LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome
Abstract
:1. Introduction
- (A)
- RLS is associated to several inflammatory and autoimmune diseases, including chronic liver disease [7], Sjogren’s syndrome [7], rheumatoid arthritis [7], sarcoidosis [7], systemic lupus erythematous [7], inflammatory bowel disease [7,8], multiple sclerosis [9], mastocytosis [10], and chronic obstructive pulmonary disease [11].
- (B)
- There is a description of patients suffering from recurrent and severe RLS always coinciding with infectious-inflammatory conditions [12].
- (C)
- (D)
- There is an association between increased serum/plasma hsCRP levels and odds for severe periodic leg movements of sleep (PLMS) in untreated patients with RLS [18].
- (E)
- There is a description of significantly higher serum/plasma levels of hsCRP in patients with end-stage kidney disease with RLS compared with those without RLS, and correlation between hsCRP and RLS severity, according to one study [19]. Another three studies in patients with chronic kidney disease did not show significant differences in serum/plasma hsCRP between patients with and without RLS [20,21,22]. Mandal et al. [11] showed a lack of significant differences in serum/plasma hsCRP levels in patients with chronic obstructive pulmonary disease with and without RLS.
- (F)
- There is a description of a higher neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, in patients with RLS than in controls in a cross-sectional [23] and a prospective longitudinal study [14], although in the latter the statistical significance disappeared after adjusting for sex, age, body mass index and smoking status [14].
- (G)
- There is a description of higher serum interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α) levels in RLS patients than in controls according to one study [16], and of similar plasma cytokine-specific autoantibodies (c-aAb) against IL-1α, IL-6, IL-10, and GM-CSF (granulocyte-macrophage colony-stimulating factor) in patients with RLS and controls, a higher frequency of c-aAb against IFN-α (interferon-alpha) in RLS patients, and significantly higher plasma suPAR (soluble urokinase-type plasminogen activator receptor) levels in patients with severe RLS (although the latter disappeared after adjusting for sex, age, body mass index, and smoking status) in another [14]. IL-6 and TNF-α were not related to the presence of PLMS in RLS patients [18]. Serum IL-6 was increased in patients with end-stage kidney disease and RLS compared with those without RLS [18] and was similar in patients with hematologic malignancies with and without RLS [24].
- (H)
- (I)
- There is a description of an association of several polymorphisms in the IL-1β IL-17α genes but of a lack of association of polymorphisms of other IL, IFN, TNF-α, and nuclear factor kappa-B (NFKB) genes with the risk for RLS in patients with HIV infection [27].
2. Results
3. Discussion
4. Materials and Methods
4.1. Patients and Controls
4.2. Ethical Aspects
4.3. Genotyping of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 Variants
4.4. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Genotype | RLS Patients (n = 285, 570 alleles) | Controls (n = 350, 700 alleles) | OR (95% CI), P; Pc; NPV (95% CI) |
