CXCL12 Gene Polymorphisms and Serum Levels: Associations with Multiple Sclerosis Prevalence and Clinical Parameters in Lithuania
Abstract
:1. Introduction
2. Results
2.1. CXCL12 Single-Nucleotide Polymorphism Was Associated with MS Risk
2.2. CXCL12 Serum Levels in MS Patients and Healthy Subjects
2.3. Patients with Multiple Sclerosis Clinical Characteristics and Their Associations with CXCL12 SNP Genotypes
3. Discussion
4. Materials and Methods
4.1. Ethical Statement and Study Participants
- MS group (n = 250): MS patients that received treatment at the Hospital of Lithuanian University of Health Sciences Kaunas Clinics from 1 January 2020 to 31 December 2023. The participants included individuals 18 years and older diagnosed with MS according to the revised 2017 McDonald criteria [16]. Disability was assessed using the Kurtzke Expanded Disability Status Scale (EDSS) before the venous blood draw, and was used for the MSSS calculation [31]. For the retrospective analysis, the following data were collected: age at the time of MS diagnosis; MS disease course and duration; presence of symptoms related to the pyramidal, sensory, brainstem, cerebellar, pelvic systems, and vision; and disability according the EDSS score.
- Control group (n = 250): Matched by sex and age and comprised individuals without medical history of autoimmune, oncological, or neurological diseases and in self-reported good health. Subjects with recent blood product transfusions, growth factor treatments, organ transplants, or diagnosed with oncological, systemic tissue, infectious, or other autoimmune diseases were excluded.
4.2. DNA Extraction and CXCL12 Genotyping
4.3. CXCL12 Protein Concentration Measurement
4.4. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Characteristic | Group | p-Value | |
---|---|---|---|
Control (n = 250) | MS (n = 250) | ||
Men n (%) | 85 (34.0) | 85 (34.0) | 1.000 |
Women n (%) | 165 (66.0) | 165 (66.0) | |
Men median age (IQR) | 44 (27) | 40 (14) | 0.094 |
Women median age (IQR) | 37 (24) | 38 (16) | 0.120 |
CXCL12 SNP | Genotype/Allele | Control Group n (%) | Control Group HWE p-Value | MS Group n (%) | MS Group HWE p-Value | Difference across Groups p-Value |
---|---|---|---|---|---|---|
rs1029153 | AA | 124 (49.6) | 0.903 | 132 (52.8) | 0.186 | 0.591 |
AG | 102 (40.8) | 91 (36.4) | ||||
GG | 24 (9.6) | 27 (10.8) | ||||
A allele | 350 (70.0) | 355 (71.0) | 0.622 | |||
G allele | 150 (30.0) | 145 (29.0) | ||||
rs1801157 | CC | 152 (60.8) | 0.824 | 166 (66.4) | 0.348 | 0.244 |
CT | 88 (35.2) | 71 (28.4) | ||||
TT | 10 (4.0) | 13 (5.2) | ||||
C allele | 392 (78.4) | 403 (80.6) | 0.260 | |||
T allele | 108 (21.6) | 97 (19.4) | ||||
rs2297630 | GG | 129 (51.6) | 0.659 | 139 (55.6) | 0.508 | 0.659 |
AG | 97 (38.8) | 90 (36.0) | ||||
AA | 24 (9.6) | 21 (8.4) | ||||
