotype disorders

frequencies and linkage disequilibria in different seizure

Significantly highfrequency (p<O.OOI) DllOOO Relatively highfrequency (p<O.O1-O.O05) DllOOO Significantly lowfrequency (p<O.OOI) DllOOO Relatively lowfrequency (p<O.O1-O.O05) D/1000 IdiopathicPatients

AlllBw6

180 generalized (x2=18.906)

seizuresParents

AlliBw6

156

A2lB5

96

(x2=21.737) (x2=7,736)

SimplePatients

AliB17

57 partial (x2=9.991) .selzures

A2lBw22

66 (x2=6.808) A26lB35 96 (x2=7.348) Parents

A9iBw6

74 (x2=12.371) FebrilePatients convulsionsParents AlliB40 46 (x2=6.870)

DllOOO:delta values per thousand.

Table 10 HLA-A ; B haplotype analysis in several families with different types of

disorders, in both patients and their siblings

seizure Patients Siblings Fathers Mothers

FamilyA Idiopathic g,ei",e.r,a.l,iZedFamiiyB

A9IB5iCw3

A2iB17

A2iBw4lCw3

A9iB40iCw7

A9lB5iCw3

A2lB17

A2iBw4iCw3

A9lB40iCw7

A2lB17

A2lB5iCw3

A9lB40lCw7

A9iBw73;Cw3

A9lB5lCw3

A26IB40 A2;BwhT4lCw3

A2;BI7lCw3

SimpleFamilyC

partial.selzures

A2lB401Cw7

A26lB13lCw3

A2iB40lCw7

A26lB13iCw3

A21Bw6lCw7

A26lB13lCw3

A2lB40iCw7

A26lB7lCw3

FamilyD Febrile convulsionsFamilyE

A9lB40iCw3

AlllB35 A26lB27

A30+311Bw22

A9lB40lCw3

AllIB35 A26lB27

A30+31;Bw22

A91B40iCw3

A9lBw6

A30+3IlBw22

A9lB4e

AlliB35

A3lB40

A26lB27 Bw22

with normal controls (Tables 7 and 9).

Only a relatively low frequency and significant linkage disequilibrium of HLA AII; B40 (x2=6.870,

p<O.Ol, D/1000=46) were found in parents of

febrile convulsion cases (Tables 8 and 9).

Discussion

Although the influence of inheritance in the

etiology of seizure disorders has long been

recQg-nized and has been an issue of debate for many

years, our understanding of the genetic basis has been slow in developing and its relative roles in predisposition to or causation of various types of seizures have not been clearly established. A part of the prQblem probably arises from differences in

populations, seizure definitions, measurement

data, and analytical methods, but the complexity of the nervous system, especially in its

devel-opmental aspect, has also presented formidable

obstacles. However, from the many genetic

studies of epilepsy reviewed by Newmark and

Penry38), several important trends are apparent.

First, generalized seizure disorders (absence,

generalized tonic-clonic, and photic-induced

sei-zures) most often have been associated with a

family history of epilepsy. Benign Rolandic epi-lepsy, which is usually partial, and febrile sei-zures, which may be partial or generalized, are the only potentially inheritable partial seizure

dis-orders. Second, although many metabolic and

inherited disorders are associated with epilepsy,

no single metabolic abnormality predominates; E201

(15)

-epilepsy may arise via many mechanisms. Third, the most closely related family members are at

highest risk of inheriting epilepsy. The highest

rates of epilepsy (60-80%) in relatives of an

epileptic proband are found in monozygotic

twins7)8). Nevertheless, it seems that some

evi-dence for a strong genetic contribution to the manifestation of epiiepsy has been provided by

twin and EEG studiesi).

The genes controlling HLA are located on the

short arm of the 6th chromosome. The HLA

system consists of A, B, C, D and DR loci, which are responsible for extreme polymorphism in in-heritance, and serve as good genetic markers for research. More than 300,OOO,OOO genetically dif-ferent individuals can be found on the basis of the known alleles of the above mentioned loci and, of theSe, more than 30,OOO,OOO have distinguishable combinations of antigens39}. The frequencies of the main alleles at each of the HLA-A, -B, -C, and

-D (and-DR) loci in representative populations vary among different races. Antigens which are

frequent in one population may be absent or rare in another40). Furthermore, antisera which have

been well characterized in one population may

show unexplained extra reactivity, or a lack of reactivity, in other populations4i}. As shown in Tables 1, 2 and 3, the frequencies of HLA-A2, -Al1

and -B40 were higher, and those of HLA -AIO, Aw23, -Bw29, -Bw49 and -Bw55 were very low in the Chinese population examined in this study.

