- Email: [email protected]
MTHFR 1298A>C is a risk factor for autism spectrum disorder in the Korean population
Psychiatry Research 215 (2014) 258–259
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor MTHFR 1298A4 C is a risk factor for autism spectrum disorder in the Korean population To the editors: Methylenetetrahydrofolate reductase (MTHFR) participates in converting homocysteine into methionine as a cofactor, plays a critical role in regulating homocysteine concentration in the blood. The large amount of homocysteine and oxidative stress is associated with neuropsychiatric disorders such as autism (Chauhan and Chauhan, 2006). Associations of two single nucleotide polymorphisms (SNPs) in the MTHFR, 677C 4T and 1298A 4 C with autism spectrum disorder (ASD) in a Korean population were tested. A total of 251 ASD patients (227 males and 24 females) and 425 controls without any genetic or neurological disorders participated in this study (Supplementary Table 1). Two board-certified child psychiatrists took part in making diagnosis according to the Diagnostic and Statistical Manual of Mental Disorder-IV (DSMD-IV) and the Korean version of the Childhood Autism Rating Scale (K-CARDS). This study was conducted under the approval of the Institutional Review Board of CHA University. Significant differences were tested using logistic regression analysis and permutation test for
correction of multiple testing. All significance thresholds were o0.05 after performing permutation tests. Statistics methods are described in the Supplementary Materials and Methods. As a result, the distribution of the two SNPs satisfied the requirements for Hardy–Weinberg equilibrium (p40.05). There was a significant difference between genotype frequencies of cases and controls in 1298A4C (all group: pper ¼0.0206, male group: pper ¼0.0119, pper ¼ 0.0264, Table 1). The results of the genotype association test for subtypes of ASD showed significant associations between autistic disorder or atypical autism and the 1298A4C (autistic of All group: pper ¼ 0.04034; pper ¼ 0.034, atypical of male group: pper ¼0.0498, Supplementary Table 2). In addition, interaction analyses in the male group showed that a SNP–SNP combination, 677CT/1298AC was significantly associated with an increased risk of ASD by 2.11-fold compared with the combination 677CC/1298AA (p¼0.0207, Supplementary Table 3). However, we could not find any significant result throughout all analyses in female group. This may due to small number of female samples, but our gender-specific significant results might be related to the higher prevalence of ASD in males. We guess that this higher prevalence could be caused by differences in gene expression, possibly through a greater sensitivity to environmental effects in males.
Table 1 Genotype distribution and association analysis for genetic model by logistic regression for SNPs within MTHFR. Gender
All
Male
Female
SNP
Genotype
ASD
Control
Additive
Dominant
Recessive
Freq (%)
Freq (%)
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
rs1801131 (1298A 4C)
AA AC CC
147 (62.29) 75 (31.78) 14 (5.93)
298 (70.45) 114 (26.95) 11 (2.60)
1.442 (1.087–1.912)
0.01117 0.02063per
1.443 (1.031–2.02)
0.03231 0.06275per
2.362 (1.055–5.29)
0.0367 0.06577per
rs1801133 (677C4 T)
CC CT TT
76 (30.52) 136 (54.62) 37 (14.86)
139 (32.86) 204 (48.23) 80 (18.91)
0.9644 (0.7678–1.211)
0.7549 0.9319per
1.114 (0.795–1.561)
0.5303 0.7717per
0.7483 (0.4889–1.145)
0.1818 0.346per
rs1801131 (1298A 4C)
AA AC CC
128 (59.81) 72 (33.64) 14 (6.54)
179 (70.75) 67 (26.48) 7 (2.77)
1.572 (1.138–2.171)
0.006068 0.01186per
1.625 (1.106–2.388)
0.01337 0.02639per
2.46 (0.9742–6.212)
0.05682 0.09362per
rs1801133 (677C4 T)
CC CT TT
71 (31.56) 122 (54.22) 32 (14.22)
90 (35.43) 114 (44.88) 50 (19.69)
0.9675 (0.7467–1.254)
0.8027 0.9563per
1.19 (0.8132–1.742)
0.3701 0.6092per
0.6765 (0.4163–1.099)
0.1145 0.218per
rs1801131 (1298A 4C)
AA AC CC
19 (86.36) 3 (13.64) 0
119 (70.0) 47 (27.65) 4 (2.35)
0.3731 (0.1103–1.261)
0.1127 0.2084per
0.3684 (0.1044–1.3)
0.1207 0.2567per
-
-
rs1801133 (677C4 T)
CC CT TT
5 (20.83) 14 (58.33) 5 (20.83)
49 (28.99) 90 (53.25) 30 (17.75)
1.282 (0.6787–2.421)
0.444 0.688per
1.552 (0.5486–4.388)
0.4075 0.6501per
1.219 (0.4219–3.524)
0.7142 0.7701per
ASD: autism spectrum disorders, CI: confidence interval, OR: odds ratio, P: calculated p-value by χ2 test, Pper: adjusted p-value by permutation test. Additive (AA vs. AB vs. BB), dominant (AA vs. ABþ BB), recessive (AA þAB vs. BB).