G allele | 355 (71.0) | 368 (73.6) | 0.362 | |||
A allele | 145 (29.0) | 132 (26.4) |
Model | Genotype/Allele | Odds Ratio (95% CI) | p-Value | AIC |
---|---|---|---|---|
CXCL12 (rs1029153) | ||||
Codominant | AG vs. AA | 0.84 (0.58–1.22) | 0.355 | 692.093 |
GG vs. AA | 1.06 (0.58–1.93) | 0.857 | ||
Dominant | AG+GG vs. AA | 0.88 (0.62–1.25) | 0.474 | 692.635 |
Recessive | GG vs. AA+AG | 1.14 (0.64–2.04) | 0.658 | 692.951 |
Overdominant | AG vs. GG+AA | 0.83 (0.58–1.19) | 0.312 | 692.126 |
Additive | G | 0.96 (0.74–1.24) | 0.738 | 693.035 |
CXCL12 (rs1801157) | ||||
Codominant | CT vs. CC | 0.74 (0.5–1.08) | 0.121 | 690.317 |
TT vs. CC | 1.19 (0.51–2.79) | 0.689 | ||
Dominant | CT+TT vs. CC | 0.79 (0.55–1.13) | 0.194 | 691.453 |
Recessive | TT vs. CC+CT | 1.32 (0.57–3.06) | 0.523 | 692.736 |
Overdominant | CT vs. TT+CC | 0.73 (0.5–1.07) | 0.103 | 690.478 |
Additive | T | 0.88 (0.65–1.19) | 0.395 | 692.422 |
CXCL12 (rs2297630) | ||||
Codominant | AG vs. GG | 0.86 (0.59–1.25) | 0.433 | 692.312 |
AA vs. GG | 0.81 (0.43–1.53) | 0.519 | ||
Dominant | AG+AA vs. GG | 0.85 (0.6–1.21) | 0.370 | 692.343 |
Recessive | AA vs. GG+AG | 0.86 (0.47–1.6) | 0.639 | 692.927 |
Overdominant | AG vs. AA+GG | 0.89 (0.62–1.28) | 0.518 | 692.729 |
Additive | A | 0.89 (0.68–1.16) | 0.374 | 692.355 |
Women | ||||
---|---|---|---|---|
Model | Genotype/Allele | Odds Ratio (95% CI) | p-Value | AIC |
CXCL12 (rs1029153) | ||||
Codominant | AG vs. AA | 0.66 (0.41–1.04) | 0.075 | 452.270 |
GG vs. AA | 1.37 (0.65–2.86) | 0.409 | ||
Dominant | AG+GG vs. AA | 0.77 (0.5–1.18) | 0.226 | 456.006 |
Recessive | GG vs. AA+AG | 1.66 (0.82–3.37) | 0.161 | 455.467 |
Overdominant | AG vs. GG+AA | 0.62 (0.4–0.97) | 0.034 | 452.960 |
Additive | G | 0.96 (0.7–1.33) | 0.806 | 457.417 |
CXCL12 (rs1801157) | ||||
Codominant | CT vs. CC | 0.99 (0.62–1.59) | 0.964 | 457.176 |
TT vs. CC | 1.35 (0.45–4.01) | 0.594 | ||
Dominant | CT+TT vs. CC | 1.03 (0.65–1.62) | 0.908 | 457.464 |
Recessive | TT vs. CC+CT | 1.35 (0.46–3.98) | 0.586 | 457.178 |
Overdominant | CT vs. TT+CC | 0.97 (0.61–1.56) | 0.904 | 457.463 |
Additive | T | 0 (0–0) | 0.000 | 0.000 |
CXCL12 (rs2297630) | ||||
Codominant | AG vs. GG | 0.71 (0.45–1.12) | 0.139 | 454.959 |
AA vs. GG | 1.07 (0.49–2.3) | 0.871 | ||
Dominant | AG+AA vs. GG | 0.77 (0.5–1.18) | 0.226 | 456.009 |
Recessive | AA vs. GG+AG | 1.24 (0.59–2.6) | 0.572 | 457.156 |
Overdominant | AG vs. AA+GG | 0.7 (0.45–1.09) | 0.115 | 454.986 |
Additive | A | 0.89 (0.64–1.24) | 0.503 | 457.027 |
Men | ||||
Model | Genotype/Allele | Odds Ratio (95% CI) | p-Value | AIC |
CXCL12 (rs1029153) | ||||
Codominant | AG vs. AA | 1.42 (0.73–2.74) | 0.301 | 232.733 |
GG vs. AA | 0.53 (0.17–1.67) | 0.278 | ||
Dominant | AG+GG vs. AA | 1.16 (0.63–2.13) | 0.641 | 235.452 |
