Polymorphisms of Dopamine Receptor Genes and Parkinson’s Disease: Clinical Relevance and Future Perspectives
Abstract
:1. Introduction
2. Pharmacogenetics of Dopaminergic Receptors
2.1. Genetic Polymorphisms in Dopamine Receptor D1 Gene
2.2. Genetic Polymorphisms in Dopamine Receptor D2 Gene
2.3. Genetic Polymorphisms in Dopamine Receptor D3 Gene
2.4. Genetic Polymorphisms in Dopamine Receptor D4 Gene
2.5. Genetic Polymorphisms in Dopamine Receptor D5 Gene
3. Genetic Polymorphisms in Dr and Parkinson’s Disease Risk
4. Genetic Polymorphisms in DR and Parkinson’s Disease Symptoms
4.1. PD Motor Symptoms
4.2. Gastrointestinal Symptoms
4.3. Impulse Control Disorders
4.4. Visual Hallucinations
4.5. Cognitive Decline
4.6. Sleep Attacks
5. Genetic Polymorphisms in Dr Genes and Response to Antiparkinsonian Dopaminergic Treatment
Levodopa-Induced Dyskinesia
6. Role of Dr Genetic Polymorphisms in Peripheral Immunity: Possible Relevance for Pd
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Study Population | Considered SNPs | Main Results | Reference |
---|---|---|---|
Parkinson Disease (PD) Risk | |||
100 PD patients and 100 healthy controls | DRD2: dinucleotide (GT) repeat | Individuals who were homozygous for allele 3 were more frequent in the sporadic PD than in controls. | [73] |
122 PD patients and 127 healthy controls | DRD4: VNTR 7/48-base pair repeat | No association with PD risk. | [77] |
154 PD patients and 125 healthy controls | DRD2: TG/CA repeat (intron 2) | No association with PD risk. | [70] |
152 PD patients and 231 healthy controls | DRD2: rs1800497 (2137 C > T) rs1079597 (54716 G > A) | No association with PD risk. | [67] |
135 PD patients and 202 healthy controls | DRD2: rs1800497 (2137 C > T) rs1079597 (54716 G > A) rs1801028 (−141 C ins/del) rs1799732 (932 C > G) | rs1800497 (CC genotype) and rs1079597 (GG genotype) were more frequent in PD patients than in healthy controls. | [65] |
72 PD patients and 81 healthy controls | DRD2: rs1800497 (2137 C > T) | rs1800497 (CC genotype) was more frequent in PD patients than in healthy controls. | [66] |
204 PD patients and 216 healthy controls | DRD2: rs1800497 (2137 C > T) rs1079597 (54716 G > A) | No association with PD risk. | [69] |
487 PD patients and 474 healthy controls | DRD1: rs4532 (−48 A > G) rs5330 (150 G > T) rs5331 (595 T > G) rs13306309 (685 G > A) DRD2: rs1799732 (−141 C ins/del) rs1800497 (2137 C > T) rs1800498 (59414 C > T) rs2234689 (72519 C > G) DRD3: rs6280 (25 A > G) rs324026 (32213 G > A) rs1503670 (23948 C > G) rs905568 (g.773 G > A) DRD4: VNTR 120 bp duplication −521 C > T VNTR 7/48-base pair repeat | DRD4 12-bp duplication seems to be associated with PD risk. | [63] |
767 PD patients and 1989 healthy controls | DRD2: rs1800497 (2137 C > T) rs1079597 (54716 G > A) | No association with PD risk. | [71] |
70 PD patients and 100 healthy controls | DRD2: rs1800497 (2137 C > T) rs1079597 (54716 G > A) | No association with PD risk. | [72] |
448 PD patients and 428 healthy controls | DRD3: rs6280 (25 A > G) | No association with PD risk. | [76] |