0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.11.006
Letter to the Editor / Psychiatry Research 215 (2014) 258–259
Previously, there are controversial association between the 677C 4T and ASD had been reported in many ethnic groups (Boris et al., 2004, Guo et al., 2012, Mohammad et al., 2009). In southern Brazil, however, the 677C 4T was not associated with ASD (dos Santos et al., 2010). In addition, Boris et al. found that the combination of 677CT/1298AC was more frequent in ASD patients; Mohammad et al. showed 677CTþ TT/1298AC þCC combinations increased the risk for ASD by 8.11-fold. In the present study, we found significant associations between ASD and the 1298A 4C but not the 677C4T in male group or all subjects, and the combination of 677CT/1298AC was significantly associated with ASD in male group. Therefore, the association of 677C4 T and 1298A 4 C may be affected by race or the combination of these SNPs. The activity of MTHFR was reduced to 32–64% by 677C 4T and 50–60% by the coexistence of 1298A 4C and 677C4T (Chango et al., 2000). This could support the combined effect of the two SNPs. In further studies, it should be examined whether variants in the MTHFR of parents affect the prevalence of ASD in their children, and researches with more female subjects should be performed. This study was supported by Grants from the Korea Health 21 R&D Project (MHW of Korea, A040002) and the Priority Centers Program (NRF, MEST of Korea, 2009-0093821).
259
Guo, T., Chen, H., Liu, B., Ji, W., Yang, C., 2012. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genetic Testing and Molecular Biomarkers 16, 968–973. Mohammad, N.S., Jain, J.M., Chintakindi, K.P., Singh, R.P., Naik, U., Akella, R.R., 2009. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatric Genetics 19, 171–176.
JungWon Park, MyungJa Ro, Jung-A Pyun, KyuBum Kwack n Department of Biomedical Science, College of Life Science, CHA University, 222 Yatapdong, Bundanggu, Seongnamsi, Gyeonggido 463-836, Republic of Korea E-mail addresses: [email protected], [email protected] (K. Kwack)
Min Nam Department of Psychiatry, Seoul Metropolitan Children’s Hospital, 260 Heolleungno, Seocho-gu, Seoul, Republic of Korea
Hee Jung Bang Department of Psychology, College of Social Science, Ewha Womans University, Seoul, Republic of Korea
Appendix A. Supporting information Jae Won Yang Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea
Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2013.11.006. References Boris, M., Goldblatt, A., Galanko, J., James, S.J., 2004. Association of MTHFR gene variants with autism. Journal of the American Physicians and Surgeons 9, 106–108. Chango, A., Boisson, F., Barbe, F., Quilliot, D., Droesch, S., Pfister, M., Fillon-Emery, N., Lambert, D., Fremont, S., Rosenblatt, D.S., Nicolas, J.P., 2000. The effect of 677C-T and 1298A-C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. British Journal of Nutrition 83, 593–596. Chauhan, A., Chauhan, V., 2006. Oxidative stress in autism. Pathophysiology 13, 171–181. dos Santos, P.A., Longo, D., Brandalize, A.P., Schuler-Faccini, L., 2010. MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil. Psychiatric Genetics 20, 187–189.