These results were very similar to those reports of Chen et al.`2) in Taiwan, and Fujii et al`3) inJapan, but markedly different from the two earlier re-ports44}45) of normal Taiwan Chinese. A difference in the HLA profile for the same area may in part be due to differences in the antisera used. HLA typing is used primarily for determination of HLA compatibility prior to transplantation, for paternity testing, for anthrbpological studies, and for establi.shing HLA-disease associations. Dis-eases associated with HLA antigens have several characteristics. In general, these diseases (1) have

an unknown cause and unknown

pathophysiolog-ic mechanism, with a hereditary pattern of

dis-tribution but weak penetrance; (2) are associated

with immunologic abnormalities; and (3) have

little or no effect on reproduction`6). However, several hypotheses have been advanced to explain HLA-disease associations. Three of these appear to be most likely. The first hypothesis holds that

HLA antigens are merely markers for irnmurte

response genes or immune suppress'ive genes. The immunologic response (or lack thereof) to an agent may indicate a predisposition to a disease. The

second hypothesis suggests that HLA antigens

may act as receptors for etiologic agents. If par-ticular HLA antigens act as receptors for viruses,

toxins or other foreign substances, and these substances are the etiologic agents for given diseases, then HLA-disease associations would

result. The third hypothesis is that of molecular mimicry. It postulates that a disease-associated HLA antigen is structurally and immunologically similar to the etiologic agent for the disease and further postulates one of two alternatives. The first alternative is that because of the similarity between the etiologic agent and the HLA antigen, no immune response is elicited, and therefore the etiologic agent produces the disease without any interference. The second alternative suggests that a vigorous immune response is elicited against the etiologic agent. Because of the similarity of the

agent and the HLA antigen, the immune response

is turned against the.HLA antigen, a･nd this

"autoimmuner' response then produces the

dis-ease46). As HLA antigens trigger the immune

defense mechanism, several diseases such as an-kylosing spondylitis (with HLA-B27) and juvenile

diabetes mellitus (with HLA DR3 and DR4) have

been shown to have a very close association with

the HLA antigens. On the other hand, some

diseases are transmitted with a certain HLA

haplotype, such as idiopathic hemochromatosis

and 21-hydroxylase deficiency, which are two

examples that have been shown to be transmitted as recessive HLA-associated diseases47)48).

In the early 1970s the first HLA and disease

associations were described, among which was

multiple sclerosis49). Since then, numerous HLA

(16)

-and disease associations have been reported, as well as several studies of the genetic aspect of human epilepsy47)50)'"58), concentrating on a possi-ble association between HLA and epilepsy types. The first such attempts to be published were the studies of Smeraldi and co-workers (1975)50} on the association of the Lennox-Gastaut syndrome with

antigen HLA-B7, and of Smeraldi and co-workers

(1976)5i} on mixed lymphocyte culture (MLC) in 15 unrelated children with the same syndrome. Some of the several subsequent investigations concern-ed with different types of seizure disorders, such as primary generalized epilepsy, partial epilepsy, petit mal epilepsy, etc, showed a good correlation to certain HLA antigens. For instance,

signifi-cantly increased HLA-B7 antigen and HLA A3; B7 haplotype in the Lennox-Gastaut syndrome52);

increased frequency of Al; B8 haplotype, HLA-B5

and -B8 antigens, and decreased frequency of

HLA-A2 antigen in 3 C/S SW absence

epi-lepsy53)54); increased frequency of HLA-B5 antigen in focal seizures54); decreased frequency of HLA

AI; B8 haplotype in benign epilepsy of

child-hood47); increased frequency of HLA-A9 antigen in generalized tonic-clonic and absences55} and

in-creased frequency of HLA-DR5 antigen in grand mal primary generalized seizures have been

re-ported. In investigations concerning this topic by Eeg-Olofsson et a147) and Hafez et a155}, an antigen

HLA-A9 prevalence of 25--47% was found among

European patients with idiopathic epilepsy, which was comparable to that in the Chinese population (31.1%) in this study (Table 1).

However, Howitz and Platz57) and Monaghan et

al.58) found no differences in HLA antigens

be-tween controls and probands with infantile

spasms or cryptogenic myoclonic epilepsy. As shown in Table 5, a statistically significant

high frequency and deviating high RR value

(7.23"--18.32, positive association) of HLA-Cw7

antigen were noted in both patients and their

parents for simple partial seizures and febrile convulsions. For other antigens, HLA-AIO, -Bw21, and -Bw73, etc, showing relatively high

frequen-cies, there were relatively high RR values

(II.52N17.15). This indicates that the higher the relative risk (above 1), the more frequent is the antigen among the patient population, which can be regarded as the chance an individual with the disease-associated HLA antigen has of developing the disease compared to an individual who lacks that antigen46).

The statistically significant HLA-A; B haplo-types, A9; Bw6 and All; Bw6, with significantly high delta values (D/1000=74-180, Table 9) found in this study imply that these particular HLA-A; B haplotypes occur in the seizure populations with frequencies which are higher than expected from the gene frequencies of the alleles in the same populations.