Recessive | GG vs. AA+AG | 0.47 (0.15–1.44) | 0.184 | 233.810 |
Overdominant | AG vs. GG+AA | 1.54 (0.81–2.92) | 0.193 | 233.961 |
Additive | G | 0.95 (0.6–1.5) | 0.814 | 235.615 |
CXCL12 (rs1801157) | ||||
Codominant | CT vs. CC | 0.43 (0.22–0.83) | 0.012 | 229.004 |
TT vs. CC | 0.93 (0.24–3.66) | 0.913 | ||
Dominant | CT+TT vs. CC | 0.48 (0.26–0.89) | 0.020 | 230.147 |
Recessive | TT vs. CC+CT | 1.27 (0.33–4.89) | 0.732 | 235.552 |
Overdominant | CT vs. TT+CC | 0.43 (0.23–0.83) | 0.011 | 229.016 |
Additive | T | 0.62 (0.37–1.05) | 0.074 | 232.385 |
CXCL12 (rs2297630) | ||||
Codominant | AG vs. GG | 1.31 (0.68–2.51) | 0.424 | 232.142 |
AA vs. GG | 0.41 (0.12–1.39) | 0.152 | ||
Dominant | AG+AA vs. GG | 1.05 (0.57–1.93) | 0.876 | 235.646 |
Recessive | AA vs. GG+AG | 0.37 (0.11–1.23) | 0.105 | 232.783 |
Overdominant | AG vs. AA+GG | 1.45 (0.76–2.75) | 0.256 | 234.374 |
Additive | A | 0.87 (0.54–1.39) | 0.552 | 235.315 |
CXCL12 SNP | Genotype | Number of Individuals with Genotype n (%) | CXCL12 Concentration (pg/mL) Median (IQR) | CXCL12 Concentration Comparison across Groups (p-Value) | ||
---|---|---|---|---|---|---|
Control (n = 38) | MS (n = 40) | Control | MS | |||
rs1029153 | AA | 22 (57.9) | 20 (50.0) | 37.72 (6.84) | 36.575 (10.54) | 0.314 |
AG | 10 (26.3) | 12 (30.0) | 37.55 (8.9) | 33.75 (7.41) | 0.254 | |
GG | 6 (15.8) | 8 (20.0) | 35.815 (0.92) | 34.59 (17.94) | 0.985 | |
Genotype distribution or CXCL12 concentration differences (p-value) | 0.774 | 0.560 | 0.738 | |||
rs1801157 | CC | 22 (57.9) | 31 (77.5) | 36.14 (4.79) | 35.39 (10.19) | 0.607 |
CT | 13 (34.2) | 9 (22.5) | 39.72 (5.45) | 36.74 (17.09) | 0.164 | |
TT | 3 (7.9) | 0 (0.0) | 30.35 (15.4) | - * | - | |
Genotype distribution or CXCL12 concentration differences (p-value) | 0.074 | 0.028 | 0.910 | |||
rs2297630 | GG | 22 (57.9) | 23 (57.5) | 37.08 (5.93) | 36.41 (10.26) | 0.401 |
GA | 9 (23.7) | 12 (30.0) | 39.1 (7.94) | 35.075 (6.71) | 0.310 | |
AA | 7 (18.4) | 5 (12.5) | 35.92 (4.81) | 30 (18.41) | 0.639 | |
Genotype distribution or CXCL12 concentration differences (p-value) | 0.693 | 0.678 | 0.976 |
Variable | Gender | p-Value | |
---|---|---|---|
Women n (%) | Men n (%) | ||
CIS | 5 (3.0) | 5 (5.9) | 0.194 |
RR | 153 (92.7) | 72 (84.7) | |
SP | 2 (1.2) | 1 (1.2) | |
PP | 5 (3.0) | 7 (8.2) | |
Pyramidal system symptoms n (%) | 141 (85.5) | 77 (90.6) | 0.250 |
Sensory system symptoms n (%) | 112 (67.9) | 47 (55.3) | 0.050 |
Brainstem system symptoms n (%) | 96 (58.2) | 50 (58.8) | 0.922 |
Cerebellar system symptoms n (%) | 88 (53.3) | 47 (55.3) | 0.786 |
Pelvic system symptoms n (%) | 59 (35.8) | 30 (35.3) | 0.942 |
Visual system symptoms n (%) | 89 (53.9) | 50 (58.8) | 0.462 |
CXCL12 SNP | Genotype | Phenotype n (%) | p-Value | |||
---|---|---|---|---|---|---|
CIS | RRMS | SPMS | PPMS | |||
