Genetic Markers as Risk Factors for the Development of Impulsive-Compulsive Behaviors in Patients with Parkinson’s Disease Receiving Dopaminergic Therapy
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Ethical Principles
2.3. Methods
- ACE (rs4646994)
- BDNF (rs2049046, rs6265)
- COMT (rs4680)
- DBH (rs141116007, rs2097629, rs1611115)
- DRD1 (rs686)
- DRD2 (rs1799732, rs6275, rs2283265, rs12364283, rs1076560)
- MAOA (VNTR)
- SLC6A3 (rs27072)
- SLC6A4 (rs38130034)
2.3.1. DNA Isolation
2.3.2. PCR Testing
2.3.3. Restriction Analysis
2.4. Statistical Analysis
2.5. Principal Component Analysis
3. Results
3.1. Association between the Genetic Markers in PD Patients without ICD (PD2 Group)
- rs2097629 substitution in the DBH gene (9q34.2, 1434 + 1579A > G, 3′ region) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of the G allele with PD (p = 0.016, OR = 2.97, CI95% [1.17–8.97]). The mode of inheritance was found to be dominant.
- rs1611115 substitution in the DBH gene (9q34.2, 1021T > C, 5′ region) is associated with the disease. Analysis of the frequencies of alleles of this substitution also showed an association of the allele with PD (p = 2.8 × 10−3, OR = 3.71, CI95% [1.46–8.77]). The mode of inheritance was found to be recessive.
- rs6265 substitution in the BDNF gene (11p14.1, 196G > A, Val66Met, Exon 2) it is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of Allele A with PD (p = 6.7 × 10−3, OR = 2.83, CI95% [1.27–6.29]). The mode of inheritance was found to be dominant.
- rs6275 substitution in the DRD2 gene (11q23.2, 939T > C, His313His, Exon 7) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of the T allele with PD (p = 2.9 × 10−8, OR = 9.00, CI95% [3.97–20.14]). The mode of inheritance was found to be recessive.
- rs12364283 substitution in the DRD2 gene (11q23.2, 4047A > G, 5′ region) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of the T allele with PD (p = 0.012, OR = 3.30, CI95% [1.25–10.19]). The mode of inheritance was found to be recessive.
- rs686 substitution in the DRD1 gene (5q35.1, 7464G > A, 3′ region) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of Allele A with PD (p = 0.017, OR = ∞, CI95% [1.3583–∞]). The mode of inheritance was found to be dominant.
3.2. Association between the Genetic Markers and ICD in PD Patients (PD1 Group)
- rs1611115 substitution in the DBH gene (9q34.2, 1021T > C, 5′ region) is associated with the disease. Analysis of the frequencies of alleles of this substitution also showed an association of the allele with PD (p = 2.8 × 10−3, OR = 3.71, CI95% [1.46–8.77]). The mode of inheritance was found to be dominant.
- rs6265 substitution in the BDNF gene (11p14.1, 196G > A, Val66Met, Exon 2) it is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of Allele A with PD (p = 6.7 × 10−3, OR = 2.83, CI95% [1.27–6.29]). The mode of inheritance was found to be dominant.
- rs6275 substitution in the DRD2 gene (11q23.2, 939T > C, His313His, Exon 7) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of the T allele with PD (p = 2.9 × 10−8, OR = 9.00, CI95% [3.97–20.14]). The mode of inheritance was found to be dominant.
- rs12364283 substitution in the DRD2 gene (11q23.2, 4047A > G, 5′ region) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of the T allele with PD (p = 0.012, OR = 3.30, CI95% [1.25–10.19]). The mode of inheritance was found to be recessive.
- rs1076560 substitution in the DRD2 gene (11q23.2, 67314C > A, Intron 6) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of the T allele with PD (p = 0.012, OR = 3.30, CI95% [1.25–10.19]). The mode of inheritance was found to be dominant.
- rs4646994 substitution in ACE gene (11q23.2, I/D 289bp, Intron 16) is associated with the disease. Analysis of allele frequencies of this substitution also showed an association of the T allele with PD (p = 0.024, OR = 2.64, CI95% [1.12–7.22]). The mode of inheritance was found to be dominant.
