- Email: [email protected]
Apolipoprotein E (APOE), PARKIN and catechol-O-methyltransferase (COMT) genes and susceptibility to sporadic Parkinson's disease in Finland
Neuroscience Letters 330 (2002) 296–298 www.elsevier.com/locate/neulet
Apolipoprotein E (APOE), PARKIN and catechol-O-methyltransferase (COMT ) genes and susceptibility to sporadic Parkinson’s disease in Finland J. Eerola a,*, J. Launes a, O. Hellstro¨m b, P.J. Tienari a a
Department of Neurology, Helsinki University Central Hospital, and University of Helsinki, Biomedicum-Helsinki, Neuroscience Programme C524, PL 700, Haartmaninkatu 8, Helsinki, Finland b Department of Neurology, Seina¨joki Central Hospital, Seina¨joki, Finland Received 28 May 2002; received in revised form 18 July 2002; accepted 18 July 2002
Abstract Recent studies have demonstrated that genetic factors modify susceptibility to sporadic Parkinson’s disease (PD). So far the results of candidate gene studies have been conflicting. It has been suggested that polymorphisms in apolipoprotein E (APOE), PARKIN and catechol-O-methyltransferase (COMT ) genes might increase the risk of PD. We studied 147 Finnish non-demented patients with sporadic PD and 137 controls. APOE e allele and genotype frequencies in PD patients did not differ significantly from controls. Three single nucleotide polymorphisms of the PARKIN gene and an intronic and an exonic (Val158Met) polymorphism of the COMT gene were studied. None of these polymorphisms showed association with PD in our series. In contrast to reports in oriental populations, our results do not support a major role of APOE, PARKIN and COMT polymorphisms in PD susceptibility in the Finnish population. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Gene studies; Finland
The etiology of sporadic idiopathic Parkinson’s disease (PD) is considered multifactorial with both genetic and environmental factors modifying the expression of the disease. Environmental background has been suspected mostly. However, increased risk of PD in patients’ close relatives has been reported [10], and recently increased relatedness among PD patients compared with the non-PD population was found [17]. Further, a higher concordance rate for striatal PD pathology in positron emission tomography, has been found in monozygotic as compared with dizygotic twins [7,13]. Three genes associated with rare forms of autosomal dominant or recessive PD have been identified to date [2]. Much less is known about the genetic background of sporadic PD. Previously, polymorphisms in apolipoprotein E (APOE), PARKIN or catechol-O-methyltransferase (COMT ) genes have become candidates for increased susceptibility to sporadic PD. We investigated these loci in a case-control dataset from Finland. We studied 147 patients (87 men, 60 women) with spora* Corresponding author. Fax: 1358-9-4717-1964. E-mail address: [email protected] (J. Eerola).
dic idiopathic PD. All patients had clinical PD according to PD Society Brain Bank criteria and were either followed for at least 4, or 2 years and had additional 123I-b-CIT-SPECT findings supporting idiopathic PD [1]. Patients with dementia were excluded, and no cases of hereditary PD were included. The control group consisted of the patients’ spouses (n ¼ 137, 50 men, 87 women), who did not have PD. The mean age was 67.2 years (range 38–88) in the patient group and 65.8 years (range 37–87) in the control group. Informed consent from the subjects and the approval of the Ethical Review Committee of the Helsinki University Central Hospital were obtained. DNA was extracted from peripheral blood leukocytes using standard procedures. Genetic markers were amplified by polymerase chain reaction, digested with the appropriate restriction enzyme and electrophoretically separated on agarose gels. Marker alleles were visualized with ethidiumbromide in ultraviolet light. APOE e genotypes were determined with HhaI digestion. Three PARKIN single-nucleotide polymorphisms (SNP) were analyzed. These were Ser167Asn (AlwNI, exon 4), Arg366Trp (NciI, exon 10) and Val380Leu (Bsp1286I, exon 10) [20]. Three COMT SNPs were analyzed:
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0 30 4- 39 40 ( 02) 0 08 19- 4
J. Eerola et al. / Neuroscience Letters 330 (2002) 296–298 Table 1 Association of ApoE e polymorphism with Parkinson’s disease (PD) APOE allele/genotype
PD patients n (%)
e2 e3 e4
21 (7) 22 (8) 222 (75) 196 (71) 51 (17) 56 (20) x 2 ¼ 1.17, 2 df, P ¼ 0.56
e2/e2 e2/e3 e2/e4 e3/e3 e3/e4 e4/e4
1 (0.7) 1 (0.7) 17 (12) 14 (10) 3 (2) 6 (4) 82 (56) 70 (51) 40 (27) 42 (30) 4 (2) 4 (2) x 2 ¼ 1.41 a, 3 df, P ¼ 0.70
a
Controls n (%)
Rare events (2/2, 2/4, 4/4) were pooled in the x 2 test.