1325 PD patients and 1735 healthy controls | DRD2: rs1800497 (2137 C > T) rs1076563 (55093 T > G) rs6279 (376 C > G) rs6278 (725 G > T) rs273482 (18232490 C > T) DRD3: rs6280 (25 A > G) rs2134655 (65054 G > A) | DRD2 rs1800497 (TT genotype) was associated with increased PD risk in non-Hispanic whites. DRD3 rs6280 (GG genotype) was associated with a decreased PD risk in Hispanics. | [64] |
293 PD patients and 369 healthy controls | DRD2: rs1800497 (2137 C > T) DRD4: rs1800955 (4480 T > G) | No association with PD risk. | [68] |
4279 PD patients and 5661 healthy controls | DRD2: rs1800497 (2137 C > T) rs1079597 (54716 G > A) rs6279 (376 C > G) rs6278 (725 G > T) rs273482 (18232490 C > T) rs1799732 (−141 C ins/del) rs1076563 (55093 T > G) DRD3: rs6280 (25 A > G) rs2134655 (65054 G > A) | DRD3 rs2134655 and DRD2 rs1800497 were associated with PD risk. | [74] |
664 PD patients and 718 healthy controls | DRD2: rs1800497 (2137 C > T) DRD3: rs6280 (25 A > G) | DRD3 rs6280 (genotype CC) was associated with earlier age at onset. | [75] |
PD Motor Symptoms | |||
126 PD patients (31 with tremor) | DRD2 rs1799732 (−141 ins/del) DRD2 rs6280 | DRD2 −141 ins/del was associated with rigidity. | [80] |
591 PD patients (62 with tremor) | DRD3 rs6280 (25 A > G) | No association with tremor in PD. | [78] |
Gastrointestinal Symptoms | |||
217 PD patients (56 with GS) | DRD2: rs1799732 (−141 C ins/del) DRD3: rs6280 (25 G > A) | rs1799732 (−141 C ins/ins genotype) and DRD3 rs6280 (GG genotype) was associated with levodopa-induced gastrointestinal symptoms. | [85] |
Impulse Control Disorders (ICD) | |||
404 PD patients (58 with ICD) and 559 healthy controls | DRD2: rs1800497 (2137 C > T) DRD3: rs6280 (25 G > A) | DRD3 rs6280 (AA genotype) was associated with ICD. | [95] |
89 PD patients (41 with ICDs) | DRD2: rs1800497 (2137 C > T) | No association with ICD. | [93] |
91 PD patients (52 with ICD) | DRD1: rs4532 (−48 A > G) rs4867798 (863 A > C) rs265981 (−684 T > A) DRD2: rs1800497 (2137 C > T) DRD3: rs6280 (25 G > A) rs3732783 (51 A > G) | DRD1 rs4532 (AG genotype), rs4867798 (CC genotype) and DRD2 rs1800497 (TT genotype) were associated with ICD increased risk. | [92] |
276 PD patients (52 with ICD) | DRD2: rs1800497 (2137 C > T) DRD3: rs6280 (25 G > A) | No association with ICD. | [94] |
170 PD patients (70 with ICD) and 285 healthy controls | DRD3: rs6280 (25 G > A) | DRD3 rs6280 (CT genotype) is associated with ICD. | [96] |
126 non early-onset PD (NEOPD) and 73 EOPD (age at onset < 45). | DRD3: rs6280 (25 G > A) | rs6280 was associated with ICD in PD patients with an early onset of the disease. | [97] |
Visual Hallucinations (VHs) | |||
155 PD patients (84 with VHs) | DRD2 rs1800497 2137 C > T rs1799732 (141 C ins/del) DRD3: rs6280 (25 G > A) | rs1800497 (C allele) was associated with late-onset hallucination. | [104] |
88 PD patients (44 with chronic hallucinations) | DRD1 B1/B2 DRD2 rs1801028 (932 C > G) DRD3 1/2 DRD4 7/48-base pair repeat (exon 3) | No association with VHs. | [118] |
