- Email: [email protected]
Association study between late-onset Alzheimer's disease and the transferrin gene polymorphisms in Chinese
Neuroscience Letters 349 (2003) 209–211 www.elsevier.com/locate/neulet
Association study between late-onset Alzheimer’s disease and the transferrin gene polymorphisms in Chinese Peng Zhanga, Ze Yangb, Chuanfang Zhanga, Zeping Luc, Xiaohong Shib, Weidong Zhengb, Chunling Wand, Duanyang Zhangd, Chenguang Zhengc, Shu Lia, Feng Jina,*, Li Wangd a
Laboratory for Human & Animal Genetic Studies, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China b Laboratory for Medical Genetics, Institute of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, 100730, China c Jiangbin Hospital, Nanning, Guangxi, 530021, China d Department of Medical & Human Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China Received 12 June 2003; accepted 9 July 2003
Abstract To investigate the possible involvement of the transferrin (TF) gene polymorphism in the manifestation of Alzheimer’s disease (AD), we analyzed the TF and apolipoprotein E (APOE) genotypes of 67 sporadic late-onset AD patients and 131 normal elderly controls in the Chinese population. Our data showed that the TF C1 homozygosity carriers had an increased risk of AD in subjects $75 years of age, showing that homozygosity for the TF C1 allele was associated with an approximately three-fold increased risk (OR ¼ 3:57, 95% CI, 1.24 – 10.27, P ¼ 0:014). No synergic effects were found between the APOE 14 allele and TF gene polymorphisms. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Gene polymorphisms; Alzheimer’s disease; Apolipoprotein E; Transferrin; Chinese
Alzheimer’s disease (AD) is one of the most frequent neurodegenerative disorders with heterogeneous etiologies including genetic factors. Most of the rare early-onset familial AD cases can be explained by mutations in the Presenilin 1 gene (PS-1) on chromosome 14q, the Presenilin 2 gene (PS-2) on chromosome 1q, and the amyloid b protein precursor gene (APP) on chromosome 21q. However, the etiology of the more common late-onset AD (LOAD) can only partly be explained by the apolipoprotein E (APOE) 14 allele [9]. The APOE 14 allele is neither necessary nor sufficient for the expression of AD, suggesting that there might be other genetic factors. Recently, Namekata et al. reported an association between the transferrin gene (TF) and LOAD. The TF C2 allele was demonstrated to have a higher frequency in LOAD patients than in healthy controls [8]. Since it is the major transport protein for iron and a component of senile plaques (SP), which itself is a major factor in free radical *
Corresponding author. Tel.: þ86-10-6488-0089; fax: þ 86-10-64850152. E-mail address: [email protected] (F. Jin).
generation, it might be another possible risk factor for LOAD. In the present study we examined the TF and APOE genotypes to determine whether the TF polymorphisms were associated with LOAD and their synergic effects with the APOE 14 allele in the Chinese population. All subjects were from Nanning, Guangxi, China, which included sporadic AD patients (n ¼ 67, 40 female, 27 male, age 80.0 ^ 6.6 years) and healthy controls (n ¼ 131, 41 female, 90 male, age 69.0 ^ 9.4 years). The diagnosis of dementia was based on the DSM-III-R criteria [1] and the clinical diagnosis of AD was based on the NINCDS-ADRDA with the exclusion of vascular dementia [7]. All the LOAD patients were confirmed through MRI. DNA was extracted from peripheral vein blood with standard procedures. The APOE genotype was detected using the method as previously described [3]. The TF C2 variant was detected using the method previously described by Namekata et al. [8]. Allelic and genotypic distributions were estimated by allele counting and compared in the AD and control groups by x 2 test. Logistic regression analysis was performed using Statistic Package for the Social
0304-3940/03/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00837-1
210
P. Zhang et al. / Neuroscience Letters 349 (2003) 209–211
Table 1 Allele and genotype frequencies of apolipoprotein E in LOAD patients and control subjects n
LOAD Controls
63 131
Genotypes (%)
1212
1213
0 0
6 (9) 23 (18)
Alleles (%)
1214
1313
3 (5) 37 (59) 1 (1) 91 (69) x2 ¼ 11:34, d:f: ¼ 3, P ¼ 0:01
