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Discordance of T-cell receptor -chain genes in familial multiple sclerosis.

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Discordance of T-cell Receptor f3-Chain
Genes in Famdd Multiple Sclerosis
Sharon G. Lynch, MD,”S John W. Rose, MD,”S Jack H. Petajan, MD, PhD,S Dora Stauffer, BSc,t
Craig Kamerath, BS,” and Mark Leppert, PhDt
Restriction fragment length polymorphisms of the T-cell receptor P-chain gene were studied in DNA obtained from
96 individuals from 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS
and two had probable MS. Five normal family members had abnormal findings on cranial magnetic resonance imaging
(MRI) scans. Linkage analysis was performed using the BglII and the KpnI polymorphisms. With penetrance values
from 0.1 to 0.7, and altering the scoring of the normal individuals with abnormal findings on MRI scans from
“unknown” to “affected,” log of the odds scores between -4.59 to -12.76 were found for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1.0, the LOD scores ranged from
-8.20 to -32.98. These findings do not support a direct role of T-cell receptor P-chain gene in the inheritance
of MS.
Lynch SG, Rose JW, Petajan JH, Stauffer D, Kamerath C, Leppert M. Discordance of T-cell receptor
P-chain genes in familial multiple sclerosis. Ann Neurol 1991;30:402-4 10
Multiple sclerosis (MS) is characterized by infiltration
of mononuclear cells into white matter associated with
plaques of demyelination [l]. Although no specific hereditary pattern has been identified in this disorder,
both an unknown environmental factor and a genetic
risk factor have been implicated in susceptibility to MS
[2-53. First-degree relatives of patients with MS have
30 to 50 times the risk of developing MS, compared
with the general population 161. Investigations of MS
in twins have demonstrated a high concordance of MS
in monozygotic twins as compared to dizygotic twins
15-93. Of particular note is a recent study of MS in
monozygotic versus dizygotic twins that demonstrated
a concordance of 25.9% in monozygotic twins as opposed to 2.3% in dizygotic twins 171.
An autoimmune pathogenesis is suspected, based on
the presence of (1) lymphocytes at the periphery of the
demyelinated plaques, (2) oligoclonal immunoglobulin
bands in the spinal fluid, and (3) the association of major histocompatibility complex (MHC) antigens DR2
and DQ1 with MS [ S , 10-127. Recently, the infiltrating lymphocytes were identified as predominantly T
cells {13}. Cerebrospinal fluid T cells from patients
with MS exhibit restricted clonal expression 1143 and
include activated subpopulations. Activated lymphocytes are also present within the brain parenchyma of
MS patients 1151.
From the *Neurovirology Research Laboratory, Veterans Adrninistration Medical Center, and ?Howard Hughes Medical Institute and
the
Of
universiq
Of
Salt Lake City, UT.
402
Recent interest in T cell-mediated autoimmune diseases has focused on the genetics of the immune system, specifically the ti-imolecular complex, consisting
of the T-cell receptor (TCR), the MHC molecules, and
the antigen involved [16]. The antigens involved in
MS remain unknown, but have been postulated to be
of either myelin or viral origin 1167. MHC antigens
DR2 and DQ1 are associated with MS, but not linked
to disease susceptibility 15, 10-123. The genes of the
TCR are of considerable interest since deletions in
TCR genes have been identified in mice susceptible to
the experimental T cell-mediated autoimmune disease, experimental allergic encephalomyelitis (EAE)
117, 181. In addition, the immune response to antigen
in EAE is characterized by a restriction of T-cell specificity [19, 201. A recent study of human T-cell lines
reactive with myelin basic protein demonstrated restricted usage of the variable (V) p-chain genes in MS
121). A second study suggested limited use of the achain V regions in the brains of patients with MS 122).
Recent studies indicated a possible association of the
P-chain (TCRP) gene with MS [23, 241, and a sibling
pair study demonstrated that the TCRP gene was more
commonly shared by MS patients than by their normal
siblings [24}.