90 PD patients (45 with VHs) | DRD2: rs1800497 (2137 C > T) DRD3: rs6280 (25 G > A) DRD5: rs6283 (978 T > C) | No association with VHs. | [103] |
82 PD patients (42 with VHs) | DRD1: rs4532 (−48 A > G) rs686 (62 G > A) DRD2: rs1800497 2137 C > T rs6277 (957 C > T) DRD3: rs6280 (25 G > A) rs1800828 (−712 G > C) DRD4: rs747302 (−616 C > G) VNTR (7/48-base pair repeat) DRD5: rs6283 (978 T > C) | DRD1 rs686 (AA genotype) was associated with increased VHs risk. DRD1 rs4532 (GG genotype) and rs686 (TT genotype) displayed shorter time to VHs, whereas a longer time to VHs was found in subjects carrying DRD4 rs747302 (CG genotypes). | [18] |
Cognitive Decline | |||
134 patients (84 with dementia) | DRD2 rs6277 (957 C > T) | T/T genotype was associated with increased risk of developing dementia. | [111] |
Sleep Attacks | |||
274 PD patients, 137 with sudden onset of sleep (SOS) | DRD2: rs1800497 2137 C > T DRD3: rs6280 (25 G > A) DRD4: VNTR (7/48-base pair repeat) | DRD2 rs1800497 (allele C) was associated with SOS. | [116] |
204 PD patients (102 with sleep attacks) | DRD2: rs1799732 (141 C ins/del) DRD2: rs1800497 (2137 C > T) DRD3: rs6280 (25 G > A) DRD4: VNTR (7/48-base pair repeat) | DRD4*2 (short) allele was associated with sleep attacks without warning signs. | [117] |
Motor Complications | |||
136 PD patients and 224 healthy controls | DRD1 D1.1 in the 5′ untranslated region (UTR), D1.7 in the 39 UTR DRD2 short tandem repeat polymorphism (STRP) | STRP 13- and 14-repetition genotype polymorphism were significantly higher in non-dyskinetic PD patients compared with dyskinetic patients. | [119] |
140 PD patients and 140 healthy controls | DRD2: rs1800497 (2137 C > T) DRD3: Bal1, Msp1 | DRD2 rs1800497 SNPs may be associated with increased risk for motor fluctuations in PD. | [120] |
120 PD patients and 110 healthy controls | DRD5 978 T > C | No association with risk of developing motor fluctuation. | [121] |
183 PD patients | DRD2: rs1800497 (2137 C > T) rs1800496 (928 C > T) rs1801028 67518 C > G DRD3: rs6280 (25 A > G) DRD4: VNTR (7/48-base pair repeat) | No association with L-Dopa induced ADR. | [122] |
92 PD patients | DRD2 short tandem repeat polymorphism (STRP) | STRP 14- and/or 14/15-repetition genotype was a risk factor for dyskinesia. | [123] |
591 PD patients | DRD3: rs6280 (25 A > G) | No association with motor complications. | [124] |
503 PD patients and 559 healthy controls | DRD2: rs1800497 (2137 C > T) DRD3: rs6280 (25 A > G) | DRD3 rs6280 (AA genotype) was associated with diphasic dyskinesia. | [125] |
199 PD patients | DRD2: rs1800497 (2137 C > T) rs1799732 (−141 C ins/del) rs2283265 (67314 G > T) rs6277 (957 C > T) rs1076560 (63314 G > T) rs2734849 (1472 A > G) | DRD2 rs2283265, rs1076560, rs100497 are associated with dyskinesia. | [126] |
352 PD patients | DRD2: rs4245147 (32995 G > A) rs6275 (939 T > C) rs6276 (52 G > A) rs6277 (957 C > T) rs4630328 (16793 C > T) rs17529477 (33935 C > T) rs1079597 (54716 G > A) rs4938017 (47073 G > A) rs4245148 (30583 A > C) rs1079594 (68190 T > A) rs1800497 (2137 C > T) | No association with LID | [127] |