Sciences (SPSS) software. The level of statistical significance was defined as P , 0:05. Allele and genotype frequencies for the APOE gene and TF gene are shown in Tables 1 and 2. The polymorphism distributions of APOE and TF corresponded well with Hardy – Weinberg equilibrium. The APOE 14 allele frequency in AD patients was significantly higher than that in controls (x2 ¼ 8:69, d:f: ¼ 1, P , 0:01), suggesting that our sample was representative. Although the genotype frequency of TF C1/C1 in AD patients was higher than that of controls, it did not reach statistical significance (0.64 vs. 0.56, x2 ¼ 3:199, P ¼ 0:202). The TF allele frequency between AD patients and controls was also not significantly different (P . 0:1). The C2 allele frequency in AD patients was 22%, which was slightly less than that of 28% in Japanese AD patients [8]. Neither of the frequencies of TF genotypes nor alleles were significantly different in both the APOE 14 positive subjects and APOE 14 negative subjects (P . 0:1), which was consistent with the report of Kim et al. [4] but in contrast to that of Namekata et al. [8]. Since the effects of many of the risk factors for LOAD were age-dependent and it had been reported that the effect of APOE 14 had a peak effect in the seventh decade [2,9], we stratified the population by 75 years of age in order to test whether the gene polymorphisms were associated with AD in different age groups. Our data showed that possession of TF C1 homozygosity had a significant increased
1314
1414
12
13
14
17 (27) 16 (12)
0 0
9 (7) 97 (77) 20 (16) 24 (9) 221 (84) 17 (7) x2 ¼ 8:69, d:f: ¼ 1, P , 0:01
frequency in LOAD patients as compared with controls (0.61 vs. 0.35, x2 ¼ 5:46, d:f: ¼ 1, P ¼ 0:019) in the $ 75 years age group, while the TF allele frequencies of C1 and C2 were not significantly different between the case and control in this age group (x2 ¼ 2:45, d:f: ¼ 1, P ¼ 0:118) (Table 2). Conditional logistic regression analysis was used to test the association between the TF polymorphisms and AD in the $ 75 years age group. In order to correct for significant differences in mean age and sex distribution between the AD and control, the two factors were entered as co-variants in the logistic regression analysis, along with TF C1 homozygosity and combined TF C1 homozygosity/APOE 14 carrier status. As expected, the APOE 14 effect became non-significant in the $ 75 years age group (OR ¼ 1:67, 95% CI, 0.53 –5.35, P ¼ 0:129). Homozygosity for the TF C1 allele was associated with an approximately three-fold increased risk (OR ¼ 3:57, 95% CI, 1.24 – 10.27, P ¼ 0:014), while possession of both TF C1 homozygosity and APOE 14 allele was not significantly associated with LOAD (OR ¼ 7:18, 95% CI, 0.85– 158.46, P ¼ 0:154) (Table 3). While the etiology of AD has not been clearly resolved, population and family studies showed that genetic factors played a major role in the onset of AD [9]. Iron and its binding proteins have been considered to be involved in AD pathogenesis, since iron was significantly increased in AD
Table 2 Allele and genotype frequencies of TF gene in LOAD patients and control subjects n
Genotypes (%) C1C1
LOAD Controls
Alleles (%) C1C2
C2C2
C1
C2
67 131
43 (64) 74 (56)
19 (28) 52 (40) x2 ¼ 3:199, d:f: ¼ 2, P ¼ 0:202
5 (8) 5 (4)
105 (78) 29 (22) 204 (77) 62 (23) x2 ¼ 0:14, d:f: ¼ 1, P ¼ 0:707
43 114
28 (65) 67 (59)
12 (28) 43 (38) x2 ¼ 1:908, d:f: ¼ 2, P ¼ 0:385
3 (7) 4 (3)
68 (79) 18 (21) 177 (78) 51 (22) x2 ¼ 0:08, d:f: ¼ 1, P ¼ 0:783
APOE 14 carriers LOAD Controls
20 17
12 (60) 7 (41)
6 (30) 9 (53) x2 ¼ 2:019, d:f: ¼ 2, P ¼ 0:364
2 (10) 1 (6)
30 (75) 10 (25) 23 (68) 11 (32) x2 ¼ 0:49, d:f: ¼ 1, P ¼ 0:484
Subjects $75 years of age LOAD Controls
52 29
32 (61) 10 (35)
16 (31) 18 (62) x2 ¼ 5:46, d:f: ¼ 1, P ¼ 0:019
4 (8) 1 (3)
80 (77) 24 (23) 38 (66) 20 (34) x2 ¼ 2:45, d:f: ¼ 1, P ¼ 0:118
Non-APOE 14 carriers LOAD Controls
P. Zhang et al. / Neuroscience Letters 349 (2003) 209–211 Table 3 Conditional logistic regression for the effects of TF C1 homozygosity on the risk for LOAD in subjects $75 years of age (LOAD 52, control 29) Variable
Estimated OR
95% CI
P value
APOE 14 carrier TF C1 homozygosity TF C1 homozygosity/14 carrier
1.67 3.57 7.18
0.53–5.35 1.24–10.27 0.85–158.46
0.129 0.014 0.154
Variables entered into the logistic regression model were: age, sex, APOE4 carrier status, TF C1 homozygosity, TF C1 homozygosity/14 carrier status.