To study further the relationship of the TCRp with
MS, we evaluated multiplex families in which at least
Received Aug 24, 1990, and in revised form Dec 2 1. 1990, and Feb
13, 1991. Accepted for publication Mar 19, 1991.
Address correspondeficeto Dr Rose, Neurovirolo~Research Laboratory (151B),VA Medical Center, 500 Foothill Drive, Salt Lake
City, UT 84148.
Copyright 0 1991 by the American Neurological Association
two first-degree relatives had MS. In the present study,
restriction fragment length polymorphisms (RFLPs) of
the TCRP gene are discordant by linkage analysis in
14 multiplex families with MS.
Materials and Methods
Pgtient Popzllation
Fourteen families were recruited from the MS clinic at the
University of Utah Health Sciences Center (Fig 1).Individual
histories were obtained and examinations performed, and individuals were classified as having definite or probable MS
according to the criteria of Poser and colleagues f251.
Ninety-six individuals were examined, and 34 had clinically
definite or laboratory-supported definite MS. Two had clinically probable MS. One individual had a history of a myelopathy with no other history finding consistent with demyelination. Five family members had a normal history and normal
findings on examination, but cranial magnetic resonance imaging (MRI) showed lesions in the white matter that were
suggestive of subclinical demyelination [26}.
The MLINK program of the LINKAGE system was used
for this analysis 1341. The allele frequencies calculated for
the MS susceptibility factor were based on a population frequency of MS of 0.001 (lOO/lOO,OOO), which is the frequency in Colorado, a state adjacent to Utah and of equivalent latitude 1351. Thus, for an autosomal dominant model
with a penetrance of 0.25, the gene frequency would be
0.004; for an autosomal recessive model with a penetrance
of 0.25, the gene frequency would be 0.063. One analysis
was also performed using a penetrance of 0.25 and allowing
for the possibility that an individual who did not inherit a
susceptibility factor might develop MS; a frequency of 0.001
was chosen for the probability factor in the analysis of such
sporadics. This estimate is high enough to account for all
affected individuals in the population.
All individuals with definite or probable MS were scored
as “affected” in all linkage analyses. The 5 clinically normal
family members who had abnormal findings on MRl studies
and the individuals with a myelopathy were scored for the
first analysis as “unknown” and for a second analysis as “affected.”
D N A Prepmution and Hybridization
Whole blood was collected from all family members. The
lymphocytes were isolated using a Ficoll gradient and transformed with Epstein-Barr virus (EBV) obtained from an
EBV-infected marmoset line, IA3, derived from the B95-8
cell line [27].Following transformation, DNA was extracted
from the lymphoblastoid cell lines 1283 and subjected to
restriction digests with either KpnI or BglIl [29]. The
restricted DNA was separated by size on a 0.8% agarose
gel by electrophoresis for 20 hours at 35 V, denatured
with sodium hydroxide (NaOH), and transferred onto
charged nylon membranes (HybondN+, Amersham, Arlington Heights, IL) [30].
The TCRP probe used for hybridization contains human
sequences for the joining
and constant (C) regons and
was generously provided by Dr Tak Mak 1311. The probe
was labeled with 32P-deoxy-cytidinetriphosphate
1321 and hybridized to the filters in 50% formamide, 5X saline-sodium
citrate buffer (SSC), 20 mM sodium phosphate buffer, 5%
dextran sulfate, 1 x Denhardt solution, 0.1% sodium dodecyl sulfate (SDS), and 0.25 pg/ml of placental human DNA
at 42°C for 22 to 24 hours. The filters were washed in 2 x
SSC and 0.1% SDS for 30 minutes and then in 0.2 x SSC
and 0.5% SDS for 20 minutes C331. The blots were autoradiographed using Kodak XAR-5 x-ray film, in cassettes with
intensifying screens, for 72 hours.
u)
Linkage Analysir
Since the inheritance pattern of the MS susceptibility factor
is unknown, linkage analysis was performed on these families
using both autosomal dominant and autosomal recessive
models with varying penetrance. Penetrance values ranging
from 0.1 to 0.7 were chosen for the autosomal dominant
model and values from 0.1 to 1.0 for the autosomal recessive
model. These values were chosen because they encompassed
any reasonable estimates of penetrance for the MS population and included the data from monozygous cwins that suggest a concordance of 25% in individuals with identical genetic material, or penetrance of 25%.