---|---|---|---|
rs1922452 A/A | 52 (18.2; 13.8–22.7) | 59 (16.9; 12.9–20.8) | 1.10 (0.73–1.66); 0.647; 0.955; 0.56 (0.54–0.57) |
rs1922452 A/G | 135 (47.4; 41.6–53.2) | 165 (47.1; 41.9–52.4) | 1.01 (0.74–1.38); 0.955; 0.955; 0.55 (0.51–0.59) |
rs1922452 G/G | 98 (34.4; 28.9–39.9) | 126 (36.0; 31.0–41.0) | 0.94 (0.67–1.29); 0.672; 0.955; 0.55 (0.52–0.58) |
rs951818 A/A | 99 (34.7; 29.2–40.3) | 127 (36.3; 31.2–41.3) | 0.94 (0.67–1.30); 0.685; 0.955; 0.55 (0.52–0.58) |
rs951818 A/C | 144 (50.5; 44.7–56.3) | 169 (48.3; 43.1–53.5) | 1.09 (0.80–1.50); 0.575; 0.955; 0.56 (0.52–0.60) |
rs951818 C/C | 42 (14.7; 10.6–18.9) | 54 (15.4; 11.6–19.2) | 0.95 (0.61–1.47); 0.809; 0.955; 0.55 (0.53–0.57) |
rs870849 C/C | 120 (42.1; 36.4–47.8) | 138 (39.4; 34.3–44.5) | 1.17 (0.81–1.54); 0.499; 0.955; 0.56 (0.53–0.60) |
rs870849 C/T | 128 (44.9; 39.1–50.7) | 168 (48.0; 42.8–53.2) | 0.88 (0.65–1.21); 0.438; 0.955; 0.54 (0.50–0.57) |
rs870849 T/T | 37 (13.0; 9.1–16.9) | 44 (12.6; 9.1–16.0) | 1.04 (0.65–1.66); 0.877; 0.955; 0.55 (0.54–0.57) |
Alleles | |||
rs1922452 A | 239 (41.9; 37.9–46.0) | 283 (40.4; 36.8–44.1) | 1.06 (0.85–1.33); 0.589; 0.877; 0.56 (0.53–0.58) |
rs1922452 G | 331 (58.1; 54.0–62.1) | 417 (59.6; 55.9–63.2) | 0.94 (0.75–1.17); 0.589; 0.877; 0.54 (0.51–0.58) |
rs951818 A | 342 (60.0; 56.0–64.0) | 423 (60.4; 56.8–64.1) | 0.98 (0.78–1.23); 0.877; 0.877; 0.55 (0.51–0.58) |
rs951818 C | 228 (40.0; 36.0–44.0) | 277 (39.6; 35.9–43.2) | 1.02 (0.81–1.28); 0.877; 0.877; 0.55 (0.53–0.58) |
rs870849 C | 368 (64.6; 60.6–68.5) | 444 (63.4; 59.9–67.0) | 1.05 (0.83–1.32); 0.676; 0.877; 0.56 (0.52–0.60) |
rs870849 T | 202 (35.4; 31.5–39.4) | 256 (36.6; 33.0–40.1) | 0.95 (0.76–1.20); 0.676; 0.877; 0.55 (0.53–0.57) |
Genotype | Positive Family History of RLS (N = 182, 364 ALLELES) | Negative Family History of RLS (N = 99, 198 ALLELES) | Intergroup Comparison Values OR (95%CI) P, PC, NPV (95%CI) |
---|---|---|---|
rs1922452 A/A | 26 (14.3; 9.2–19.4) | 25 (25.3; 16.7–33.8) | 0.49 (0.27–0.91); 0.023; 0.207; 0.32 (0.29–0.35) |
rs1922452 A/G | 93 (51.1; 43.8–58.4) | 41 (41.4; 31.7–51.1) | 1.48 (0.90–2.42); 0.121; 0.363; 0.40 (0.34–0.45) |
rs1922452 G/G | 63 (34.6; 27.7–41.5) | 33 (33.3; 24.0–42.6) | 1.06 (0.63–1.78); 0.829; 0.906; 0.36 (0.31–0.40) |
rs951818 A/A | 68 (37.4; 30.3–44.4) | 29 (29.3; 20.3–38.3) | 1.44 (0.85–2.44); 0.175; 0.394; 0.38 (0.34–0.42) |
rs951818 A/C | 85 (46.7; 39.5–54.0) | 57 (57.6; 47.8–67.3) | 0.65 (0.39–1.06); 0.082; 0.363; 0.30 (0.24–0.36) |
rs951818 C/C | 29 (15.9; 10.6–21.3) | 13 (13.1; 6.5–19.8) | 1.25 (0.62–2.54); 0.530; 0.906; 0.36 (0.33–0.38) |
rs870849 C/C | 76 (41.8; 34.6–48.9) | 43 (43.4; 33.7–53.2) | 0.93 (0.57–1.53); 0.786; 0.906; 0.35 (0.30–0.40) |
rs870849 C/T | 83 (45.6; 38.4–52.8) | 43 (43.4; 33.7–53.2) | 1.09 (0.67–1.79); 0.727; 0.906; 0.36 (0.31–0.41) |
rs870849 T/T | 23 (12.6; 7.8–17.5) | 13 (13.1; 6.5–19.8) | 0.96 (0.46–1.98); 0.906; 0.906; 0.35 (0.33–0.37) |
Alleles | |||
rs1922452 A | 145 (39.8; 34.8–44.9) | 91 (46.0; 39.0–52.9) | 0.96 (0.46–1.98); 0.160; 0.480; 0.35 (0.33–0.37) |