rs1029153 | AA | 5 (50.0) | 121 (53.8) | 0 (0.0) | 6 (50.0) | 0.225 |
AG | 4 (40.0) | 81 (36.0) | 1 (33.3) | 5 (41.7) | ||
GG | 1 (10.0) | 23 (10.2) | 2 (66.7) | 1 (8.3) | ||
rs1801157 | CC | 8 (80.0) | 147 (65.3) | 3 (100.0) | 8 (66.7) | 0.461 |
CT | 2 (20.0) | 67 (29.8) | 0 (0.0) | 2 (16.7) | ||
TT | 0 (0.0) | 11 (4.9) | 0 (0.0) | 2 (16.7) | ||
rs2297630 | GG | 5 (50.0) | 127 (56.4) | 0 (0.0) | 7 (58.3) | 0.097 |
AG | 5 (50.0) | 79 (35.1) | 1 (33.3) | 5 (41.7) | ||
AA | 0 (0.0) | 19 (8.4) | 3 (66.7) | 0 (0.0) |
CXCL12 SNP | Genotype | Patients Affected by Symptoms in Different Systems n (%) | |||||
---|---|---|---|---|---|---|---|
Pyramidal | Sensory | Brainstem | Cerebellar | Pelvic | Visual | ||
rs1029153 | AA | 110 (83.3) | 83 (62.9) | 75 (56.8) | 74 (56.1) | 46 (34.8) | 73 (55.3) |
AG | 84 (92.3) | 58 (63.7) | 56 (61.5) | 48 (52.7) | 34 (37.4) | 51 (56.0) | |
GG | 24 (88.9) | 18 (66.7) | 15 (55.6) | 13 (48.1) | 9 (33.3) | 15 (55.6) | |
p-value | 0.138 | 0.932 | 0.743 | 0.721 | 0.897 | 0.994 | |
rs1801157 | CC | 145 (87.3) | 114 (68.7) | 99 (59.6) | 91 (54.8) | 60 (63.1) | 93 (56.0) |
CT | 64 (90.1) | 40 (56.3) | 40 (56.3) | 36 (50.7) | 27 (38.0) | 39 (54.9) | |
TT | 9 (69.2) | 5 (38.5) | 7 (53.8) | 8 (61.5) | 2 (15.4) | 7 (53.8) | |
p-value | 0.116 | 0.030 | 0.844 | 0.722 | 0.283 | 0.98 | |
rs2297630 | GG | 117 (84.2) | 88 (63.3) | 81 (58.3) | 79 (56.8) | 51 (36.7) | 79 (56.8) |
AG | 82 (91.1) | 58 (64.4) | 55 (61.1) | 46 (51.1) | 32 (35.6) | 48 (53.3) | |
AA | 19 (90.5) | 13 (61.9) | 10 (47.6) | 10 (47.6) | 6 (28.6) | 12 (57.1) | |
p-value | 0.276 | 0.971 | 0.528 | 0.578 | 0.769 | 0.864 |
Women | |||||||
---|---|---|---|---|---|---|---|
CXCL12 SNP | Genotype | Patients Affected by Symptoms in Different Systems n (%) | |||||
Pyramidal | Sensory | Brainstem | Cerebellar | Pelvic | Visual | ||
rs1029153 | AA | 69 (82.1) | 59 (70.2) | 43 (51.2) | 46 (54.8) | 31 (36.9) | 45 (53.6) |
AG | 53 (89.8) | 39 (66.1) | 42 (71.2) | 33 (55.9) | 23 (39.0) | 33 (55.9) | |
GG | 19 (86.4) | 14 (63.6) | 11 (50.0) | 9 (40.9) | 5 (22.7) | 11 (50.9) | |
p-value | 0.435 | 0.786 | 0.041 | 0.451 | 0.379 | 0.889 | |
rs1801157 | CC | 93 (86.1) | 81 (75.0) | 66 (61.1) | 60 (55.6) | 42 (38.9) | 59 (54.6) |
CT | 42 (85.7) | 29 (59.2) | 26 (53.1) | 23 (46.9) | 17 (34.7) | 27 (55.1) | |
TT | 6 (75.0) | 2 (25.0) | 4 (50.0) | 5 (62.5) | 0 (0.0) | 3 (37.5) | |
p-value | 0.69 | 0.004 | 0.569 | 0.525 | 0.085 | 0.632 | |
rs2297630 | GG | 75 (83.3) | 63 (70.0) | 48 (53.3) | 50 (55.6) | 35 (38.9) | 50 (55.6) |
AG | 51 (87.9) | 39 (67.2) | 41 (70.7) | 31 (53.4) | 21 (36.2) | 30 (51.7) | |
AA | 15 (88.2) | 10 (58.8) | 7 (41.2) | 7 (41.2) | 3 (17.6) | 9 (52.9) | |
p-value | 0.698 | 0.658 | 0.037 | 0.552 | 0.245 | 0.898 | |
Men | |||||||
CXCL12 SNP | Genotype | Patients Affected by Symptoms in Different Systems n (%) | |||||