Results
Hybridization of TCRP probe with BgfII-digested
D N A revealed two polymorphic bands of 9.3 (Bl) and
8.6 (B2) kb in size 1363. Allele frequencies were
4i.3% and 52.7@, respectively. Normal family members had an allele frequency of 45.3% for B1 and
54.79% for B2. Family members with MS had frequencies of 51.5% for B1 and 48.5% for B2. T h e difference in allele frequencies between normal family members and patients with MS was not statistically
significant by chi-square analysis.
KpnI-digested DNA revealed a polymorphism with
two alleles: a 5.7-kb band (K1) and a doublet of 3.9
and 1.8 kb (K2) 1373. Allele frequencies were 32.6%
for K1 and 67.4% for K2. Normal family members
had allele frequencies of 31.7% for K1 and 68.3%
for K2. Individuals with MS had allele frequencies of
37.9% and 62.l@, respectively. No significant difference was found between individuals with MS and normal family members.
Discordance of inheritance could be seen among the
individuals with MS in two families by inspection of
the pedigree (Figs 2 and 3). In each family, n o single
haplotype could be identified in all individuals with
MS. Neither of the individuals with probable MS were
among the recombinants.
Because the inheritance pattern of MS is uncertain,
linkage analysis of MS in these families with both the
BgfII polymorphism and the KpnI polymorphism was
performed for the autosomal dominant, the autosomal
recessive, and the codominant models. When normal
family members with abnormal findings on M R I scans
were scored as affection status “unknown,” the log of
the odds (LOD) scores for the autosomal dominant
model for MS with the BgfII polymorphism at a re-
Lynch et al: Discordance of TCRP Genes in Familial MS 403
Family 1
B2K1
BZK2
B1 K1 B l K l
BZKZ B l K l
81K1 B l K l
B2KZ
B2Kl
B1 K1
B2KZ
BZK2
BZK1
B2K2
BlKZ
07
B2K2
Family 2
Family
81 K2
BZK2
3
I
B1 K1
BIK2
07
B2K2
81 K1
BZK2
B2KZ
01
B2K2
BZK2
B1 K 2
61 K 2
BZK2
BZK2
B1 KZ
81 K2
02
Family 4
06
81 KZ
BZK2
B2Kl
B*l
04
or
B1KZ
BX1
B2Kl
B2K2
B1 KZ
BZK2
Family 5
B2K2
BZK2
B l KZ
WK.2
BZKZ
5x2
B2K2
B2K1
01
nz
Family 6
0s
03
B1 K1
BlKZ
04
81 K1
B l K2
Fig 1. Pedigrees of I4 families having at leart t w o first-degree
relatives with MS with huplotyped duta on faMily members. Affected individaab are designuted by black symbols. Normal fami(y members having an abnomal MRI finding are designated by
partiakly @led-in symbols. One individual with a histoPy of a
myelopathy, bat no other symptom consistent with MS,is also
marked with a partial(v filled-in symbol. Birth order bas been
08
changed in the interest of anonymity. The letters and nambers
below each symbol represent a pair of haplotypes. The letter B
designates a BgllI allele and the letter K designates a KpnI allele. Each line is a sepayate haplotype. For 2 farnib members,
the haplotypes are not certain. In those 2 cases, both possible
pairs of haplotypes are given.
Family 7
Family 8
Ob?