100 PD patients (50 with dyskinesia) | DRD1: rs4532 (−48 A > G) rs686 (62 G > A) DRD2: rs1800497 2137 C > T rs6277 (957 C > T) DRD3: rs6280 (25 G > A) rs1800828 (−712 G > C) DRD4: rs747302 (−616 C > G) VNTR (7/48-base pair repeat) DRD5: rs6283 (978 T > C) | DRD3 rs2680 was associated with earlier LID development. | [17] |
220 PD patients | DRD2 rs1799732 | DRD2 rs1799732 was associated with LIDs. | [128] |
228 PD patients | DRD1 rs4532 (−48 A > G) DRD3 rs6280 (25 A > G) | DRD1 rs4532 (G/G genotype) may play a role in occurrence of LID. | [129] |
195 PD patients | DRD2 rs1800497 (2137 C > T) | No association with the development of motor fluctuations/dyskinesia. | [130] |
Approved Indications | Receptor Affinity (ki, nm) | Ddd (g) | Adm.r | Snps | Main Results | Refs. |
---|---|---|---|---|---|---|
Levodopa | ||||||
PD [b] | Dopamine precursor with no intrinsic receptor affinity, which acts indirectly by increasing dopamine levels [b] | 3.5 [a] | O [a] | DRD1 rs4532 DRD3 rs6280 | DRD1 was associated with occurrence of LID. | [129] |
DRD1 rs4532 DRD2 rs1799732 rs1800497 rs1079597 DRD3 rs6280 | No associations between tested SNPs and LID | [147] | ||||
DRD2 rs1799732 rs1801028 DRD3 rs6280 | DRD2 rs1799732 and DRD3 rs6280 were associated to occurrence of motor fluctuation after levodopa treatment. DRD2 rs1799732 was associated with time occurrence of LID | [128] | ||||
DRD2 rs1800497 | No associations with motor fluctuation or LID | [130] | ||||
DRD1 rs4532 rs686 DRD2 rs1800497 2137 rs6277 DRD3 rs6280 rs1800828 DRD4 rs747302 DRD5 rs6283 | DRD3 rs2680 was associated with earlier LID | [17] | ||||
DRD2 rs1799732 DRD3 rs6280 | DRD2 rs1799732 and DRD3 rs6280 were associated with an increased prevalence of gastrointestinal symptoms associated with levodopa treatment | [85] | ||||
DRD2: rs4245147 rs6275 rs6276, rs6277 rs4630328 rs17529477 rs1079597 rs4938017 rs4245148 rs1079594 rs1800497 | No association with LID | [127] | ||||
DRD3 rs6280 DRD2 rs1800497 | DRD3 rs6280 and DRD2 rs1800497 were not associated with LID in Israel and Italian sample of PD | [148] | ||||
DRD2 rs 1076560 | DRD2 rs1076560 was not associated with motor sequence learning task and change in manual motor abilities after levodopa treatment | [138] | ||||
DRD2 rs2283265 rs1076560 rs6277, rs1800497, rs2734849 | DRD2 rs2283265, rs1076560, rs100497 were associated with LID | [126] | ||||
DRD2 rs1800497 DRD3 rs6280 | DRD3 rs6280 (AA genotype) was associated with diphasic, but not pick-dose LID | [125] | ||||
DRD3 rs6280 | DRD3 rs6280 did not increase susceptibility to develop levodopa-induced motor complications | [133] | ||||
DRD2 short tandem repeat polymorphism (STRP) | STRP 14 and/or 14/15 repetition genotype was a risk factor for LID | [123] | ||||
DRD2 CAn-STR | 13,14 CA repeats was associated with decreased risk to developing peak-dose LID | [146] | ||||
