Genetic variation and cognitive dysfunction in opioid-treated patients with cancer Geana Paula Kurita1,2, Ola Ekholm3, Stein Kaasa4,5, P al Klepstad6,7, Frank Skorpen8 & 9,10 Per Sjøgren 1
Multidisciplinary Pain Centre, Department of Neuroanaesthesiology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark 3 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 4 Department of Oncology, Oslo University Hospital/University of Oslo, Norway 5 European Palliative Care Research Centre, Faculty of Medicine Norwegian University of Science and Technology, Trondheim, Norway 6 Department of Intensive Care Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway 7 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Norway 8 Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway 9 Section of Palliative Medicine, Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark 10 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 2
Keywords Cognition, genes, neoplasms, opioids, polymorphism, single nucleotide Correspondence Geana Paula Kurita, Rigshospitalet Dept. 4111, Blegdamsvej 9, 2100 Copenhagen, Denmark. Fax: +45 3545 7157; E-mail:
[email protected] Received: 6 August 2015; Revised: 10 March 2016; Accepted: 11 March 2016 Brain and Behavior, 2016; 6(7), e00471, doi: 10.1002/brb3.471
Abstract Background and purpose: The effects of single-nucleotide polymorphisms (SNPs) on the cognitive function of opioid-treated patients with cancer until now have not been explored, but they could potentially be related to poor functioning. This study aimed at identifying associations between SNPs of candidate genes, high opioid dose, and cognitive dysfunction. Methods: Cross-sectional multicenter study (European Pharmacogenetic Opioid Study, 2005–2008); 1586 patients; 113 SNPs from 41 genes. Inclusion criteria: cancer, age ≥18 year, opioid treatment, and available genetic data. Cognitive assessment by Mini-Mental State Examination (MMSE). Analyses: SNPs were rejected if violation of Hardy–Weinberg equilibrium (P < 0.0005), or minor allele frequency G
T>C G>A A>G T>C
G>C A>G G>T G>T G>T A>G G>C A>G A>G G>C A>G G>C A>G C>A C>T
C>A
T>G T>C A>G
Alleles
(29.6) (39.8) (66.2) (44.1)
(68.8) (28.7) (46.2) (27.3) (27.8) (32.2) (37.3) (25.8) (30.3) (45.8) (74.8) (36.1) (25.5) (34.0) (72.5)
424 (32.2) 1138 (87.4)
395 525 878 545
911 365 609 345 354 413 478 313 377 598 979 462 323 430 917
963 (77.9)
772 (58.8) 467 (35.7) 360 (26.8)
(49.9) (45.8) (29.9) (43.4)
(27.6) (50.1) (41.0) (46.8) (48.3) (47.0) (47.4) (50.4) (48.6) (43.1) (23.5) (48.1) (51.6) (49.3) (25.1)
635 (48.3) 157 (12.1)
666 604 397 536
366 638 541 591 614 603 607 611 605 563 308 613 655 623 318
253 (20.5)
469 (35.7) 630 (48.2) 683 (50.9)
Genotypes; n (%)
(20.6) (14.4) (3.8) (12.5)
(3.5) (21.2) (12.7) (25.9) (23.9) (20.9) (15.3) (23.8) (21.1) (11.0) (1.6) (15.7) (22.9) (16.7) (2.4)
(Continued)
257 (19.5) 7 (0.5)
275 190 51 154
47 270 168 327 304 268 196 289 262 144 21 200 291 211 30
20 (1.6)
71 (5.4) 210 (16.1) 299 (22.3)
G. P. Kurita et al. Genetic Variation and Cognition in Cancer
Brain and Behavior, doi: 10.1002/brb3.471 (5 of 14)
Brain and Behavior, doi: 10.1002/brb3.471 (6 of 14)
GABBR2 (gamma-aminobutyric acid (GABA) B receptor, 2)
ADRB1 (adrenoceptor beta 1) ADRB2 (adrenoceptor beta 2)
HTR3C (5-hydroxytryptamine (serotonin) receptor 3C, ionotropic) HTR3D (5-hydroxytryptamine (serotonin) receptor 3D, ionotropic) HTR3E (5-hydroxytryptamine (serotonin) receptor 3E, ionotropic) HTR4 (5-hydroxytryptamine (serotonin) receptor 4, G protein-coupled) HRH1 (histamine receptor H1)
HTR3A (5-hydroxytryptamine (serotonin) receptor 3A, ionotropic HTR3B (5-hydroxytryptamine (serotonin) receptor 3B, ionotropic)
Gene (gene product)
Table 2. Continued.