rs1922452 G | 219 (60.2; 55.1–65.2) | 107 (54.0; 47.1–61.0) | 1.28 (0.91–1.82); 0.160; 0.480; 0.39 (0.34–0.43) |
rs951818 A | 221 (60.7; 55.7–65.7) | 115 (58.1; 51.2–65.0) | 1.12 (0.78–1.59); 0.543; 0.815; 0.37 (0.32–0.42) |
rs951818 C | 143 (39.3; 34.3–44.3) | 83 (41.9; 35.0–48.8) | 0.90 (0.63–1.28); 0.543; 0.815; 0.34 (0.31–0.38) |
rs870849 C | 235 (64.6; 59.6–69.5) | 129 (65.2; 58.5–71.8) | 0.97 (0.68–1.40); 0.889; 0.889; 0.35 (0.29–0.41) |
rs870849 T | 129 (35.4; 30.5–40.4) | 69 (34.8; 28.2–41.5) | 1.03 (0.71–1.48); 0.889; 0.889; 0.35 (0.32–0.38) |
Age at Onset (SD) Years | Two-Tailed t-Test Compared to A/A | Two-Tailed t-Test Compared to A/G | |
---|---|---|---|
rs1922452 AA | 40.13 (18.09) | ||
rs1922452 AG | 42.52 (16.71) | 0.394 | |
rs1922452 GG | 46.28 (18.85) | 0.038 | 0.069 |
Two-Tailed t-Test compared to A/A | Two-Tailed t-Test compared to A/C | ||
rs951818 AA | 42.86 (18.02) | ||
rs951818 AC | 44.75 (17.24) | 0.413 | |
rs951818 CC | 41.19 (19.44) | 0.624 | 0.256 |
Two-Tailed t-Test compared to C/C | Two-Tailed t-Test compared to C/T | ||
rs870849 CC | 44.79 (17.89) | ||
rs870849 CT | 43.27 (18.13) | 0.507 | |
rs870849 TT | 40.47 (16.64) | 0.199 | 0.407 |
IRLSSG (SD) | Two-Tailed t-Test Compared to A/A | Two-Tailed t-Test Compared to A/G | |
---|---|---|---|
rs1922452 AA | 24.91 (6.80) | ||
rs1922452 AG | 23.27 (6.72) | 0.157 | |
rs1922452 GG | 26.10 (6.38) | 0.316 | 0.002 |
Two-Tailed t-Test compared to A/A | Two-Tailed t-Test compared to A/C | ||
rs951818 AA | 25.39 (5.94) | ||
rs951818 AC | 24.11 (6.86) | 0.144 | |
rs951818 CC | 23.90 (7.85) | 0.235 | 0.870 |
Two-Tailed t-Test compared to C/C | Two-Tailed t-Test compared to C/T | ||
rs870849 CC | 24.50 (5.32) | ||
rs870849 CT | 24.55 (7.53) | 0.950 | |
rs870849 TT | 24.43 (7.96) | 0.951 | 0.932 |
Group | Controls (n = 350) | RLS (n = 285) |
---|---|---|
Age, y, mean (SD) | 55.7 (16.3) | 56.1 (14.9) |
Age at onset, y, mean (SD) | NA | 43.7 (17.6) |
Female % | 270 (77.1%) | 217 (77.1%) |
Positive family history % | NA | 190 (66.6%) 1 |
IRLSSG, mean (SD) | NA | 24.74 (6.39) |
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Jiménez-Jiménez, F.J.; Gómez-Tabales, J.; Alonso-Navarro, H.; Rodríguez, C.; Turpín-Fenoll, L.; Millán-Pascual, J.; Álvarez, I.; Pastor, P.; Calleja, M.; García-Ruiz, R.; et al. LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome. Int. J. Mol. Sci. 2022, 23, 14795. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314795
Jiménez-Jiménez FJ, Gómez-Tabales J, Alonso-Navarro H, Rodríguez C, Turpín-Fenoll L, Millán-Pascual J, Álvarez I, Pastor P, Calleja M, García-Ruiz R, et al. LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome. International Journal of Molecular Sciences. 2022; 23(23):14795. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314795
Chicago/Turabian StyleJiménez-Jiménez, Félix Javier, Javier Gómez-Tabales, Hortensia Alonso-Navarro, Christopher Rodríguez, Laura Turpín-Fenoll, Jorge Millán-Pascual, Ignacio Álvarez, Pau Pastor, Marisol Calleja, Rafael García-Ruiz, and et al. 2022. "LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome" International Journal of Molecular Sciences 23, no. 23: 14795. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314795