Val158Met (NlaIII) [5], rs 6270 (BsmFI) and rs6267 (BsmI) (http://www.ncbi.nlm.nih.gov/SNP). The primers used for amplification of rs6267 were 5 0 -AGCATGCGGAGCCCGGGAAT*-3 0 and 5 0 -CTGGAAATGGGGTGATAACAGC-3 0 . A restriction site for BsmI was generated by a mutation (C- . T) of the last base of the forward primer. Digestion of the G-allele yielded 170 and 23 bp fragments whereas T-allele had no restriction site for BsmI. We chose to study APOE since APOE e polymorphism has been reported to associate with diverse conditions such as Alzheimer’s disease and the outcome of brain ischemia or trauma [16]. Thus, APOE may modulate the fate of neuronal cells in several distinct pathological states. In PD the results with APOE have been conflicting [3,4,8,9,12,18,19], but a few studies have found increased frequencies of e2 and e4 in PD patients. In our series the APOE e allele and genotype frequencies were very similar in PD patients and in controls (Table 1). Neither e2 nor e4 showed any trend towards association with PD and the frequencies in both PD and the control group were similar to the general population frequencies in Finland in the 45–64 age group [15].
297
We studied PARKIN gene since it is one of the loci of autosomal recessive early-onset PD [2]. In the Japanese population an association has been reported with Asn167Ser and Arg366Trp polymorphisms, the latter of which is predicted to alter the protein conformation [14,20]. We studied three parkin polymorphisms, Ser167Asn, Arg366Trp and Val380Leu. In our subjects, Arg366Trp site was not at all polymorphic, whereas the allele and genotype frequencies at the Ser167Asn and Val380Leu sites did not differ in PD from those of the controls (Table 2). We were interested to analyze the COMT gene, since Val at the polymorphic residue 158 of COMT results in lower enzyme activity and this Val158Met polymorphism has been associated with PD in the Japanese population [6]. In our series there was no significant association between the COMT Val158Met polymorphism and PD (Table 3). Two other COMT SNP’s were analyzed as well, but no associations with PD were detected (Table 3). We have analyzed the role of APOE, PARKIN and COMT polymorphisms in a reasonably large case-control dataset from Finland. The spouses of the PD patients were used as controls, which should, to some extent, reduce the variation in environmental factors between the cases and the controls. As PD is expectedly a heterogeneous disease, it may be advantageous to study subjects from the genetically homogeneous Finnish population. Our results on APOE did not support any role of APOE e polymorphisms in sporadic PD susceptibility and hence are in line with other previously published studies on Caucasian patients [3,4,8,9]. This issue is less clear in Orientals, since an association with APOE e2/4 genotype was recently reported in Chinese patients [18]. Our patient selection was focused on the cardinal PD symptoms, which reflect striatal pathology. Demented patients, with presumable cortical pathology, were not included in our series. APOE polymorphism may play a different role in striatal and cortical pathologies, as a few groups have reported increased frequencies of e2 or e4 only in patients with dementia, cortical amyloid pathology or cortical Lewy bodies [3,9,12,19].
