- Email: [email protected]
Association between the 9 repeat allele of the dopamine transporter 40 bp variable tandem repeat polymorphism and Alzheimer’s disease
Psychiatry Research 220 (2014) 730–731
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association between the 9 repeat allele of the dopamine transporter 40 bp variable tandem repeat polymorphism and Alzheimer’s disease
art ic l e i nf o Keywords: Alzheimer’s disease Dopamine transporter (DAT) rs28363170
a b s t r a c t A case-control study was performed to investigate the association between the dopamine transporter (DAT) gene (SLC6A3) rs28363170 polymorphism and the risk for Alzheimer’s disease (AD). Our results indicated a statistically significant correlation between the inheritance of the SLC6A3 9 repeat allele and the genetic susceptibility to AD in a dose-dependent manner. & 2014 Elsevier Ireland Ltd. All rights reserved.
To the Editors: Late-onset Alzheimer’s disease (AD) is a neurodegenerative disorder with multifactorial genetic background. Although several mechanisms, including amyloid-β peptide accumulation and aggregation, tau protein hyperphosphorylation and inflammatory responses, have been recognized to be involved in the pathogenesis of AD, defects in dopaminergic neurotransmission may also contribute to the cognitive deficits and behavioral and psychological symptoms of dementia seen in AD. One of the suitable candidate genes for AD, the solute carrier family 6 member 3 (SLC6A3; MIM#126455) encodes the dopamine transporter (DAT). The 3ʹ untranslated region of the SLC6A3 gene contains a 40 bp variable number of tandem repeat (VNTR) polymorphism (rs28363170). The copy number of this VNTR ranges from 3 to 11; however, the 10-repeat (10R) and the 9-repeat (9R) alleles are the most common (Vandenbergh et al., 1992). The present study aimed to test the hypothesis that SLC6A3 rs28363170 polymorphism is associated with the susceptibility to late-onset AD. A total of 220 Hungarian patients with late-onset AD (72 men; age: 75.3 77.4 years/mean 7S.D.) and 205 cognitively intact, elderly, Hungarian control subjects (67 men; age: 74.7 77.1 years/mean 7S.D.) were involved in the study. A consensus clinical diagnosis of probable late-onset AD (4 65 years of age) was established according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria (McKhann et al., 1984). Ethical permission for all protocols was granted by the Ethics Committee of the Hungarian Council on Science and Health, and all subjects gave informed consent. Genomic DNA was extracted from peripheral blood leukocytes by standard procedures using the Roche kit (Roche Holding AG, Basel, Switzerland), and genotyping of the SLC6A3 polymorphism was performed by polymerase chain reaction as formerly described (Sano et al., 1993). http://dx.doi.org/10.1016/j.psychres.2014.07.060 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
Categorical variables were studied applying Fisher exact and Pearson χ2-tests. The mean age was compared using the t-test for independent samples. No statistically significant difference was found in the distribution of genders or in mean age between AD and control groups (p 40.05). The genotype distributions did not deviate significantly from Hardy–Weinberg equilibrium (p 40.05). Post-hoc power calculations were conducted using GPower 3.0 software (Faul et al., 2007). Our study sample (n ¼425) has 69% power at the significance level of 0.05 to detect differences in SLC6A3 genotype frequencies between the two groups (effect size: w¼0.142). SLC6A3 rs28363170 genotype frequencies are presented in Table 1. Compared with the controls, there was a significantly higher frequency of R9/R9 and R9/R10 genotypes and lower frequency of R10/R10 and R10/R11 genotypes in the AD group (p ¼0.036). No R9/R11 or R11/R11 genotype carriers were detected in our sample. A significantly higher risk for AD was observed among R9 allele carriers (R9/R9 and R9/R10) when R9-genotypes (R10/R10 and R10/R11) were considered as the reference category (OR ¼1.679; 95% CI ¼1.144–2.465; p¼ 0.008). We also investigated the influence of the homozygous and heterozygous R9 allele containing genotypes severally on AD risk. The effect of the R9/R9 genotype on AD risk was more marked (OR ¼2.426; 95% CI ¼ 1.119–5.257; p¼ 0.025) than the effect of R9/R10 (OR ¼1.577; 95% CI ¼1.057– 2.351; p ¼0.025) compared to R9-genotypes. Our study demonstrated a statistically significant correlation between the inheritance of the SLC6A3 R9 allele and the genetic susceptibility to AD. Considering the absence of the R9 allele as the reference category, the significantly higher risk conferred by R9/ R10 genotype was even more pronounced in the case of the homozygous R9/R9 genotype, suggesting that R9 allele affects AD risk in a dose dependent manner. The medium sample size of our study must be addressed as a limitation, and the results should be treated with appropriate caution until independent confirmations are completed.