03
B1 K1
B1 K 2
B1 K1
B2K2
81 K1
B2K2
or
OT
B1 K 2
BZKl
B1 K 2
B2Kl
B 1 K1
BlKZ
LQA
IBlK2
01
Family 9
OAo4p7&@
Family 10
B2K1
81
K 2 05
03
B1 K 2
B1 K 2
B1 K 2
B1K2
B1 K 2
B2K1
o~~
81 K2
BlKZ
B1 KZ
81 K1
81 K1
~ 1
~
B2K2
B2K2
BZK2
B2KZ
81 K Z
B1K2
Family 11
81 K1
B1 K 2
B1 K1
B2K2
BlKl
2B l K Z
BlK2
B2KZ
BlKl
BIKZ
w
Family 12
03
08
05
BZK2
04
I
Family 13
B l K1
B2K1
B2K1
BZKl
B2K1
06
B1 K 2
BZK2
B1 K1
B1K2
Family 14
B2Kl
B2K2
B2K2
81 K 2
BZKZ
B2K1
B2K2
B2K1
B2K2
B1 KZ
Lynch et al: Discordance of TCRp Genes in Familial MS 405
CR-B chain gene with Kpnl
03
I?
1,l
I?
I?
I,?
1.2
Fig 2. Pedigree and restriction fragment length polymorphism
(RFLPI analysis of an extended family having 6 individuals
with MS (filled symbols). A seventh indzviduaf had an abnormal finding on MRI, but no clinical abnormalities (half-filled
symbol). Two alleles can be identified using KpnI-a 5.7-kb
band ( A l ) and a doublet of 3.9- and 1.8-kb bands (A2). No
single haplatype can be identified in all family members with
MS. At least two recombinant etlents have occurred between the
T-cell receptor pchain fTCRP) gene and MS in this family.
fsubject 13 is not shown on the autoradiograph.)
combination value of 0.001 ranged from - 3.20 (penetrance = 0.1) to -7.25 (penetrance = 0.7). For MS
with the KpnI polymorphism, LOD scores ranged from
- 1.17 (penetrance = 0.1) to -3.56
(penetrance =
0.7).
After the status of the normal family members with
abnormal findings on MRI scans was changed to “affect-ed,” LOD scores for MS with the BghI polymorphism ranged from -3.51 (penetrance = 0.1) to
-7.79 (penetrance = 0.7). LOD scores for MS with
the KpnI polymorphism varied from - 1.91 (penetrance = 0.1) to -4.98 (penetrancc = 0.7).
Because the KpnI polymorphism and the BgdI polymorphism are both reported to be located in the C
region of the TCRP gene 135, 361, we constructed
haplotypes and performed linkage analysis using the
haplotypes (see Fig 1).LOD scores ranged from - 3.34
(penctrance = 0.1) to -8.84 (penetrance = 0.7)
22
when the family members with positive findings on
MRI were scored as “unknown” (Table 1, A). When
these individuals were scored as “affected,” the LOD
scores ranged from -5.17 (penetrance = 0.1) to
- 12.22 (penetrance = 0.7) (see Table 1, B). LOD
scores for individual families at a penetrance of 0.25
are shown in Table 2.
LOD scores for the codominant model were virtually identical to the scores for the autosomal dominant
model when a twofold risk was included for an individual homozygous for the MS susceptibility factor (data
not shown).
The autosomal recessive model was also explored,
using penetrance values from 0.1 to 1.0. When the
family members with positive findings on MRI were
considered to have an “unknown” affection status,
LOD scores for the BgLII polymorphism ranged from
- 4.06 (penetrance = 0.1) to - 15.89 (penetrance =
1.0). For the Q n I polymorphism, the LOD scores
were - 3.16 (penetrance = 0.1) to - 14.40 (penetrance = 1.0). LOD scores for haplotypes ranged from
-5.68 (penetrance = 0.1) to -30.57 (penetrance =
1.0) (see Table 1, C).
