Volume 03 Issue 11-2023
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VOLUME
03
ISSUE
11
Pages:
184-192
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A
BSTRACT
The article discusses the genetic mechanisms underlying the development of neuropathies in myeloma -
a tumor of bone marrow plasma cells. Although these mechanisms are not yet fully understood, research
points to several potential factors, including mutations in myeloma cell lineage-associated genes such as
the MMSET/NSD2 gene and transcription factors such as IRF4. Another important factor is the immune
system disorder that accompanies myeloma and can lead to damage to nerve fibers. More detailed
studies are required to fully understand the genetic mechanisms of the development of neuropathies in
myeloma.
K
EYWORDS
Genetic mechanisms, neuropathies, myeloma, mutations, MMSET/NSD2, IRF4, immune system, nerve
fibers.
I
NTRODUCTION
Myeloma is a tumor of bone marrow plasma cells
that can lead to various complications, including
neuropathies. Although the genetic mechanisms
underlying the development of neuropathies in
myeloma are still being studied, some studies
point to several potential factors.
One such factor is the presence of mutations in
genes associated with the myeloma cell line. For
Journal
Website:
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Copyright:
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4.0 licence.
Research Article
GENETIC MECHANISMS OF DEVELOPMENT OF
NEUROPATHIES IN MYELOMA
Submission Date:
November 09, 2023,
Accepted Date:
November 14, 2023,
Published Date:
November 19, 2023
Crossref doi:
https://doi.org/10.37547/ijasr-03-11-31
Kakhkharova N.Kh.
Republican Specialized Scientific and Practical Medical Center of Hematology, Uzbekistan
Kayumov A.A.
Republican Specialized Scientific and Practical Medical Center of Hematology, Uzbekistan
Volume 03 Issue 11-2023
185
International Journal of Advance Scientific Research
(ISSN
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2750-1396)
VOLUME
03
ISSUE
11
Pages:
184-192
SJIF
I
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(2021:
5.478
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5.636
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(2023:
6.741
)
OCLC
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1368736135
example, mutations in the MMSET/NSD2 gene
and genes encoding transcription factors such as
IRF4 are thought to be associated with
neuropathies in myeloma.
In addition, immune system disorders may also
play a role in the development of neuropathies in
myeloma. Myeloma causes immune system
dysfunction and inflammation, which can
damage nerve fibers.
More detailed studies and analyzes of the genetic
mechanisms of the development of neuropathies
in myeloma are necessary to fully understand
this process. But existing evidence points to the
importance of genetic factors and immune
system dysfunction in this context.
Gene polymorphism, polymorphism is a
structural difference between alternative
variants of a gene (usually normal and mutant).
The occurrence of gene variants is caused by
mutations. Genotyping of polymorphic loci of
selected immune response genes revealed
differences in the frequency of detection of
haplotypes of the TLR6(Ser249Pro), IL1β (G-
1473C), IL2(T-330G), IL4(C-589T) and IL10(G-
1082A) genes.
Interleukin-4 (IL-4) is a cytokine that plays a
significant role in immune responses and is
involved in the growth and survival of certain
immune cells, including B cells and plasma cells.
Changes in IL-4 levels due to genetic
polymorphisms can potentially influence the
immune response and consequently the risk or
progression of diseases such as myeloma.
The C-589T polymorphism, also known as
rs2243250, is a genetic variation located in the
promoter region of the IL4 (interleukin-4) gene.
This polymorphism has been investigated in
various diseases, including myeloma, due to its
potential role in modulating interleukin-4
production.
In myeloma, it has been found that IL-4 levels
may be elevated in both the blood and myeloma
cells of patients. This cytokine may stimulate the
growth and survival of myeloma cells and may
also help protect them from the cellular immune
response. Moreover, IL-4 may participate in the
formation of the tumor microenvironment,
creating favorable conditions for the progression
of myeloma.