Letter to the Editor / Psychiatry Research 220 (2014) 730–731
Table 1 Genotype frequencies of the SLC6A3 rs28363170 polymorphism. Genotypes
AD n¼220
Controls n¼ 205
R9/R9 R9/R10 R9/R11 R10/R10 R10/R11 R11/R11
22 (10.0%) 104 (47.3%) n.d. 92 (41.8%) 2 (0.9%) n.d.
11 (5.4%) 80 (39.0%) n.d. 110 (53.6%) 4 (2.0%) n.d.
2
χ ¼ 8.549 (3); p ¼0.036 for genotypes. AD: Alzheimer’s disease; SLC6A3: solute carrier family 6 member 3 gene encoded for dopamine transporter; n.d.: not detected.
Acknowledgments The study was supported by the Hungarian Ministry of Education and Culture under grant TÁMOP-4.2.2A11/1/KONV-20120052. References Faul, F., Erdfelder, E., Lang, A.G., Buchner, A., 2007. GnPower 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods 39, 175–191.
731
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34, 939–944. Sano, A., Kondoh, K., Kakimoto, Y., Kondo, I., 1993. A 40-nucleotide repeat polymorphism in the human dopamine transporter gene. Human Genetics 91, 405–406. Vandenbergh, D.J., Persico, A.M., Hawkins, A.L., Griffin, C.A., Li, X., Jabs, E.W., Uhl, G. R., 1992. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14, 1104–1106.
Ágnes Fehérn, Anna Juhász, Magdolna Pákáski, János Kálmán, Zoltán Janka Department of Psychiatry, University of Szeged, 57 Kálvária Ave, Szeged H-6724, Hungary E-mail addresses: [email protected], [email protected]. hu (Á. Fehér), [email protected] (A. Juhász), [email protected] (M. Pákáski), [email protected] (J. Kálmán), offi[email protected] (Z. Janka) Received 22 May 2014 15 July 2014 25 July 2014 Available online 31 July 2014
n Corresponding author. Tel.: þ 36 62 490 590/516; fax: þ36 62 490 590/518. Tel.: þ36 62 490 590/516; fax: þ 36 62 490 590/518.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association between the 9 repeat allele of the dopamine transporter 40 bp variable tandem repeat polymorphism and Alzheimer’s disease
art ic l e i nf o Keywords: Alzheimer’s disease Dopamine transporter (DAT) rs28363170
a b s t r a c t A case-control study was performed to investigate the association between the dopamine transporter (DAT) gene (SLC6A3) rs28363170 polymorphism and the risk for Alzheimer’s disease (AD). Our results indicated a statistically significant correlation between the inheritance of the SLC6A3 9 repeat allele and the genetic susceptibility to AD in a dose-dependent manner. & 2014 Elsevier Ireland Ltd. All rights reserved.
To the Editors: Late-onset Alzheimer’s disease (AD) is a neurodegenerative disorder with multifactorial genetic background. Although several mechanisms, including amyloid-β peptide accumulation and aggregation, tau protein hyperphosphorylation and inflammatory responses, have been recognized to be involved in the pathogenesis of AD, defects in dopaminergic neurotransmission may also contribute to the cognitive deficits and behavioral and psychological symptoms of dementia seen in AD. One of the suitable candidate genes for AD, the solute carrier family 6 member 3 (SLC6A3; MIM#126455) encodes the dopamine transporter (DAT). The 3ʹ untranslated region of the SLC6A3 gene contains a 40 bp variable number of tandem repeat (VNTR) polymorphism (rs28363170). The copy number of this VNTR ranges from 3 to 11; however, the 10-repeat (10R) and the 9-repeat (9R) alleles are the most common (Vandenbergh et al., 1992). The present study aimed to test the hypothesis that SLC6A3 rs28363170 polymorphism is associated with the susceptibility to late-onset AD. A total of 220 Hungarian patients with late-onset AD (72 men; age: 75.3 77.4 years/mean 7S.D.) and 205 cognitively intact, elderly, Hungarian control subjects (67 men; age: 74.7 77.1 years/mean 7S.D.) were involved in the study. A consensus clinical diagnosis of probable late-onset AD (4 65 years of age) was established according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria (McKhann et al., 1984). Ethical permission for all protocols was granted by the Ethics Committee of the Hungarian Council on Science and Health, and all subjects gave informed consent. Genomic DNA was extracted from peripheral blood leukocytes by standard procedures using the Roche kit (Roche Holding AG, Basel, Switzerland), and genotyping of the SLC6A3 polymorphism was performed by polymerase chain reaction as formerly described (Sano et al., 1993). http://dx.doi.org/10.1016/j.psychres.2014.07.060 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