Table 2 Association of PARKIN polymorphisms with Parkinson’s disease (PD)
Table 3 Association of COMT polymorphisms with Parkinson’s disease (PD) a
Genotype
Genotype
Ser167Asn GG GA AA
Val380Leu GG GC CC
PD patients N (%)
Controls N (%)
0 0 3 (2) 2 (1) 144 (98) 135 (99) P ¼ 0.53, Fisher’s exact test
106 (72) 38 (26) 3 (2) x 2 ¼ 0.22 a, P ¼ 0.64
94 (69) 38 (28) 5 (4)
a The chi-square contribution of the CC genotype omitted Arg366Trp was not polymorphic in our subjects.
Val158Met Val/Val Val/Met Met/Met
rs6267 TT TG GG
PD patients N (%)
Controls N (%)
30 (20) 71 (48) 46 (31) x 2 ¼ 1.16, 2 df, P ¼ 0.56
31 (23) 71 (52) 35 (26)
0 10 (7) 137 (93) x 2 ¼ 0.16, 2 df, P ¼ 0.69
0 11 (8) 126 (92)
a The SNP rs6270 was not polymorphic in 40 PD and 40 control chromosomes.
298
J. Eerola et al. / Neuroscience Letters 330 (2002) 296–298
Our results did not support a role of either PARKIN or COMT polymorphism in sporadic PD susceptibility. Previously associations with two PARKIN polymorphisms (Trp366 and Asn167) have been reported in Japanese patients. An ethnic effect may be present since the Trp366 polymorphism was not found at all in our Finnish subjects and the Asn167 was very rare similarly as in another previously published study on Caucasian patients [11]. For this reason we chose to study a third, more polymorphic, marker of the PARKIN gene, which also did not reveal any association. In case of the Val158Met polymorphism of COMT an association has been reported in Japanese patients, while previous studies on Caucasian and Chinese patients failed to find it [5,6,21]. We tested an additional SNP of COMT besides the Val158Met polymorphism, but not even a trend towards an association was found. This work was financially supported by the Helsinki University Central Hospital and the Finnish Cultural Foundation.
[9]
[10]
[11]
[12]
[13]
[14] [1] Eerola, J., Tienari, P.J., Kaakkola, S., Nikkinen, P., Launes, J., How good is 123I-b-CIT in clinical practice? (Submitted) [2] Foltynie, T., Brayne, C. and Barker, R.A., The heterogeneity of idiopathic Parkinson’s disease, J. Neurol., 249 (2002) 138–145. [3] Harhangi, B.S., de Rijk, M.C., van Duijn, C.M., van Broeckhoven, C., Hofman, A. and Breteler, M.M., APOE and the risk of PD with or without dementia in a population-based study, Neurology, 54 (2000) 1272–1276. [4] Helisalmi, S., Linnaranta, K., Lehtovirta, M., Mannermaa, A., Heinonen, O., Ryyna¨ nen, M., Riekkinen, P.Sr and Soininen, H., Apolipoprotein E polymorphism in patients with different neurodegenerative disorders, Neurosci. Lett., 205 (1996) 61–65. [5] Hoda, F., Nicholl, D., Bennett, P., Arranz, M., Aitchison, K.J., Al-Chalabi Kunugi, H., Vallada, H., Leigh, P.N., Chaudhuri, K.R. and Collier, D.A., No association between Parkinson’s disease and low-activity alleles of catechol-O-methyltransferase, Biochem. Biophys. Res. Commun., 228 (1996) 780–784. [6] Kunugi, H., Nanko, S., Ueki, A., Otsuka, E., Hattori, M., Hoda, F., Vallada, H., Arranz, M.J. and Collier, D.A., High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson’s disease, Neurosci. Lett., 221 (1997) 202–204. [7] Laihinen, A., Ruottinen, H., Rinne, J.O., Haaparanta, M., Bergman, J., Solin, O., Koskenvuo, M., Marttila, R. and Rinne, U.K., Risk for Parkinson’s disease: twin studies for the detection of asymptomatic subjects using 18F-6-fluorodopa PET, J. Neurol., 247 (2000) 110–113. [8] Maraganore, D.M., Farrer, M.J., Hardy, J.A., McDonnell, S.K., Schaid, D.J. and Rocca, W.A., Case-control study of debrisoquine-hydroxylase, N-acetyltransferase 2, and