Pyramidal | Sensory | Brainstem | Cerebellar | Pelvic | Visual | ||
rs1029153 | AA | 41 (85.4) | 24 (50.0) | 32 (66.7) | 28 (58.3) | 15 (31.3) | 28 (58.3) |
AG | 31 (96.9) | 19 (59.4) | 14 (43.8) | 15 (46.9) | 11 (34.4) | 18 (56.3) | |
GG | 5 (100.0) | 4 (80.0) | 4 (80.0) | 4 (80.0) | 4 (80.0) | 4 (80.0) | |
p-value | 0.173 | 0.369 | 0.076 | 0.312 | 0.094 | 0.601 | |
rs1801157 | CC | 52 (89.7) | 33 (56.9) | 33 (56.9) | 31 (53.4) | 18 (31.0) | 34 (58.6) |
CT | 22 (100.0) | 11 (50.0) | 14 (63.6) | 13 (59.1) | 10 (45.5) | 12 (54.5) | |
TT | 3 (60.0) | 3 (60.0) | 3 (60.0) | 3 (60.0) | 2 (40.0) | 4 (80.0) | |
p-value | 0.02 | 0.838 | 0.86 | 0.881 | 0.471 | 0.579 | |
rs2297630 | GG | 42 (85.7) | 25 (51.0) | 33 (67.3) | 29 (59.2) | 16 (32.7) | 29 (59.2) |
AG | 31 (96.9) | 19 (59.4) | 14 (43.8) | 15 (46.9) | 11 (34.4) | 18 (56.3) | |
AA | 4 (100.0) | 3 (75.0) | 3 (75.0) | 3 (75.0) | 3 (75.0) | 3 (75.0) | |
p-value | 0.196 | 0.547 | 0.086 | 0.397 | 0.232 | 0.77 |
CXCL12 SNP | Genotype | Age of MS Diagnosis Median (IQR) | MS Duration Years Median (IQR) | EDSS Median (IQR) | MSSS Median (IQR) |
---|---|---|---|---|---|
rs1029153 | AA | 29 (15) | 5 (8) | 3 (2) | 5.93 (2.3) |
AG | 32 (17) | 8 (7) | 3.5 (2) | 5.57 (2.1) | |
GG | 33 (13) | 5 (7) | 3.5 (2) | 6.46 (1.9) | |
p-value | 0.085 | 0.078 | 0.660 | 0.335 | |
rs1801157 | CC | 32 (16) | 6 (7) | 3.5 (2.5) | 5.995 (2.2) |
CT | 30 (13) | 7 (9) | 3.5 (2) | 5.46 (2.4) | |
TT | 39 (15.5) | 3 (2) | 2.5 (0.3) | 6.37 (1.7) | |
p-value | 0.262 | 0.007 | 0.261 | 0.677 | |
rs2297630 | GG | 29 (15) | 5 (8) | 3 (2) | 5.93 (2.3) |
AG | 32 (16.3) | 7.5 (7) | 3.5 (2.1) | 5.515 (1.9) | |
AA | 35 (8) | 5 (7) | 3.5 (2) | 6.46 (1.9) | |
p-value | 0.103 | 0.335 | 0.851 | 0.299 |
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Valiukevicius, P.; Kaikaryte, K.; Gedvilaite-Vaicechauskiene, G.; Balnyte, R.; Liutkeviciene, R. CXCL12 Gene Polymorphisms and Serum Levels: Associations with Multiple Sclerosis Prevalence and Clinical Parameters in Lithuania. Int. J. Mol. Sci. 2024, 25, 9554. https://doi.org/10.3390/ijms25179554
Valiukevicius P, Kaikaryte K, Gedvilaite-Vaicechauskiene G, Balnyte R, Liutkeviciene R. CXCL12 Gene Polymorphisms and Serum Levels: Associations with Multiple Sclerosis Prevalence and Clinical Parameters in Lithuania. International Journal of Molecular Sciences. 2024; 25(17):9554. https://doi.org/10.3390/ijms25179554
Chicago/Turabian StyleValiukevicius, Paulius, Kriste Kaikaryte, Greta Gedvilaite-Vaicechauskiene, Renata Balnyte, and Rasa Liutkeviciene. 2024. "CXCL12 Gene Polymorphisms and Serum Levels: Associations with Multiple Sclerosis Prevalence and Clinical Parameters in Lithuania" International Journal of Molecular Sciences 25, no. 17: 9554. https://doi.org/10.3390/ijms25179554