Categorical variables were studied applying Fisher exact and Pearson χ2-tests. The mean age was compared using the t-test for independent samples. No statistically significant difference was found in the distribution of genders or in mean age between AD and control groups (p 40.05). The genotype distributions did not deviate significantly from Hardy–Weinberg equilibrium (p 40.05). Post-hoc power calculations were conducted using GPower 3.0 software (Faul et al., 2007). Our study sample (n ¼425) has 69% power at the significance level of 0.05 to detect differences in SLC6A3 genotype frequencies between the two groups (effect size: w¼0.142). SLC6A3 rs28363170 genotype frequencies are presented in Table 1. Compared with the controls, there was a significantly higher frequency of R9/R9 and R9/R10 genotypes and lower frequency of R10/R10 and R10/R11 genotypes in the AD group (p ¼0.036). No R9/R11 or R11/R11 genotype carriers were detected in our sample. A significantly higher risk for AD was observed among R9 allele carriers (R9/R9 and R9/R10) when R9-genotypes (R10/R10 and R10/R11) were considered as the reference category (OR ¼1.679; 95% CI ¼1.144–2.465; p¼ 0.008). We also investigated the influence of the homozygous and heterozygous R9 allele containing genotypes severally on AD risk. The effect of the R9/R9 genotype on AD risk was more marked (OR ¼2.426; 95% CI ¼ 1.119–5.257; p¼ 0.025) than the effect of R9/R10 (OR ¼1.577; 95% CI ¼1.057– 2.351; p ¼0.025) compared to R9-genotypes. Our study demonstrated a statistically significant correlation between the inheritance of the SLC6A3 R9 allele and the genetic susceptibility to AD. Considering the absence of the R9 allele as the reference category, the significantly higher risk conferred by R9/ R10 genotype was even more pronounced in the case of the homozygous R9/R9 genotype, suggesting that R9 allele affects AD risk in a dose dependent manner. The medium sample size of our study must be addressed as a limitation, and the results should be treated with appropriate caution until independent confirmations are completed.
Letter to the Editor / Psychiatry Research 220 (2014) 730–731
Table 1 Genotype frequencies of the SLC6A3 rs28363170 polymorphism. Genotypes
AD n¼220
Controls n¼ 205
R9/R9 R9/R10 R9/R11 R10/R10 R10/R11 R11/R11
22 (10.0%) 104 (47.3%) n.d. 92 (41.8%) 2 (0.9%) n.d.
11 (5.4%) 80 (39.0%) n.d. 110 (53.6%) 4 (2.0%) n.d.
2
χ ¼ 8.549 (3); p ¼0.036 for genotypes. AD: Alzheimer’s disease; SLC6A3: solute carrier family 6 member 3 gene encoded for dopamine transporter; n.d.: not detected.
Acknowledgments The study was supported by the Hungarian Ministry of Education and Culture under grant TÁMOP-4.2.2A11/1/KONV-20120052. References Faul, F., Erdfelder, E., Lang, A.G., Buchner, A., 2007. GnPower 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods 39, 175–191.
731
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34, 939–944. Sano, A., Kondoh, K., Kakimoto, Y., Kondo, I., 1993. A 40-nucleotide repeat polymorphism in the human dopamine transporter gene. Human Genetics 91, 405–406. Vandenbergh, D.J., Persico, A.M., Hawkins, A.L., Griffin, C.A., Li, X., Jabs, E.W., Uhl, G. R., 1992. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14, 1104–1106.
Ágnes Fehérn, Anna Juhász, Magdolna Pákáski, János Kálmán, Zoltán Janka Department of Psychiatry, University of Szeged, 57 Kálvária Ave, Szeged H-6724, Hungary E-mail addresses: [email protected], [email protected]. hu (Á. Fehér), [email protected] (A. Juhász), [email protected] (M. Pákáski), [email protected] (J. Kálmán), offi[email protected] (Z. Janka) Received 22 May 2014 15 July 2014 25 July 2014 Available online 31 July 2014
n Corresponding author. Tel.: þ 36 62 490 590/516; fax: þ36 62 490 590/518. Tel.: þ36 62 490 590/516; fax: þ 36 62 490 590/518.