3.3. Principal Component Analysis
4. Discussion
4.1. Association between the Genetic Markers and PD
4.2. Analysis of Complex Genotype Associations in PD Patients
4.3. Association between the Genetic Markers and ICD in PD Patients
4.4. Analysis of Complex Genotype Associations in PD Patients with ICD
4.5. Association between the Genetic Markers and ICD in PD Patients
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameters described | PD + ICD, PD1, n = 49 | PD2, n = 36 |
Mean age, years | 65.8 ± 8 | 70.6 ± 5.9 |
Number of subjects male | 23 | 18 |
Number of subjects female | 26 | 18 |
Education duration, years | 15.9 ± 3 | 15.8 ± 3.6 |
Duration of the disease, years | 6.6 ± 4.94 | 7.53 ± 4.9 |
Hoehn and Yahr stage | 2.2 ± 0.5 | 2.5 ± 0.5 |
UPDRS, total score | 33.4 ± 11.9 | 36.3 ± 12.2 |
LEDD, mg/day | 731.5 ± 454 | 762.4 ± 342.1 |
Duration of the use of dopaminergic therapy, years | 6.6 ± 4.94 | 7.53 ± 4.9 |
Breakdown of the types of dopaminergic therapy | Levodopa + DA (n = 13; 26.5%), Levodopa + DA + amantadine (n = 13; 26.5%), DA monotherapy (n = 7; 14.3%), Levodopa monotherapy (n = 4; 8.25%), DA + amantadine (n = 4; 8.25%), Levodopa + COMT inhibitor + DA + amantadine (n = 3; 6.1%), Levodopa + amantadine (n = 2; 4.1%), Levodopa + COMT inhibitor + DA (n = 1; 2%), Levodopa + MAO-B inhibitor (n = 1; 2%), Levodopa + DA + amantadine + MAO-B inhibitor (n = 1; 2%). | Levodopa + DA + amantadine (n = 14; 38.9%), Levodopa + DA (n = 12; 33.3%), DA + amantadine (n = 5; 13.9%), DA monotherapy (n = 4; 11.1%), Levodopa + COMT inhibitor + DA + amantadine (n = 1; 2.8%). |
Gene | Substitution | PD2 | Control | Chi, p | Fi (p) | OR | CI95% | |
---|---|---|---|---|---|---|---|---|
DBH | rs141116007 | II + ID | 26 | 282 | 1.017 | 0.294 | 0.67 | 0.30–1.64 |
DD | 10 | 73 | 0.313 | 1.49 | 0.61–3.36 | |||
BDNF | rs2049046 | AA | 7 | 50 | 0.847 | 0.327 | 1.51 | 0.53–3.76 |
AT + TT | 29 | 312 | 0.358 | 0.66 | 0.27–1.90 | |||
DRD2 | rs1799732 | CC | 15 | 18 | 1.911 | 0.189 | 1.83 | 0.71–4.68 |
CD + DD | 21 | 46 | 0.167 | 0.55 | 0.21–1.42 | |||
MAOA | VNTR | SS + SL | 20 | 129 | 3.309 | 0.076 | 1.89 | 0.89–4.05 |
LL | 16 | 195 | 0.069 | 0.53 | 0.25–1.12 | |||
DRD2 | rs6275 | TT | 18 | 34 | 43.706 | 2.9 × 10−8 | 9.00 | 3.97–20.14 |
CT + CC | 18 | 306 | 3.8 × 10−11 | 0.11 | 0.05–0.25 | |||
DBH | rs2097629 | AA | 6 | 114 | 5.995 | 0.016 | 0.34 | 0.11–0.86 |
AG + GG | 30 | 192 | 0.014 | 2.97 | 1.17–8.97 | |||
BDNF | rs6265 | AA + AG | 16 | 94 | 8.308 | 6.7 × 10−3 | 2.83 | 1.27–6.29 |
GG | 16 | 266 | 3.9 × 10−3 | 0.35 | 0.16–0.79 | |||
DBH | rs1611115 | TT + CT | 26 | 328 | 11.256 | 2.8 × 10−3 | 0.27 | 0.11–0.68 |
CC | 10 | 34 | 7.9 × 10−4 | 3.71 | 1.46–8.77 | |||
COMT | rs4680 | AA + AG | 22 | 147 | 3.773 | 0.063 | 0.48 | 0.22–1.11 |