When the MRI-positive family members were
scored as “affected” with the autosomal recessive
model, LOD scores for the BgdI polymorphism ranged
from -4.86 (penetrance = 0.1) to - 19.12 (pene-
406 Annals of Neurology Vol 30 Nu 3 September 1991
TCR-B chain gene polymorphisms with Bglll
05
03
04
27
Fig 3. Extended family having 3 individuals with MS (filled
symbols). A fourth individual had white matter lesions demonstrated by M R I but no clinical history of MS (half-filled
symbol). Two alleles can be identified using Sglrl digest-a
9.2-Kbfragment ( A l ) and an 8.5-kb fragment (A2). Each indiwidual with MS has a dzrerent genotype. No common allele is
seen.
trance = 1.0). The KpnI polymorphism LOD scores
ranged from -2.85 (penetrance = 0.1) to - 15.22
(penetrance = 1.O). LOD scores for haplotypes ranged
from -5.43 (penetrance = 0.1) to -32.47 (penetrance = 1.O) (see Table 1, D). LOD scores for individual families with a penetrance of 0.25 are shown in
Table 3. LOD scores for linkage of both polymorphisms to MS remained negative for recombination
values up to 30%.
When the possibility of sporadics was included, using a penetrance of 0.25 with the family members with
positive findings on MRI scored as “unknown,” the
LOD score was -4.28 for the autosomal dominant
model. With the MRI-positive family members scored
as “affected,” the LOD score was -6.67. For the autosomal recessive model, the LOD score was -7.34
using the MRI-positive members as “unknown” and
- 7.48 using the MRI-positive members as “affected.”
Discussion
In peripheral blood lymphocytes, the TCR is a heterodimer, composed most commonly of an ct and a p
06
chain {38, 391. The TCR is responsible for the recognition of antigen in the presence of MHC [ 16, 401. The
P-chain gene, located on chromosome 7q35, is composed of V, diversity (D), J, and C regions. The formation of the p chain occurs in a fashion analogous
to the generation of antigen-specific immunoglobulins,
involving rearrangements between the V and D segments and the D and J segments, and deletion of the
intervening DNA. The final product is a sequence
comprising one V, one D, one J, and one C region
[38}. An abnormality in one of the TCR genes may
lead to abnormal or limited antigen recognition, and
result in a predisposition to autoimmunity.
The possibility that the TCRa and 0 genes could
be linked to autoimmunity has been explored in several diseases, including systemic lupus erythematosus
(SLE), diabetes mellitus, and Graves’ disease, as well as
MS {41-441. Discordance of both TCRct and p genes
with SLE has been reported [41,42). Although associations have been reported with specific RFLPs and diabetes mellitus and Graves’ disease [43, 441, no confirmed linkage has been established in either of these
diseases {45].
Studies of the TCRP gene in MS have suggested
that an association between this gene and MS exists
{23, 241. Beall and colleagues reported that a specific
haplotype was more common in individuals with MS
than in control subjects [23}. Seboun and associates
showed that siblings with MS were more likely than
Lynch et al: Discordance of‘ TCRP Genes in Familial MS
407
Table I . LOD Scores for Linkage of MS with T-cell Receptor
0-Chain Using a Haplotype of the BgUI and Kpnl
Polymorphisms in 14 Families w i t h MS
Table 2. LOD Scores for Linkage of the T-cell Receptor
0-Chain Haplotype with MS in individual Families Using a n
Autosomal Dominant Model with a Penetrance of 0.25
Recombination Values
Penetrance
0.001
0.05
0.10
0.20
Recombination Values
0.30
A. Autosomal dominant model scoring the affection status
of normal family members with abnormal MRI findings
as “unknown”
0.1
-3.34
-2.08
-1.37
-0.57
-0.20
-2.52
-1.57
-0.61
-0.20
0.25
-4.56
-1.78
-0.65
-0.18
0.5
-6.36
-3.01
0.7
-8.84
-3.55
-2.04
-0.70
-0.17
B. Autosomal dominant model with normal family members
with abnormal MRI
0.1
- 5.17
0.25
- 7.18
0.5
- 9.63
0.7
-12.22
findings scored as “affected”
-3.03
-1.97
-0.82
-0.29
-3.65
-2.26
-0.90
-0.31
-4.23
-2.52
-0.97
-0.31
-4.83
-2.84
-1.05
-0.31
C . Autosomal recessive model scoring the affection status of
normal family members with abnormal MRI findings as
“unknown”
0.1
- 5.68 -3.32
-2.09
-0.85
-0.30
- 8.49 -4.35
-2.63
-1.04
-0.37
0.25
0.5
-12.44
-5.39
-3.19
- 1.25 -0.44
1.0
-30.57
-8.47
-4.81
-1.85
-0.65
D. Autosomal recessive model with normal family members
with abnormal MRI findings scored as “affected”
0.1
- 5.43
-3.35
-2.19
-0.94
-0.35
0.25
- 8.32
-4.57
-2.86
-1.17
-0.43
- 1.43 -0.52
0.5
-12.49
-5.81
-3.53
1.0
-32.47
-7.10
-5.21
-2.03
-0.73
LOD
= log of the odds; MS
resonance imaging.