Studies confirm that IL-4 plays an important role
in the pathogenesis and progression of myeloma,
and may be a potential target for new
therapeutic approaches. Further studies are
needed to more fully understand the role of IL-4
and its impact on the development and
progression of myeloma.
To study allele frequency and genotype
frequency distribution in myeloma, a study was
conducted in which participants were divided
into two groups: main and control. The total
number of participants in the main group was
n=94, of which grade I neuropathy: n = 22, grade
II neuropathy: n = 44, grade III neuropathy: n =
28. The study results are shown in Table 1:
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Num
Group
Allele frequency
Genotype distribution frequency
C
T
C/C
C/T
T/T
n
%
n %
n %
n %
n %
1
Main group (n
= 94)
117 62,2 71 37,8 42 44,7 33 35,1 19 20,2
2
grade
I
neuropathy (n
= 22)
25
56,8 19 43,2 8
36,4 9
40,9 5
22,7
3
grade
II
neuropathy (n
= 44)
63
71,6 25 28,4 26 59,1 11 25
7
15,9
4
grade
III
neuropathy (n
= 28)
29
51,8 27 48,2 8
28,6 13 46,4 7
25
5
Control group
(n = 90)
130 72,2 50 27,8 51 56,7 28 31,1 11 12,2
Table 1. Percentage of mutation frequencies in the main and experimental groups
The study also examined the prognostic effectiveness of the studied genetic markers (C-589T
polymorphism in the IL4 gene). The results are shown in Table 2.
Factor
Groups
SE
SP
AUC
OR
95%CI
p
C
Main group// Control
group
0,62
0,28
0,45
0,63
0,4 - 0,98
0,59
grade I neuropathy //
Control group
0,57
0,28
0,43
0,51
0,26 - 0,99
0,28
grade II neuropathy //
Control group
0,72
0,28
0,5
0,97
0,56 - 1,68
0,33
grade III neuropathy
// Control group
0,52
0,28
0,4
0,41
0,22 - 0,76
0,35
grade I neuropathy //
grade II neuropathy
0,57
0,28
0,43
0,52
0,24 - 1,11
0,43
grade I neuropathy //
grade III neuropathy
0,06
0,48
0,27
0,05
0,01 - 0,25
0,41
grade II neuropathy //
grade III neuropathy
0,72
0,48
0,6
2,35
1,17 - 4,71
0,48
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VOLUME
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Pages:
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SJIF
I
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(2021:
5.478
)
(2022:
5.636
)
(2023:
6.741
)
OCLC
–
1368736135
Factor
Groups
SE
SP
AUC
OR
95%CI
p
T
Main group // Control
group
0,72
0,38
0,55
1,58
1,02 - 2,45
0,41
grade I neuropathy //
Control group
0,72
0,43
0,58
1,98
1,01 - 3,89
0,72
grade II neuropathy //
Control group
0,72
0,28
0,5
1,03
0,6 - 1,76
0,67
grade III neuropathy
// Control group
0,72
0,48
0,6
2,42
1,32 - 4,45
0,65
grade I neuropathy //
grade II neuropathy
0,72
0,43
0,58
1,92
0,9 - 4,08
0,57
grade I neuropathy //
grade III neuropathy
0,52
0,43
0,48
0,82
0,38 - 1,78
0,59
grade II neuropathy //
grade III neuropathy
0,52
0,28
0,4
0,43
0,22 - 0,85
0,52
Factor
Groups
SE
SP
AUC
OR
95%CI
p
C/C
Main group // Control
group
0,45
0,43
0,44
0,62
0,35 - 1,1
0,57
grade I neuropathy //
Control group
0,36
0,43
0,4
0,44
0,17 - 1,13
0,26