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apolipoprotein E gene polymorphisms in Parkinson’s disease, Mov. Disord., 15 (2000) 714–719. Mattila, P.M., Koskela, T., Roytta, M., Lehtima¨ ki, T., Pirttila¨ , T.A., Ilveskoski, E., Karhunen, P. and Rinne, J.O., Apolipoprotein E e4 allele frequency is increased in Parkinson’s disease only with co-existing Alzheimer pathology, Acta Neuropathol., 96 (1998) 417–420. Moilanen, J.S., Autere, J.M., Myllyla¨ , V.V. and Majamaa, K., Complex segregation analysis of Parkinson’s disease in the Finnish population, Hum. Genet., 108 (2001) 184–189. Oliveri, R.L., Zappia, M., Annesi, G., Bosco, D., Annesi, F., Spadafora, P., Pasqua, A.A., Tomaino, C., Nicoletti, G., Pirritano, D., Labate, A., Gambardella, A., Logroscino, G., Manobianca, G., Epifanio, A., Morgante, L., Savettieri, G. and Quattrone, A., The parkin gene is not involved in lateonset Parkinson’s disease, Neurology, 57 (2001) 359–362. Parsian, A., Racette, B., Goldsmith, L.J. and Perlmutter, J.S., Parkinson’s disease and apolipoprotein E: possible association with dementia but not with age at onset, Genomics, 79 (2002) 458–461. Piccini, P., Burn, D.J., Ceravolo, R., Maraganore, D. and Brooks, D.J., The role of inheritance in sporadic Parkinson’s disease: evidence from a longitudinal study of dopaminergic function in twins, Ann. Neurol., 45 (1999) 577–582. Satoh, J. and Kuroda, Y., Association of codon 167 Ser/Asn heterozygosity in the parkin gene with sporadic Parkinson’s disease, NeuroReport, 10 (1999) 2735–2739. Schiele, F., De Bacquer, D., Vincent-Viry, M., Beisiegel, U., Ehnholm, C., Evans, A., Kafatos, A., Martins, M.C., Sans, S., Sass, C., Visvikis, S., De Backer, G. and Siest, G., Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project, Atherosclerosis, 152 (2000) 475–488. Smith, J.D., Apolipoprotein E4: an allele associated with many diseases, Ann. Med., 32 (2000) 118–127. Sveinbjornsdottir, S., Hicks, A.A., Jonsson, T., Petursson, H., Gugmundsson, G., Frigge, M.L., Kong, A., Gulcher, J.R. and Stefansson, K., Familial aggregation of Parkinson’s disease in Iceland, N. Engl. J. Med., 343 (2000) 1765– 1770. Tang, G., Xie, H., Xu, L., Hao, Y., Lin, D., Ren, D., Genetic study of Apolipoprotein E gene, alpha-1 antichymotrypsin gene in sporadic Parkinson disease, Am. J. Med. Genet., 114 (2002) 446–449. Wakabayashi, K., Kakita, A., Hayashi, S., Okuizumi, K., Onodera, O., Tanaka, H., Ishikawa, A., Tsuji, S. and Takahashi, H., Apolipoprotein E e4allele and progression of cortical Lewy body pathology in Parkinson’s disease, Acta Neuropathol., 95 (1998) 450–454. Wang, M., Hattori, N., Matsumine, H., Kobayashi, T., Yoshino, H., Morioka, A., Kitada, T., Asakawa, S., Minoshima, S., Shimizu, N. and Mizuno, Y., Polymorphism in the parkin gene in sporadic Parkinson’s disease, Ann. Neurol., 45 (1999) 655–658. Xie, T., Ho, S.L., Li, L.S.W. and Ma, O.C.K., G/A 1947 polymorphism in catechol-O-methyltransferase (COMT) gene in Parkinson’s disease, Mov. Disord., 12 (1997) 426–427.