=
multiple sclerosis; MRI = magnetic
their normal siblings to share at least one haplotype
that was identical by descent {24J The present data
are not directly comparable to their results, since a
different mode of analysis was used. While the strength
of their study was in identity by descent in sibling-pair
relationships, the strength of our study lies in comparison of the TCRP genes with MS individuals with more
distant familial relationships and in the comparison of
all diseased members of a family.
The question of penetrance has always been a problem in studies of MS. Previous studies have used penetrance values ranging from 0.05 to 0.35 12-53. By
monozygous twin data, the most likely value would be
0.25 when not including normal family members who
have abnormal MRI findings. No firm statistics are
available for penetrance values that would include
these individuals. In the present study, we varied the
penetrance from 0.1 to 0.7 to allow for any reasonable
penetrance value in the MS population.
Even at a penetrance of 0.1, recombination was
clearly demonstrated between MS susceptibility and
408
Annals of Neurology
Family
0.001
0.05
0.10
0.20
A. Scoring the affection status of normal family members
with abnormal MRI findings as “unknown”
01
- 1.46
- 1.03
-0.64
- 0.24
- 0.29
- 0.22
-0.16
- 0.08
02
0.30
0.25
0.21
0.13
03
04
- 0.18
-0.14
-0.11
- 0.06
05
0.18
0.16
0.13
0.08
- 0.19
- 0.10
06
-0.36
-0.27
07
-0.19
-0.15
-0.11
- 0.06
08
0.32
0.26
0.21
0.12
09
-0.36
-0.23
-0.15
- 0.07
- 0.01
0.00
10
-0.01
-0.01
11
- 0.50
-0.35
- 0.25
-0.12
- 1.77
-0.63
-0.37
-0.15
12
13
0.06
0.05
0.04
0.02
- 0.27
- 0.22
-0.16
- 0.08
14
Total
-4.56
-2.52
- 1.57
-0.61
B. Scoring normal family members with abnormal MRI findings as “affected”
01
- 1.46
- 1.04
-0.64
- 0.24
- 0.16
- 0.08
02
-0.29
-0.22
03
0.30
0.25
0.21
0.13
04
-0.18
-0.13
-0.10
- 0.05
05
0.18
0.16
0.13
0.08
- 0.2 1
06
-1.49
-0.72
-0.46
- 0.06
-0.11
-0.15
-0.19
07
0.12
0.21
0.26
08
0.32
-0.07
-0.23
-0.15
- 0.36
09
0.00
-0.01
-0.01
-0.01
10
- 0.12
11
- 0.50
-0.25
-0.35
-0.12
-0.57
12
- 1.62
-0.33
- 0.19
- 0.43
- 1.58
- 0.68
13
- 0.16
- 0.08
-0.22
14
- 0.29
- 0.90
- 2.26
-7.18
Total
- 3.65
= log of the odds; MS = multiple sclerosis; MRI = magnetic
resonance imaging.
LOD
the TCRP gene in both the autosomal dominant and
the autosomal recessive models. LOD scores remained
negative for recombination values up to 30%; however, the results were equivocal at recombination values of more than 5%.