GG | 14 | 45 | 0.052 | 2.08 | 0.90–4.65 | |||
DRD2 | rs2283265 | TT + CT | 34 | 161 | 0.572 | 0.610 | 0.53 | 0.08–5.78 |
CC | 2 | 5 | 0.449 | 1.89 | 0.17–12.13 | |||
DRD2 | rs12364283 | TT | 30 | 100 | 6.877 | 0.012 | 3.30 | 1.25–10.19 |
CT + CC | 6 | 66 | 8.7 × 10−3 | 0.30 | 0.10–0.80 | |||
DRD2 | rs1076560 | TT + CT | 14 | 40 | 3.305 | 0.095 | 2.00 | 0.86–4.53 |
CC | 22 | 126 | 0.069 | 0.50 | 0.22–1.16 | |||
SLC6A4 | rs38130034 | TT | 13 | 43 | 2.762 | 0.140 | 1.89 | 0.81–4.28 |
CT + CC | 23 | 144 | 0.097 | 0.53 | 0.23–1.24 | |||
ACE | rs4646994 | II + ID | 26 | 228 | 0.367 | 0.708 | 1.27 | 0.57–3.05 |
DD | 10 | 111 | 0.545 | 0.79 | 0.33–1.77 | |||
SLC6A3 | rs27072 | CC | 24 | 86 | 2.634 | 0.139 | 1.86 | 0.83–4.36 |
CT + TT | 12 | 80 | 0.105 | 0.54 | 0.23–1.21 | |||
DRD1 | rs686 | CC | 0 | 23 | 5.629 | 0.017 | 0.00 | 0.0000–0.7362 |
CT + TT | 36 | 143 | 0.018 | ∞ | 1.3583–∞ |
Informative Allelic Pattern | Genotype Carriers | Fi (p) | OR | CI95% | |
---|---|---|---|---|---|
PD2 | Control | ||||
DBH_rs2097629:G; DRD1_rs686:G; DRD2_rs12364283:A,A | 75.0% | 29.7% | 6.38 × 10−7 | 7.10 | 3.11–16.21 |
DBH_rs2097629:G; DRD2_rs6275:T,T | 44.4% | 8.6% | 1.42 × 10−6 | 8.51 | 3.62–20.04 |
BDNF_rs6265:A; DRD2_rs6275:T,T | 36.4% | 4.3% | 1.92 × 10−6 | 12.57 | 4.45–35.49 |
DRD2_rs6275:T,T | 50% | 12.3% | 2.24 × 10−6 | 7.15 | 3.20–15.97 |
Informative Allelic Pattern | Genotype Carriers | Fi (p) | OR | CI95% | |
---|---|---|---|---|---|
PD2 | Control | ||||
BDNF_rs6265:G; DRD2_rs6275:C | 45.5% | 86.9% | 9.51 × 10−7 | 0.13 | 0.055–0.29 |
DRD2_rs6275:C | 50% | 87.7% | 2.24 × 10−6 | 0.14 | 0.063–0.31 |
Gene | Substitution | PD1 | Control | Chi, p | Fi (p) | OR | CI95% | |
---|---|---|---|---|---|---|---|---|
DBH | rs141116007 | II + ID | 38 | 282 | 0.312 | 0.580 | 0.82 | 0.39–1.81 |
DD | 12 | 73 | 0.576 | 1.22 | 0.55–2.53 | |||
BDNF | rs2049046 | AA | 11 | 50 | 2.335 | 0.138 | 1.76 | 0.76–3.79 |
AT + TT | 39 | 312 | 0.126 | 0.57 | 0.26–1.32 | |||
DRD2 | rs1799732 | CC | 20 | 18 | 2.506 | 0.156 | 1.89 | 0.79–4.52 |
CD + DD | 27 | 46 | 0.113 | 0.53 | 0.22–1.26 | |||
MAOA | VNTR | SS + SL | 27 | 129 | 3.585 | 0.065 | 1.77 | 0.93–3.39 |
LL | 23 | 195 | 0.058 | 0.56 | 0.29–1.07 | |||
DRD2 | rs6275 | TT | 13 | 34 | 10.528 | 3.8 × 10−3 | 3.16 | 1.40–6.81 |
CT + CC | 37 | 306 | 1.1 × 10−3 | 0.32 | 0.15–0.72 | |||
DBH | rs2097629 | AA + AG | 39 | 263 | 2.110 | 0.199 | 0.58 | 0.27–1.36 |
GG | 11 | 43 | 0.146 | 1.73 | 0.74–3.76 | |||
BDNF | rs6265 | AA + AG | 27 | 94 | 23.224 | 5.7 × 10−6 | 4.49 | 2.24–9.18 |
GG | 17 | 266 | 1.4 × 10−6 | 0.22 | 0.11–0.45 | |||
DBH | rs1611115 | TT | 14 | 209 | 15.644 | 1.1 × 10−4 | 0.28 | 0.14–0.56 |
CT + CC | 36 | 153 | 7.6 × 10−5 | 3.51 | 1.77–7.29 | |||