grade II neuropathy //
Control group
0,59
0,43
0,51
1,1
0,55 - 2,22
0,32
grade III neuropathy //
Control group
0,29
0,43
0,36
0,31
0,13 - 0,75
0,34
grade I neuropathy //
grade II neuropathy
0,36
0,41
0,39
0,4
0,14 - 1,12
0,44
grade I neuropathy //
grade III neuropathy
0,07
0,71
0,39
0,2
0,03 - 1,4
0,41
grade II neuropathy //
grade III neuropathy
0,59
0,71
0,65
3,61
1,33 - 9,76
0,47
Factor
Groups
SE
SP
AUC
OR
95%CI
p
C/T
Main group // Control
group
0,35
0,69
0,52
1,2
0,64 - 2,23
0,5
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Pages:
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SJIF
I
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(2021:
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)
(2022:
5.636
)
(2023:
6.741
)
OCLC
–
1368736135
grade I neuropathy //
Control group
0,41
0,69
0,55
1,53
0,59 - 3,96
0,17
grade II neuropathy //
Control group
0,25
0,69
0,47
0,74
0,33 - 1,66
0,35
grade III neuropathy
// Control group
0,46
0,69
0,58
1,92
0,81 - 4,54
0,19
grade I neuropathy //
grade II neuropathy
0,41
0,75
0,58
2,08
0,7 - 6,14
0,28
grade I neuropathy //
grade III neuropathy
0,41
0,54
0,48
0,8
0,26 - 2,45
0,46
grade II neuropathy //
grade III neuropathy
0,25
0,54
0,4
0,38
0,14 - 1,04
0,69
Factor
Groups
SE
SP
AUC
OR
95%CI
p
T/T
Main group // Control
group
0,2
0,88
0,54
1,82
0,82 - 4,05
0,49
grade I neuropathy //
Control group
0,23
0,88
0,56
2,11
0,66 - 6,73
0,18
grade II neuropathy //
Control group
0,16
0,88
0,52
1,36
0,49 - 3,79
0,32
grade III neuropathy
// Control group
0,25
0,88
0,57
2,39
0,84 - 6,76
0,21
grade I neuropathy //
grade II neuropathy
0,23
0,84
0,54
1,55
0,44 - 5,51
0,31
grade I neuropathy //
grade III neuropathy
0,23
0,75
0,49
0,88
0,23 - 3,37
0,45
grade II neuropathy //
grade III neuropathy
0,16
0,75
0,46
0,57
0,18 - 1,82
0,64
Studies indicate that the frequency of allelic and
genotypic variants of the C-589T polymorphism
in the IL4 gene may vary among different groups
of myeloma patients.
For example, patients with multiple myeloma
(MM) were found to have a significantly higher
frequency of the T allele of the C-589T
polymorphism compared to controls. We also
note that the presence of a homozygous TT
genotype was associated with an earlier age of
onset and progression of MM.
In general, we can see the differences in the
frequency of alleles and genotypes of the C-589T
polymorphism in the IL4 gene between groups of
myeloma patients in Table 3.
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VOLUME
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Pages:
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SJIF
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)
(2022:
5.636
)
(2023:
6.741
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Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
Main group
Control group
n
%
n
%
C
117
62,2
130
72,2
4,2
0,05
0,9
0,58 - 1,27
0,6
0,41 - 0,98
T
71
37,8
50
27,8
4,2
0,05
1,2
0,72 - 1,87
1,6
1,02 - 2,45
C/C
42
44,7
51
56,7
2,6
0,20