Apolipoprotein E (APOE), PARKIN and catechol-O-methyltransferase (COMT ) genes and susceptibility to sporadic Parkinson’s disease in Finland J. Eerola a,*, J. Launes a, O. Hellstro¨m b, P.J. Tienari a a
Department of Neurology, Helsinki University Central Hospital, and University of Helsinki, Biomedicum-Helsinki, Neuroscience Programme C524, PL 700, Haartmaninkatu 8, Helsinki, Finland b Department of Neurology, Seina¨joki Central Hospital, Seina¨joki, Finland Received 28 May 2002; received in revised form 18 July 2002; accepted 18 July 2002
Abstract Recent studies have demonstrated that genetic factors modify susceptibility to sporadic Parkinson’s disease (PD). So far the results of candidate gene studies have been conflicting. It has been suggested that polymorphisms in apolipoprotein E (APOE), PARKIN and catechol-O-methyltransferase (COMT ) genes might increase the risk of PD. We studied 147 Finnish non-demented patients with sporadic PD and 137 controls. APOE e allele and genotype frequencies in PD patients did not differ significantly from controls. Three single nucleotide polymorphisms of the PARKIN gene and an intronic and an exonic (Val158Met) polymorphism of the COMT gene were studied. None of these polymorphisms showed association with PD in our series. In contrast to reports in oriental populations, our results do not support a major role of APOE, PARKIN and COMT polymorphisms in PD susceptibility in the Finnish population. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Gene studies; Finland
The etiology of sporadic idiopathic Parkinson’s disease (PD) is considered multifactorial with both genetic and environmental factors modifying the expression of the disease. Environmental background has been suspected mostly. However, increased risk of PD in patients’ close relatives has been reported [10], and recently increased relatedness among PD patients compared with the non-PD population was found [17]. Further, a higher concordance rate for striatal PD pathology in positron emission tomography, has been found in monozygotic as compared with dizygotic twins [7,13]. Three genes associated with rare forms of autosomal dominant or recessive PD have been identified to date [2]. Much less is known about the genetic background of sporadic PD. Previously, polymorphisms in apolipoprotein E (APOE), PARKIN or catechol-O-methyltransferase (COMT ) genes have become candidates for increased susceptibility to sporadic PD. We investigated these loci in a case-control dataset from Finland. We studied 147 patients (87 men, 60 women) with spora* Corresponding author. Fax: 1358-9-4717-1964. E-mail address: [email protected] (J. Eerola).
dic idiopathic PD. All patients had clinical PD according to PD Society Brain Bank criteria and were either followed for at least 4, or 2 years and had additional 123I-b-CIT-SPECT findings supporting idiopathic PD [1]. Patients with dementia were excluded, and no cases of hereditary PD were included. The control group consisted of the patients’ spouses (n ¼ 137, 50 men, 87 women), who did not have PD. The mean age was 67.2 years (range 38–88) in the patient group and 65.8 years (range 37–87) in the control group. Informed consent from the subjects and the approval of the Ethical Review Committee of the Helsinki University Central Hospital were obtained. DNA was extracted from peripheral blood leukocytes using standard procedures. Genetic markers were amplified by polymerase chain reaction, digested with the appropriate restriction enzyme and electrophoretically separated on agarose gels. Marker alleles were visualized with ethidiumbromide in ultraviolet light. APOE e genotypes were determined with HhaI digestion. Three PARKIN single-nucleotide polymorphisms (SNP) were analyzed. These were Ser167Asn (AlwNI, exon 4), Arg366Trp (NciI, exon 10) and Val380Leu (Bsp1286I, exon 10) [20]. Three COMT SNPs were analyzed:
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0 30 4- 39 40 ( 02) 0 08 19- 4
J. Eerola et al. / Neuroscience Letters 330 (2002) 296–298 Table 1 Association of ApoE e polymorphism with Parkinson’s disease (PD) APOE allele/genotype
PD patients n (%)
e2 e3 e4
21 (7) 22 (8) 222 (75) 196 (71) 51 (17) 56 (20) x 2 ¼ 1.17, 2 df, P ¼ 0.56
e2/e2 e2/e3 e2/e4 e3/e3 e3/e4 e4/e4
1 (0.7) 1 (0.7) 17 (12) 14 (10) 3 (2) 6 (4) 82 (56) 70 (51) 40 (27) 42 (30) 4 (2) 4 (2) x 2 ¼ 1.41 a, 3 df, P ¼ 0.70
a
Controls n (%)
Rare events (2/2, 2/4, 4/4) were pooled in the x 2 test.