COMT | rs4680 | AA | 10 | 52 | 0.446 | 0.575 | 0.77 | 0.32–1.73 |
AG + GG | 35 | 140 | 0.504 | 1.30 | 0.58–3.16 | |||
DRD2 | rs2283265 | TT | 26 | 118 | 2.893 | 0.105 | 0.56 | 0.27–1.17 |
CT + CC | 19 | 48 | 0.089 | 1.80 | 2.74–25.02 | |||
DRD2 | rs12364283 | TT | 37 | 100 | 7.512 | 7.7 × 10−3 | 3.05 | 1.29–8.04 |
CT + CC | 8 | 66 | 6.1 × 10−3 | 0.33 | 0.12–0.78 | |||
DRD2 | rs1076560 | TT + CT | 19 | 40 | 5.774 | 0.024 | 2.30 | 1.08–4.83 |
CC | 26 | 126 | 0.016 | 0.43 | 0.21–0.93 | |||
SLC6A4 | rs38130034 | TT | 15 | 43 | 2.068 | 0.179 | 1.67 | 0.76–3.56 |
CT + CC | 30 | 144 | 0.150 | 0.60 | 0.28–1.31 | |||
ACE | rs4646994 | II + ID | 38 | 228 | 5.513 | 0.024 | 2.64 | 1.12–7.22 |
DD | 7 | 111 | 0.019 | 0.38 | 0.14–0.90 | |||
SLC6A3 | rs27072 | CC + CT | 43 | 149 | 1.452 | 0.377 | 2.45 | 0.55–22.65 |
TT | 2 | 17 | 0.228 | 0.41 | 0.04–1.83 | |||
DRD1 | rs686 | CC + CT | 39 | 137 | 0.438 | 0.653 | 1.38 | 0.51–4.34 |
TT | 6 | 29 | 0.508 | 0.73 | 0.23–1.96 |
Informative Allelic Pattern | Genotype Carriers | Fi (p) | OR | CI95% | |
---|---|---|---|---|---|
PD1 | Control | ||||
ACE_rs4646994:I; BDNF_rs6265:A; DRD2_rs1076560:A | 25.6% | 0.006% | 2.68 × 10−7 | 55.17 | 6.80–447.57 |
BDNF_rs6265:A; DRD2_rs1076560:A | 28.2% | 2.5% | 3.28 × 10−6 | 15.42 | 4.58–51.86 |
BDNF_rs6265:A; DBH_rs1611115:T | 43.2% | 12.4% | 1.89 × 10−5 | 5.36 | 2.51–11.44 |
BDNF_rs6265:G; DBH_rs1611115:T | 72.7% | 37.3% | 2.63 × 10−5 | 4.49 | 2.15–9.37 |
Informative Allelic Pattern | Genotype Carriers | Fi (p) | OR | CI95% | |
---|---|---|---|---|---|
PD1 | Control | ||||
BDNF_rs6265:G; DBH_rs1611115:C,C | 22.3% | 60.8% | 5.73 × 10−6 | 0.19 | 0.09–0.41 |
BDNF_rs6265:G,G; DRD2_rs6275:C | 27.3% | 64.6% | 9.77 × 10−6 | 0.21 | 0.10–0.43 |
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Fedosova, A.; Titova, N.; Kokaeva, Z.; Shipilova, N.; Katunina, E.; Klimov, E. Genetic Markers as Risk Factors for the Development of Impulsive-Compulsive Behaviors in Patients with Parkinson’s Disease Receiving Dopaminergic Therapy. J. Pers. Med. 2021, 11, 1321. https://doi.org/10.3390/jpm11121321
Fedosova A, Titova N, Kokaeva Z, Shipilova N, Katunina E, Klimov E. Genetic Markers as Risk Factors for the Development of Impulsive-Compulsive Behaviors in Patients with Parkinson’s Disease Receiving Dopaminergic Therapy. Journal of Personalized Medicine. 2021; 11(12):1321. https://doi.org/10.3390/jpm11121321
Chicago/Turabian StyleFedosova, Anna, Nataliya Titova, Zarema Kokaeva, Natalia Shipilova, Elena Katunina, and Eugene Klimov. 2021. "Genetic Markers as Risk Factors for the Development of Impulsive-Compulsive Behaviors in Patients with Parkinson’s Disease Receiving Dopaminergic Therapy" Journal of Personalized Medicine 11, no. 12: 1321. https://doi.org/10.3390/jpm11121321