We considered the possibility of sporadic cases of
MS occurring in our families. A linkage analysis was
performed to estimate a probability of 0.001 of developing MS without the susceptibility factor. This would
be a very high probability, because it assumes that all
cases of MS are sporadic in a given population 1351.
Even under these conditions, the LOD scores remained strongly negative.
The reason for the differences in our results from
those of Seboun and associates [24] remains unknown.
Vol 30 No 3 September 1991
Table 3. LOD Scores for Linkage of the T-cell Receptor
@Chain Haplotype with MS in Individual Families Using an
Autosomal Recessive Model with a Penetrance of 0.25
~~~
~
Recombination Values
Family
0.001
0.05
0.10
0.20
A. Scoring normal family members with abnormal MRI findings as “unknown”
01
- 1.82
- 1.07
-0.72
-0.33
- 1.08
-0.59
-0.38
-0.17
02
03
0.28
0.24
0.20
0.12
- 1.08
-0.59
-0.39
-0.17
04
05
0.39
0.32
0.26
0.15
-0.55
-0.37
-0.17
06
-0.94
07
-0.85
-0.47
-0.30
-0.13
0.40
0.24
08
0.58
0.49
0.07
0.04
0.11
0.09
09
-0.01
0.00
10
-0.01
-0.01
11
-0.63
-0.41
- 0.19
- 1.15
12
- 1.09
-0.64
-0.43
- 0.20
- 0.05
-0.34
-0.18
13
-0.75
14
- 1.08
-0.59
-0.38
-0.17
- 1.04
-2.63
Total
-4.35
-8.49
B. Scoring normal family members with abnormal MRI findings as “affected”
01
- 2.72
-1.62
- 1.09
- 0.50
02
03
04
05
06
07
08
09
10
11
12
13
14
Total
- 1.08
-0.59
0.24
-0.39
0.32
0.00
-0.47
0.49
0.09
-0.01
-0.63
-0.47
-0.93
0.28
- 0.60
0.39
0.00
-0.85
0.58
0.1 1
-0.01
- 1.15
-0.77
- 1.43
- 1.08
-0.59
-4.57
-8 32
LOD = log of the odds; MS
resonance imaging.
=
-0.38
0.20
-0.27
0.26
0.00
-0.30
0.40
0.07
-0.01
-0.41
-0.31
-0.64
-0.38
-2.86
-0.17
0.12
-0.13
0.15
0.00
-0.13
0.24
0.04
0.00
-0.19
-0.14
- 0.30
-0.17
- 1.19
multiple sclerosis; MRI = magnetic
One possible explanation is heterogeneity of the genes
responsible for MS susceptibility. Sibling-pair studies
may show positive results when only a portion of the
families under study have MS susceptibility due to a
specific gene, whereas linkage analysis is more likely
to yield positive results when a larger segment of the
families have MS susceptibility due to a specific gene.
Because of the positive data on sibling-pair analysis
shown by Seboun and associates 1241, a minor role of
the TCRP gene in MS susceptibility remains possible.
This study indicates that the TCRP does not play a
direct role in the inheritance of MS in our families.
Other TCR genes as well as other genes influencing
immune function should be analyzed for possible linkage with MS.
This work was supported by project PP0035 and research grant
1929-A-1 from the National Multiple Sclerosis Society, the Howard
Hughes Medical Institute, and the Department of Veteran Affairs
Medical Research Service. Dr Lynch was supported by postdoctoral
fellowship award FG 796-A-1 from the National Multiple Sclerosis
Society.
We would like to thank Dr Tak Mak for supplying the T-cell receptor P-chain probe used in the analysis; Jean-Marc Lalouel for discussion of the linkage analysis data; Dr Ray White for early discussion
of the project; Janice Gill, Lesa Nelson, and Brith Ottei-ud for their
technical assistance; and Scott Hathaway for his work on the pedigrees and figures. Ruth Foltz was also extremely helpful in editing
the manuscript. The Sweet Candy Company of Salt Lake City, UT,
provided a generous donation.
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