0,8
0,45 - 1,38
0,6
0,35 - 1,1
C/T
33
35,1
28
31,1
0,3
0,60
1,1
0,64 - 2
1,2
0,65 - 2,22
T/T
19
20,2
11
12,2
2,2
0,20
1,7
0,89 - 3,08
1,8
0,82 - 4,05
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade I
neuropathy
grade II
neuropathy
n
%
n
%
C
25
56,8
63
71,6
2,9
0,10
0,8
0,31 - 2,01
0,5
0,25 - 1,11
T
19
43,2
25
28,4
2,9
0,10
1,3
0,71 - 2,22
1,9
0,9 - 4,06
C/C
8
36,4
26
59,1
3,0
0,10
0,6
0,15 - 2,53
0,4
0,14 - 1,12
C/T
9
40,9
11
25,0
1,8
0,20
1,6
0,44 - 6,06
2,1
0,7 - 6,12
T/T
5
22,7
7
15,9
0,5
0,50
1,4
0,31 - 6,54
1,6
0,43 - 5,58
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade I
neuropathy
grade III
neuropathy
n
%
n
%
C
25
56,8
29
51,8
0,3
0,70
1,1
0,46 - 2,64
1,2
0,55 - 2,71
T
19
43,2
27
48,2
0,3
0,70
0,9
0,46 - 1,8
0,8
0,37 - 1,81
C/C
8
36,4
8
28,6
0,3
0,60
1,3
0,37 - 4,41
1,4
0,43 - 4,71
C/T
9
40,9
13
46,4
0,2
0,70
0,9
0,25 - 3,09
0,8
0,26 - 2,47
T/T
5
22,7
7
25,0
0,0
0,90
0,9
0,21 - 4,01
0,9
0,24 - 3,28
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade I
neuropathy
Control group
n
%
n
%
C
25
56,8
130
72,2
3,9
0,05
0,8
0,28 - 2,2
0,5
0,26 - 0,99
Volume 03 Issue 11-2023
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International Journal of Advance Scientific Research
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VOLUME
03
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Pages:
184-192
SJIF
I
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(2021:
5.478
)
(2022:
5.636
)
(2023:
6.741
)
OCLC
–
1368736135
T
19
43,2
50
27,8
3,9
0,05
1,3
0,93 - 1,74
2,0
1,01 - 3,87
C/C
8
36,4
51
56,7
2,9
0,10
0,6
0,14 - 2,99
0,4
0,17 - 1,13
C/T
9
40,9
28
31,1
0,8
0,40
1,3
0,3 - 5,75
1,5
0,59 - 3,99
T/T
5
22,7
11
12,2
1,6
0,30
1,9
0,35 - 9,74
2,1
0,66 - 6,75
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade II
neuropathy
grade III
neuropathy
n
%
n
%
C
63
71,6
29
51,8
5,8
0,03
1,4
0,75 - 2,56
2,3
1,17 - 4,69
T
25
28,4
27
48,2
5,8
0,03
0,7
0,33 - 1,58
0,4
0,21 - 0,85
C/C
26
59,1
8
28,6
6,4
0,03
2,1
0,98 - 4,39
3,6
1,33 - 9,77
C/T
11
25,0
13
46,4
3,5
0,10
0,5
0,21 - 1,37
0,4
0,14 - 1,04
T/T
7
15,9
7
25,0
0,9
0,40
0,6
0,21 - 1,9
0,6
0,18 - 1,83
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade II
neuropathy
Control group
n
%
n
%
C
63
71,6
130
72,2
0,0
0,95
1,0
0,47 - 2,08
1,0
0,55 - 1,71
T
25
28,4
50
27,8
0,0
0,95
1,0
0,7 - 1,46
1,0
0,59 - 1,82
C/C
26
59,1
51
56,7
0,1
0,80
1,0
0,4 - 2,74
1,1
0,53 - 2,3
C/T
11
25,0
28
31,1
0,5
0,50
0,8
0,26 - 2,46
0,7
0,33 - 1,67
T/T
7
15,9
11
12,2
0,3
0,60
1,3
0,37 - 4,54
1,4
0,49 - 3,78
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade III
neuropathy
Control group
n
%
n
%
C
29
51,8
130
72,2
8,1
0,01
0,7
0,3 - 1,73
0,4
0,22 - 0,76
T
27
48,2
50
27,8
8,1
0,01
1,4
0,98 - 1,98
2,4
1,32 - 4,45
C/C
8
28,6
51
56,7
6,7
0,01
0,5
0,12 - 2,13
0,3
0,13 - 0,75
C/T
13
46,4
28
31,1
2,2
0,20
1,5
0,43 - 5,22
1,9
0,81 - 4,53
T/T
7
25,0
11
12,2
2,7
0,20
2,0
0,53 - 7,95
2,4
0,84 - 6,79
Volume 03 Issue 11-2023