Kyung-Sik Choi Department of Elementary Special Education, College of Social Science, Joongbu University, Chungnam, Republic of Korea
Su Kang Kim, Joo-Ho Chung Kohwang Medical Research Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea 9 November 2013 Available online 18 November 2013
n
Corresponding author. Tel.: þ 82 31 725 8376; fax: þ 82 31 725 8350.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor MTHFR 1298A4 C is a risk factor for autism spectrum disorder in the Korean population To the editors: Methylenetetrahydrofolate reductase (MTHFR) participates in converting homocysteine into methionine as a cofactor, plays a critical role in regulating homocysteine concentration in the blood. The large amount of homocysteine and oxidative stress is associated with neuropsychiatric disorders such as autism (Chauhan and Chauhan, 2006). Associations of two single nucleotide polymorphisms (SNPs) in the MTHFR, 677C 4T and 1298A 4 C with autism spectrum disorder (ASD) in a Korean population were tested. A total of 251 ASD patients (227 males and 24 females) and 425 controls without any genetic or neurological disorders participated in this study (Supplementary Table 1). Two board-certified child psychiatrists took part in making diagnosis according to the Diagnostic and Statistical Manual of Mental Disorder-IV (DSMD-IV) and the Korean version of the Childhood Autism Rating Scale (K-CARDS). This study was conducted under the approval of the Institutional Review Board of CHA University. Significant differences were tested using logistic regression analysis and permutation test for
correction of multiple testing. All significance thresholds were o0.05 after performing permutation tests. Statistics methods are described in the Supplementary Materials and Methods. As a result, the distribution of the two SNPs satisfied the requirements for Hardy–Weinberg equilibrium (p40.05). There was a significant difference between genotype frequencies of cases and controls in 1298A4C (all group: pper ¼0.0206, male group: pper ¼0.0119, pper ¼ 0.0264, Table 1). The results of the genotype association test for subtypes of ASD showed significant associations between autistic disorder or atypical autism and the 1298A4C (autistic of All group: pper ¼ 0.04034; pper ¼ 0.034, atypical of male group: pper ¼0.0498, Supplementary Table 2). In addition, interaction analyses in the male group showed that a SNP–SNP combination, 677CT/1298AC was significantly associated with an increased risk of ASD by 2.11-fold compared with the combination 677CC/1298AA (p¼0.0207, Supplementary Table 3). However, we could not find any significant result throughout all analyses in female group. This may due to small number of female samples, but our gender-specific significant results might be related to the higher prevalence of ASD in males. We guess that this higher prevalence could be caused by differences in gene expression, possibly through a greater sensitivity to environmental effects in males.
Table 1 Genotype distribution and association analysis for genetic model by logistic regression for SNPs within MTHFR. Gender
All
Male
Female
SNP
Genotype
ASD
Control
Additive
Dominant
Recessive
Freq (%)
Freq (%)
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
rs1801131 (1298A 4C)
AA AC CC
147 (62.29) 75 (31.78) 14 (5.93)
298 (70.45) 114 (26.95) 11 (2.60)
1.442 (1.087–1.912)
0.01117 0.02063per
1.443 (1.031–2.02)
0.03231 0.06275per
2.362 (1.055–5.29)
0.0367 0.06577per
rs1801133 (677C4 T)
CC CT TT
76 (30.52) 136 (54.62) 37 (14.86)
139 (32.86) 204 (48.23) 80 (18.91)
0.9644 (0.7678–1.211)
0.7549 0.9319per
1.114 (0.795–1.561)
0.5303 0.7717per
0.7483 (0.4889–1.145)
0.1818 0.346per
rs1801131 (1298A 4C)
AA AC CC
128 (59.81) 72 (33.64) 14 (6.54)
179 (70.75) 67 (26.48) 7 (2.77)
1.572 (1.138–2.171)
0.006068 0.01186per
1.625 (1.106–2.388)
0.01337 0.02639per
2.46 (0.9742–6.212)
0.05682 0.09362per
rs1801133 (677C4 T)
CC CT TT
71 (31.56) 122 (54.22) 32 (14.22)
90 (35.43) 114 (44.88) 50 (19.69)
0.9675 (0.7467–1.254)
0.8027 0.9563per
1.19 (0.8132–1.742)
0.3701 0.6092per
0.6765 (0.4163–1.099)
0.1145 0.218per
rs1801131 (1298A 4C)
AA AC CC
19 (86.36) 3 (13.64) 0
119 (70.0) 47 (27.65) 4 (2.35)
0.3731 (0.1103–1.261)
0.1127 0.2084per
0.3684 (0.1044–1.3)
0.1207 0.2567per
-
-
rs1801133 (677C4 T)
CC CT TT
5 (20.83) 14 (58.33) 5 (20.83)
49 (28.99) 90 (53.25) 30 (17.75)
1.282 (0.6787–2.421)
0.444 0.688per
1.552 (0.5486–4.388)
0.4075 0.6501per
1.219 (0.4219–3.524)
0.7142 0.7701per
ASD: autism spectrum disorders, CI: confidence interval, OR: odds ratio, P: calculated p-value by χ2 test, Pper: adjusted p-value by permutation test. Additive (AA vs. AB vs. BB), dominant (AA vs. ABþ BB), recessive (AA þAB vs. BB).