Val158Met (NlaIII) [5], rs 6270 (BsmFI) and rs6267 (BsmI) (http://www.ncbi.nlm.nih.gov/SNP). The primers used for amplification of rs6267 were 5 0 -AGCATGCGGAGCCCGGGAAT*-3 0 and 5 0 -CTGGAAATGGGGTGATAACAGC-3 0 . A restriction site for BsmI was generated by a mutation (C- . T) of the last base of the forward primer. Digestion of the G-allele yielded 170 and 23 bp fragments whereas T-allele had no restriction site for BsmI. We chose to study APOE since APOE e polymorphism has been reported to associate with diverse conditions such as Alzheimer’s disease and the outcome of brain ischemia or trauma [16]. Thus, APOE may modulate the fate of neuronal cells in several distinct pathological states. In PD the results with APOE have been conflicting [3,4,8,9,12,18,19], but a few studies have found increased frequencies of e2 and e4 in PD patients. In our series the APOE e allele and genotype frequencies were very similar in PD patients and in controls (Table 1). Neither e2 nor e4 showed any trend towards association with PD and the frequencies in both PD and the control group were similar to the general population frequencies in Finland in the 45–64 age group [15].
297
We studied PARKIN gene since it is one of the loci of autosomal recessive early-onset PD [2]. In the Japanese population an association has been reported with Asn167Ser and Arg366Trp polymorphisms, the latter of which is predicted to alter the protein conformation [14,20]. We studied three parkin polymorphisms, Ser167Asn, Arg366Trp and Val380Leu. In our subjects, Arg366Trp site was not at all polymorphic, whereas the allele and genotype frequencies at the Ser167Asn and Val380Leu sites did not differ in PD from those of the controls (Table 2). We were interested to analyze the COMT gene, since Val at the polymorphic residue 158 of COMT results in lower enzyme activity and this Val158Met polymorphism has been associated with PD in the Japanese population [6]. In our series there was no significant association between the COMT Val158Met polymorphism and PD (Table 3). Two other COMT SNP’s were analyzed as well, but no associations with PD were detected (Table 3). We have analyzed the role of APOE, PARKIN and COMT polymorphisms in a reasonably large case-control dataset from Finland. The spouses of the PD patients were used as controls, which should, to some extent, reduce the variation in environmental factors between the cases and the controls. As PD is expectedly a heterogeneous disease, it may be advantageous to study subjects from the genetically homogeneous Finnish population. Our results on APOE did not support any role of APOE e polymorphisms in sporadic PD susceptibility and hence are in line with other previously published studies on Caucasian patients [3,4,8,9]. This issue is less clear in Orientals, since an association with APOE e2/4 genotype was recently reported in Chinese patients [18]. Our patient selection was focused on the cardinal PD symptoms, which reflect striatal pathology. Demented patients, with presumable cortical pathology, were not included in our series. APOE polymorphism may play a different role in striatal and cortical pathologies, as a few groups have reported increased frequencies of e2 or e4 only in patients with dementia, cortical amyloid pathology or cortical Lewy bodies [3,9,12,19].
Table 2 Association of PARKIN polymorphisms with Parkinson’s disease (PD)
Table 3 Association of COMT polymorphisms with Parkinson’s disease (PD) a
Genotype
Genotype
Ser167Asn GG GA AA
Val380Leu GG GC CC
PD patients N (%)
Controls N (%)
0 0 3 (2) 2 (1) 144 (98) 135 (99) P ¼ 0.53, Fisher’s exact test
106 (72) 38 (26) 3 (2) x 2 ¼ 0.22 a, P ¼ 0.64
94 (69) 38 (28) 5 (4)
a The chi-square contribution of the CC genotype omitted Arg366Trp was not polymorphic in our subjects.