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International Journal of Advance Scientific Research
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VOLUME
03
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Pages:
184-192
SJIF
I
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(2021:
5.478
)
(2022:
5.636
)
(2023:
6.741
)
OCLC
–
1368736135
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade I
neuropathy
grade II
neuropathy
n
%
n
%
C
25
56,8
63
71,6
2,9
0,10
0,8
0,31 - 2,01
0,5
0,25 - 1,11
T
19
43,2
25
28,4
2,9
0,10
1,3
0,71 - 2,22
1,9
0,9 - 4,06
C/C
8
36,4
26
59,1
3,0
0,10
0,6
0,15 - 2,53
0,4
0,14 - 1,12
C/T
9
40,9
11
25,0
1,8
0,20
1,6
0,44 - 6,06
2,1
0,7 - 6,12
T/T
5
22,7
7
15,9
0,5
0,50
1,4
0,31 - 6,54
1,6
0,43 - 5,58
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade I
neuropathy
grade III
neuropathy
n
%
n
%
C
25
56,8
29
51,8
0,3
0,70
1,1
0,46 - 2,64
1,2
0,55 - 2,71
T
19
43,2
27
48,2
0,3
0,70
0,9
0,46 - 1,8
0,8
0,37 - 1,81
C/C
8
36,4
8
28,6
0,3
0,60
1,3
0,37 - 4,41
1,4
0,43 - 4,71
C/T
9
40,9
13
46,4
0,2
0,70
0,9
0,25 - 3,09
0,8
0,26 - 2,47
T/T
5
22,7
7
25,0
0,0
0,90
0,9
0,21 - 4,01
0,9
0,24 - 3,28
Alleles
and
genotypes
Number of alleles and
genotypes examined
χ2
p
RR
95%CI
OR
95%CI
grade II
neuropathy
grade III
neuropathy
n
%
n
%
C
63
71,6
29
51,8
5,8
0,03
1,4
0,75 - 2,56
2,3
1,17 - 4,69
T
25
28,4
27
48,2
5,8
0,03
0,7
0,33 - 1,58
0,4
0,21 - 0,85
C/C
26
59,1
8
28,6
6,4
0,03
2,1
0,98 - 4,39
3,6
1,33 - 9,77
C/T
11
25,0
13
46,4
3,5
0,10
0,5
0,21 - 1,37
0,4
0,14 - 1,04
T/T
7
15,9
7
25,0
0,9
0,40
0,6
0,21 - 1,9
0,6
0,18 - 1,83
In conclusion of the article on the genetic
mechanisms of the development of neuropathies
in myeloma, the following can be noted:
1. The development of neuropathies in myeloma
may be associated with genetic factors. Research
suggests that certain genetic variants may
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192
International Journal of Advance Scientific Research
(ISSN
–
2750-1396)
VOLUME
03
ISSUE
11
Pages:
184-192
SJIF
I
MPACT
FACTOR
(2021:
5.478
)
(2022:
5.636
)
(2023:
6.741
)
OCLC
–
1368736135
increase the risk of developing neuropathies in
myeloma patients.
2. Some genetic polymorphisms, such as
polymorphisms in genes associated with drug
metabolism or inflammation, may influence an
individual's
susceptibility
to
developing
neuropathies.
3. Genetic variants may influence various
pathways and mechanisms associated with
neuropathy in myeloma, such as nerve fiber
damage, vasculitis, and inflammation.
4. Further research is needed to better
understand the genetic mechanisms of the
development of neuropathies in myeloma and to
develop personalized approaches to their
prevention and treatment.
Overall, genetic factors are important in the
development of neuropathies in myeloma, and
understanding these mechanisms may help
improve the diagnosis, prognosis, and treatment
of this complication.
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EFERENCES
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