rs4264931 rs19714311, rs20681901, rs18623421 rs26067311, rs3460701
Learning and memory (Meneses 1999)
Learning and memory in mice (Dai et al. 2007) Alzheimer disease (Bullido et al. 2004) IQ, memory and learning in young and elderly (Bochdanovits et al. 2009)
Epilepsy (Wang et al. 2008)
rs6443950 rs76276151, rs49125221
Learning and memory (Meneses 1999)
rs18012531 rs1042713 rs1042714 rs1042717 rs18008882, rs10427191 rs10818743 rs2304389 rs1435252 rs2779562 rs2808536 rs570138
rs6792482, rs9393341, rs76219751
rs11214763 rs1672717 rs7943062 rs1176744 rs22763071, rs37820251 rs67664101, rs68073621, rs68076701, rs68081221
rs10626131, rs22763021, rs11767191, rs11767131
Polymorphism
Learning and memory (Meneses 1999)
Learning and memory (Meneses 1999)
Learning and memory (Meneses 1999)
Link
T>G G>A C>T T>C C>A C>T
G>A C>G G>A
G>A
T>A
T>C
G>A T>C G>A T>G
Alleles
(70.6) (35.9) (70.2) (44.2)
858 918 625 321 591 787
(67.8) (71.4) (49.2) (25.0) (49.3) (61.6)
493 (39.4) 428 (34.0) 788 (64.5)
428 (32.5)
528 (40.1)
386 (31.1)
877 461 897 549
(26.7) (48.9) (27.2) (46.6)
378 327 534 646 516 424
(29.9) (25.4) (42.0) (50.4) (43.1) (33.2)
578 (46.2) 600 (47.7) 374 (30.6)
656 (49.8)
629 (47.8)
628 (50.6)
331 628 348 579
Genotypes; n (%)
(2.7) (15.3) (2.6) (9.2)
(2.3) (3.2) (8.7) (24.6) (7.6) (5.2) (Continued)
29 41 111 315 91 67
179 (14.3) 231 (18.3) 59 (4.8)
233 (17.7)
160 (12.1)
227 (18.3)
34 196 33 114
Genetic Variation and Cognition in Cancer G. P. Kurita et al.
ª 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
ª 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
Delirium (van Munster et al. 2011)
CXCL8 (chemokine (C-X-C motif) ligand 8) IL10 (interleukin 10)
Cognitive dysfunction (Licht et al. 2014) Depression, cognitive dysfunction related to aging (Oxenkrug 2011) Depression, cognitive dysfunction related to aging (Oxenkrug 2011) Neuroplasticity-related genes, age and cognitive deficit (Li et al. 2015)
IGF1 (insulin-like growth factor 1)
IFNGR1 (interferon gamma receptor 1)
NFKB1A (nuclear factor of kappa light-chain gene
IFNG (interferon gamma)
IL18 (interleukin 18)
IL13 (interleukin 13)
Inflammation impact on cognitive function (Goldstein et al. 2014) Inflammation impact on cognitive function (Goldstein et al. 2014) Neurodegeneration (Alboni et al. 2010)
IL12B (interleukin 12B)
IL6 (interleukin 6)
IL4 (interleukin 4)
Neurodegeneration (Arosio et al. 2010)
General cognitive performance (Benke et al. 2011) General cognitive performance (Benke et al. 2011) General cognitive performance (Benke et al. 2011; Sasayama et al. 2011) Inflammation impact on cognitive function (Gorelick 2010; Simen et al. 2011; Goldstein et al. 2014) Delirium (van Munster et al. 2011)
IL1R1 (interleukin 1 receptor, type I) IL1A (interleukin 1 alpha)
IL1B (interleukin 1 beta)
Link
Gene (gene product)
Table 2. Continued.