DRD2 rs1800497 rs1800496 rs1801028 DRD3 rs6280 DRD4 VNTR (7/48-base pair repeat) | No association with ADR L-Dopa induced | [122] | ||||
DRD5 rs6283 | No association with risk of developing motor fluctuation during levodopa treatment | [121] | ||||
DRD2 STR polymorphism | 13 and 14 alleles of the DRD2 STR SNP was correlated with risk reduction of developing peak-dose LID | [119] | ||||
Pergolide | ||||||
PD [b] | D2 (0.2); D3 (0.5); D4 (1.3); D5 (164); D1 (172) Others: 5HT1A (1.9); 5HT2A (8.3); 5HT1D (13.2); 5HT2B (7.1); 5HT1B (281.8); 5HT2C (295.1) [149] | 0.003 [a] | O [a] | DRD2 rs1799732, rs1800497 and DRD3 rs6280 | D2DR rs1800497 was associated with late-onset VHs, but not with early dopamine-induced VHs | [104] |
Ropinirole | ||||||
PD and RLS [b] | D3 (2.9); D2 (3.7); D4 (7.8), D5 (41,211); D1 (36,600) Others: 5HT1A (288); 5HT1 B (>10,000); 5HT1 D (1380); 5HT2A (>10,000); 5HT2B (3802); 5HT2C (>10,000) [149] | 0.006 [a] | O [a] | DRD2 rs1799732, (CA)n STR, rs1800497, DRD3 MscI | The absence of a 15× DRD2 CA repeat allele was related to a decreased discontinuation of ropinirole treatment | [139] |
Pramipexole | ||||||
PD [b] | D3 (0.5); D2 (3.9); D4 (5.1), D5 (>10,000); D1 (>50,000) Others: 5HT1A (692); 5HT1 B (8318); 5HT1 D (1660); 5HT2A (>10,000); 5HT2B (>10,000); 5HT2C (>10,000) [149] | 0.0025 [a] | O [a] | DRD3 rs6280 | DRD3 rs6280 showed a significant pattern of interaction upon behavioural addiction and higher doses for effective treatment | [97,122,123] |
DRD3 rs6280 | DRD3 rs6280 (G/G genotype) require higher pramipexole doses for effective treatment | [134] | ||||
DRD3 rs6280 | DRD3 rs6280 (A/A genotype) was associate with response rate to pramipexole | [135] | ||||
Rotigotine | ||||||
PD and RLS [b] | D3 (0.71); D4 (3.9–15); D5 (5.4); D2 (13.5); D1 (83) Others: AR- α1A (176); AR- α1B (273); AR- α2A (338); AR- α2B (27); AR- α2C (135); 5HT1A (30); 5HT7 (86); H1 (330) [150] | 0.006 [a] | TD [a] | DRD1 rs4532 DRD3 rs6280 | DRD3 rs6280 resulted to increased prevalence for VHs | [151] |
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Magistrelli, L.; Ferrari, M.; Furgiuele, A.; Milner, A.V.; Contaldi, E.; Comi, C.; Cosentino, M.; Marino, F. Polymorphisms of Dopamine Receptor Genes and Parkinson’s Disease: Clinical Relevance and Future Perspectives. Int. J. Mol. Sci. 2021, 22, 3781. https://doi.org/10.3390/ijms22073781
Magistrelli L, Ferrari M, Furgiuele A, Milner AV, Contaldi E, Comi C, Cosentino M, Marino F. Polymorphisms of Dopamine Receptor Genes and Parkinson’s Disease: Clinical Relevance and Future Perspectives. International Journal of Molecular Sciences. 2021; 22(7):3781. https://doi.org/10.3390/ijms22073781
Chicago/Turabian StyleMagistrelli, Luca, Marco Ferrari, Alessia Furgiuele, Anna Vera Milner, Elena Contaldi, Cristoforo Comi, Marco Cosentino, and Franca Marino. 2021. "Polymorphisms of Dopamine Receptor Genes and Parkinson’s Disease: Clinical Relevance and Future Perspectives" International Journal of Molecular Sciences 22, no. 7: 3781. https://doi.org/10.3390/ijms22073781