In spite of the high HLA-A2, -AIO and -B40

antigen frequencies (Tables 1, 2 and 3), and high

A2; B40 and All; B40 haplotype frequencies

(Tables 6, 7 and 8), which ,were very compatible

with the most commonly appearing antigens

men-tioned above, found by normal population analysis

in this study (a high Aw19; B17 haplotype fre-quency in Chinese59), and high Aw24; Bw52 and

Aw33; Bw44 frequencies in Japanese`3} have pre-viously been reported), the statistically significant

HLA antigens, -Bw6, -Bw22, -Cw3 and -Cw7, and

haplotypes, Al1; Bw6 and A9; Bw6, were found in the different seizure disorders (Tables 5 and 9).

These specific HLA antigens, -Bw6, -Bw22, -Cw3

and -Cw7, hOwever, may reflect an association or

linkage between the HLA system and genetic

control, and seem to be characteristic of patients with seizure disorders in this area.

Similarly, the relatively lower frequency of

haplotype All; B40 in febrile convulsions, which

was the most common haplotype in normal

con-trols in this study (Tabies 8 and 9), must thus provide some kind of biological advantage. It is

possible that All; B40 carries protector genes

against certain noxious mechanisms, e.g., infec-tious agents. A lack of this haplotype thus could

explain a lowered immunologic defensive

mecha-nism, resulting in increased risk for the appear-ance of seizure disorders47).

The. reason for linkage disequilibrium is

(17)

-E203-clear. Several hypotheses have been proposed to

explain the phenomenon of linkage

disequili-brium, including (1) a selective advantage of a given haplotype, (2) migration and admiXture of two populations, (3) inbreeding, and (4) random

drift46).

Immunological abnormalities in human epilep-tics have been reported60). An abnormal T-cell

function in drug-treated patients6i} and low serum levels, both drug-induced and drug-independent, of IgA62) have been described. A predisposition, presumably genetically determined, seems to be a prerequisite for the development of drug-induced IgA deficiency. An increased risk for developing

IgA deficiency was reported among individuals

with antigen HLA-A263)64). In the present inves-tigation, however, there was no statistically signi-ficant difference between any of the seizure dis-orders and the controls, regarding the Occurrence of HLA-A2 antigen, except for a relatively high

frequency (x2=10.402, p<O.O05, RR=2.70, as

shown in Table 3) in patients with febrile con-vulsions.

Since there are two unique HLA-B specificities,

called Bw4 and Bw6, which do not correspond to

conventional alleles of the HLA-A or HLA-B anti-gens, and their specificity resides on unique epi-topes on the HLA-B molecule (and on a few HLA-A

molecules), either Bw4 or Bw6 is expressed

to-gether with the HLA-B private specificity65); there-fore, further evaluation of the results concerning the statistically significant high frequency of the

HLA-Bw6 antigen in seizure disorders among the

Chinese population is very necessary.

The HLA Cw3 antigen was rather elusive in

this study. Despite the relatively high frequency and positive disease association <high relative

risk), in both patients and parents for simple

partial seizures, this HLA antigen still showed a statistically significant low frequency and

nega-tive disease association in parents of primary

generalized seizure cases (Table 5).

In the few publications on HLA and epilepsy,

there are no data on investigations of antigens of

the HLA-DR locus. Since it is known that the

antigens of the HLA-DR locus are of greater

importance for the' immune response than are

those of the other loci of the HLA system, the

finding of a statistically significant increased

frequency of HLA-DR5 (x2=13.08, p<O.OOI) in

patients with grand mal primary generalized seizures by Minev et a156}. can be accepted as

offering hope. But, no significant HLA-DR antigen was found in this study (Table 4).

Family studies involving haplotype analysis

were per'formed on several cases with different seizure disorders, siblings having seizure histories similar to those of the probands. All siblings had

the same haplotype as the respective probands

(Table 10). This･ haplotype, correspondence may point an inhertied susceptibility to these seizure disorders.

Nevertheless, it may be concluded that the

difficulty in demonstrating simple Mendelian

inheritance of seizure disorders with modern

techniques still argues in favour of multifactorial

inheritance. Investigations involving HLA

typing in larger populations of epileptic individ-uals and their families may provide a more reliable

and conclusive answer regarding the genetic

characteristics of seizure disorders.

Acknowledgement

The author is grateful to Professor Y. Fukuyama, Head of the Department of Pediatrics, Tokyo Women's Medical College, Japan, for critically reviewing the manuscript. The author is also grateful to Professor Y.H. Ma, forrner Head of the Department of Pediatrics, Kaohysiung Medical College, for his advice and en-couragement, and to Professor WJ. Liu, Head of the Department of Pediatrics and Clinical Laboratory, and

Miss W. Chiang, instructor of the Departrrient of

Clini-cal Laboratory, for their immunologiClini-cal assistance, and to Dr. FJ. Ko, instructor of the Department of

Pedia-trics, for her help in the statistical data processing, in

Kaohsiung Medical College.

Referecnes,

1) Annegers JF, Hauser WA, Elvebaek LR et al:

Seizure disorders in offspring of parents with a history of seizures.-a maternal-paternal difference?, Epilepsia