G>T C>T T>C T>G C>T
rs17561 rs1143634 rs1143627 rs2243248 rs2070874
rs696
rs2430561
rs360729 rs5744256 rs2043055 rs187238 rs1946519 rs11111272 rs10735380 rs7749390
rs1800925
rs1800872 rs1800896 rs1368439
G>A
T>A
T>A T>C A>G G>C C>A C>G A>G A>G
C>T
C>A A>G T>G
T>C G>T T>A
A>G C>G
rs3750344 rs2228139
rs2069835 rs1554606 rs4073
Alleles
Polymorphism
(56.6) (43.3) (86.9) (70.0)
(48.6) (57.8) (40.9) (54.0) (36.3) (51.5) (52.2) (35.2)
501 (39.7)
380 (29.8)
609 732 526 674 458 648 651 441
836 (67.2)
728 (57.7) 398 (31.3) 836 (65.7)
1062 (86.6) 411 (32.2) 357 (28.9)
711 551 1109 877
642 (50.5)
848 (67.4) 1110 (88.3)
(36.9) (45.3) (12.2) (27.5)
(42.2) (36.7) (45.5) (38.8) (46.9) (40.8) (40.3) (49.5)
598 (47.3)
646 (50.6)
529 464 585 484 592 514 503 621
364 (29.3)
461 (36.5) 577 (45.4) 397 (31.2)
155 (12.6) 616 (48.3) 600 (48.5)
464 577 156 344
515 (40.5)
248 (19.7) 141 (11.2)
Genotypes; n (%)
(6.5) (11.4) (0.9) (2.6)
(9.2) (5.5) (13.7) (7.3) (16.9) (7.7) (7.5) (15.3)
(Continued)
164 (13.0)
250 (19.6)
115 70 176 91 213 97 94 192
44 (3.5)
73 (5.8) 297 (23.3) 39 (3.1)
9 (0.7) 248 (19.5) 280 (22.6)
82 145 11 32
114 (9.0)
162 (12.9) 6 (0.5)
G. P. Kurita et al. Genetic Variation and Cognition in Cancer
Brain and Behavior, doi: 10.1002/brb3.471 (7 of 14)
Brain and Behavior, doi: 10.1002/brb3.471 (8 of 14) Neurodegeneration (Crack and Bray 2007)
Neurodegeneration (Crack and Bray 2007) Neurodegeneration (Crack and Bray 2007) Neurodevelopment in mice (Busanello et al. 2013)
TLR2 (toll-like receptor 2)
TLR4 (toll-like receptor 4) TLR5 (toll-like receptor 5) GCDH (glutaryl-CoA dehydrogenase)
rs496888 rs976881 rs3397 rs1061631 rs1061622 rs1800469 rs947712 rs1418553 rs4696480 rs3804100 rs38040991, rs57437082 rs49867902 rs5744168 rs11085824
rs1130864 rs1800947 rs1799964 rs1800629 rs767455 rs4149570
Polymorphism
C>T A>G
A>G G>A T>C G>A T>G C>T G>A C>T T>A T>C
C>T G>C T>C G>A T>C G>T
Alleles
(51.1) (44.1) (41.2) (63.7) (58.4) (46.4) (39.3) (49.9) (25.5) (86.7)
(45.7) (87.6) (63.0) (70.1) (34.3) (36.5)
1126 (89.5) 481 (38.5)
645 545 517 809 730 570 495 638 325 1091
574 1090 793 883 428 465
(42.2) (44.5) (45.3) (32.4) (36.0) (42.9) (46.6) (41.0) (49.7) (13.0)
(43.7) (12.0) (32.4) (26.9) (47.8) (46.3)
130 (10.3) 603 (48.3)
532 551 569 412 450 527 587 524 633 164
549 149 408 339 597 589
Genotypes; n (%)
(6.7) (11.4) (13.5) (3.9) (5.7) (10.7) (14.2) (9.1) (24.7) (0.2)
(10.6) (0.5) (4.6) (3.0) (17.9) (17.2)
2 (0.2) 165 (13.2)
84 141 169 50 71 131 179 117 315 3
133 6 58 38 224 219
Link refers to studies that analyzed or suggested a relation between the gene and cognitive function. The absolute numbers and the frequencies of genotypes are written in the following order: homozygous for the most common allele – heterozygotes – homozygous for the minor allele. 1 Excluded due to >25% missing values. 2 Single-nucleotide polymorphisms with allele frequency