0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.11.006
Letter to the Editor / Psychiatry Research 215 (2014) 258–259
Previously, there are controversial association between the 677C 4T and ASD had been reported in many ethnic groups (Boris et al., 2004, Guo et al., 2012, Mohammad et al., 2009). In southern Brazil, however, the 677C 4T was not associated with ASD (dos Santos et al., 2010). In addition, Boris et al. found that the combination of 677CT/1298AC was more frequent in ASD patients; Mohammad et al. showed 677CTþ TT/1298AC þCC combinations increased the risk for ASD by 8.11-fold. In the present study, we found significant associations between ASD and the 1298A 4C but not the 677C4T in male group or all subjects, and the combination of 677CT/1298AC was significantly associated with ASD in male group. Therefore, the association of 677C4 T and 1298A 4 C may be affected by race or the combination of these SNPs. The activity of MTHFR was reduced to 32–64% by 677C 4T and 50–60% by the coexistence of 1298A 4C and 677C4T (Chango et al., 2000). This could support the combined effect of the two SNPs. In further studies, it should be examined whether variants in the MTHFR of parents affect the prevalence of ASD in their children, and researches with more female subjects should be performed. This study was supported by Grants from the Korea Health 21 R&D Project (MHW of Korea, A040002) and the Priority Centers Program (NRF, MEST of Korea, 2009-0093821).
259
Guo, T., Chen, H., Liu, B., Ji, W., Yang, C., 2012. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genetic Testing and Molecular Biomarkers 16, 968–973. Mohammad, N.S., Jain, J.M., Chintakindi, K.P., Singh, R.P., Naik, U., Akella, R.R., 2009. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatric Genetics 19, 171–176.
JungWon Park, MyungJa Ro, Jung-A Pyun, KyuBum Kwack n Department of Biomedical Science, College of Life Science, CHA University, 222 Yatapdong, Bundanggu, Seongnamsi, Gyeonggido 463-836, Republic of Korea E-mail addresses: [email protected], [email protected] (K. Kwack)
Min Nam Department of Psychiatry, Seoul Metropolitan Children’s Hospital, 260 Heolleungno, Seocho-gu, Seoul, Republic of Korea
Hee Jung Bang Department of Psychology, College of Social Science, Ewha Womans University, Seoul, Republic of Korea
Appendix A. Supporting information Jae Won Yang Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea
Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2013.11.006. References Boris, M., Goldblatt, A., Galanko, J., James, S.J., 2004. Association of MTHFR gene variants with autism. Journal of the American Physicians and Surgeons 9, 106–108. Chango, A., Boisson, F., Barbe, F., Quilliot, D., Droesch, S., Pfister, M., Fillon-Emery, N., Lambert, D., Fremont, S., Rosenblatt, D.S., Nicolas, J.P., 2000. The effect of 677C-T and 1298A-C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. British Journal of Nutrition 83, 593–596. Chauhan, A., Chauhan, V., 2006. Oxidative stress in autism. Pathophysiology 13, 171–181. dos Santos, P.A., Longo, D., Brandalize, A.P., Schuler-Faccini, L., 2010. MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil. Psychiatric Genetics 20, 187–189.
Kyung-Sik Choi Department of Elementary Special Education, College of Social Science, Joongbu University, Chungnam, Republic of Korea
Su Kang Kim, Joo-Ho Chung Kohwang Medical Research Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea 9 November 2013 Available online 18 November 2013
n
Corresponding author. Tel.: þ 82 31 725 8376; fax: þ 82 31 725 8350.