Val158Met Val/Val Val/Met Met/Met
rs6267 TT TG GG
PD patients N (%)
Controls N (%)
30 (20) 71 (48) 46 (31) x 2 ¼ 1.16, 2 df, P ¼ 0.56
31 (23) 71 (52) 35 (26)
0 10 (7) 137 (93) x 2 ¼ 0.16, 2 df, P ¼ 0.69
0 11 (8) 126 (92)
a The SNP rs6270 was not polymorphic in 40 PD and 40 control chromosomes.
298
J. Eerola et al. / Neuroscience Letters 330 (2002) 296–298
Our results did not support a role of either PARKIN or COMT polymorphism in sporadic PD susceptibility. Previously associations with two PARKIN polymorphisms (Trp366 and Asn167) have been reported in Japanese patients. An ethnic effect may be present since the Trp366 polymorphism was not found at all in our Finnish subjects and the Asn167 was very rare similarly as in another previously published study on Caucasian patients [11]. For this reason we chose to study a third, more polymorphic, marker of the PARKIN gene, which also did not reveal any association. In case of the Val158Met polymorphism of COMT an association has been reported in Japanese patients, while previous studies on Caucasian and Chinese patients failed to find it [5,6,21]. We tested an additional SNP of COMT besides the Val158Met polymorphism, but not even a trend towards an association was found. This work was financially supported by the Helsinki University Central Hospital and the Finnish Cultural Foundation.
[9]
[10]
[11]
[12]
[13]
[14] [1] Eerola, J., Tienari, P.J., Kaakkola, S., Nikkinen, P., Launes, J., How good is 123I-b-CIT in clinical practice? (Submitted) [2] Foltynie, T., Brayne, C. and Barker, R.A., The heterogeneity of idiopathic Parkinson’s disease, J. Neurol., 249 (2002) 138–145. [3] Harhangi, B.S., de Rijk, M.C., van Duijn, C.M., van Broeckhoven, C., Hofman, A. and Breteler, M.M., APOE and the risk of PD with or without dementia in a population-based study, Neurology, 54 (2000) 1272–1276. [4] Helisalmi, S., Linnaranta, K., Lehtovirta, M., Mannermaa, A., Heinonen, O., Ryyna¨ nen, M., Riekkinen, P.Sr and Soininen, H., Apolipoprotein E polymorphism in patients with different neurodegenerative disorders, Neurosci. Lett., 205 (1996) 61–65. [5] Hoda, F., Nicholl, D., Bennett, P., Arranz, M., Aitchison, K.J., Al-Chalabi Kunugi, H., Vallada, H., Leigh, P.N., Chaudhuri, K.R. and Collier, D.A., No association between Parkinson’s disease and low-activity alleles of catechol-O-methyltransferase, Biochem. Biophys. Res. Commun., 228 (1996) 780–784. [6] Kunugi, H., Nanko, S., Ueki, A., Otsuka, E., Hattori, M., Hoda, F., Vallada, H., Arranz, M.J. and Collier, D.A., High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson’s disease, Neurosci. Lett., 221 (1997) 202–204. [7] Laihinen, A., Ruottinen, H., Rinne, J.O., Haaparanta, M., Bergman, J., Solin, O., Koskenvuo, M., Marttila, R. and Rinne, U.K., Risk for Parkinson’s disease: twin studies for the detection of asymptomatic subjects using 18F-6-fluorodopa PET, J. Neurol., 247 (2000) 110–113. [8] Maraganore, D.M., Farrer, M.J., Hardy, J.A., McDonnell, S.K., Schaid, D.J. and Rocca, W.A., Case-control study of debrisoquine-hydroxylase, N-acetyltransferase 2, and
[15]
[16] [17]
[18]
[19]
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