globus pallidus and frontal cortex, and transferrin was significantly increased in AD frontal cortex, compared with elderly controls [5]. It has also been reported that ionic iron, ionic zinc, and aluminum can induce the potentially toxic Ab aggregates in vitro [6]. Also iron levels affect the processing of APP to Ab. Since the first report of an association between TF C2 allele and AD, similar results have been replicated in some studies [10,11], and there has also been an opposite report [4]. The present study was the first report of the association analysis of TF polymorphism with LOAD in the Chinese population. Our data showed that the frequency of TF C1 homozygosity was associated with significantly increased risk of LOAD in the $ 75 years age group. The TF C1 and C2 allele frequencies were not significantly different between LOAD patients and controls. No synergic effects between TF polymorphisms and APOE 14 allele were found in our samples (LOAD and control populations). These results are different from those of Namekata et al. [8], who reported that the C2 allele was significantly associated with LOAD and had a synergic effect with homozygosity for the APOE 14 allele. A possible explanation could be the ethnic diversity of the different populations. Our results suggested that the frequencies of genotypes instead of alleles were significantly different between LOAD and controls. It has been reported that the total iron-binding capacity (TIBC) was significantly higher in subjects carrying TF C1/C1 than in those carrying C1/C2 or C2/C2, but was not significantly different in different TF allele carriers. Also the serum transferrin concentrations were not significantly different among subjects with different TF genotypes [12]. An increase in the TIBC might relate to a high iron level accumulation in the brain and thus more susceptibility to LOAD. In conclusion, our data revealed that TF C1 homozygosity carriers have an increased risk for LOAD in subjects $ 75 years of age. And the effect was independent of APOE 14 carrier status. However, it should be noticed that the effect of TF C1 homozygosity in our data was on the
211
borderline of significance (0:01 , P , 0:05). Further studies in a larger population and family based analysis are required, which will be helpful in clarifying whether the TF gene polymorphisms are risk factors in LOAD.
Acknowledgements This work was supported by the National “863” Program (2002AA223031), the National “973” Program (TG2000057009) and the Chinese National Natural Science Fund (30225019).
References [1] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition., American Psychiatric Association, Washington, DC, 1994. [2] D. Blacker, J.L. Haines, L. Rodes, H. Terwedow, R.C. Go, L.E. Harrell, R.T. Perry, S.S. Bassett, G. Chase, D. Meyers, M.S. Albert, R. Tanzi, ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative, Neurology 48 (1997) 139–147. [3] X.F. Hu, X.R. Zhang, A. Xuan, X.R. Cao, Association between Apolipoprotein E gene polymorphism and the patients with persistent vegetative state in the Chinese, Acta Genetica Sinica 29 (2002) 757–760. [4] K.W. Kim, J.H. Jhoo, J.H. Lee, D.Y. Lee, K.U. Lee, J.Y. Youn, J.I. Woo, Transferrin C2 variant does not confer a risk for Alzheimer’s disease in Koreans, Neurosci. Lett. 308 (2001) 45–48. [5] D.A. Loeffler, R. Connor, P.L. Juneau, B.S. Snyder, L. Kanaley, A.J. DeMaggio, H. Nguyen, C.M. Brickman, P.A. LeWitt, Transferrin and iron in normal, Alzheimer’s disease, and Parkinson’s disease brain regions, J. Neurochem. 65 (1995) 710–724. [6] P.W. Mantyh, J.R. Ghilardi, S. Rogers, E. DeMaster, C.J. Allen, E.R. Stimson, J.E. Maggio, Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide, J. Neurochem. 61 (1993) 1171–1174. [7] G. McKhamm, D. Drachman, M. Folstein, R. Datzman, D. Price, E.M. Stadlan, 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 (1984) 939–944. [8] K. Namekata, M. Imagawa, A. Terashi, S. Ohta, F. Oyama, Y. Ihara, Association of transferrin C2 allele with late-onset Alzheimer’s disease, Hum. Genet. 101 (1997) 126 –129. [9] R.E. Tanzi, A genetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders, J. Clin. Invest. 104 (1999) 1175–1179. [10] G.F. Van Landeghem, C. Sikstrom, L.E. Beckman, R. Adolfsson, L. Beckman, Transferrin C2, metal binding and Alzheimer’s disease, NeuroReport 9 (1998) 177 –179. [11] S.J. Van Rensburg, M.E. Carstens, F.C. Potocnik, A.K. Aucamp, J.J. Taljaard, Increased frequency of the transferrin C2 subtype in Alzheimer’s disease, NeuroReport 4 (1993) 1269–1271. [12] C.T. Wong, N. Saha, Effects of transferrin genetic phenotypes on total iron-binding capacity, Acta Haematol. 75 (1986) 215–218.
Association study between late-onset Alzheimer’s disease and the transferrin gene polymorphisms in Chinese Peng Zhanga, Ze Yangb, Chuanfang Zhanga, Zeping Luc, Xiaohong Shib, Weidong Zhengb, Chunling Wand, Duanyang Zhangd, Chenguang Zhengc, Shu Lia, Feng Jina,*, Li Wangd a
Laboratory for Human & Animal Genetic Studies, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China b Laboratory for Medical Genetics, Institute of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, 100730, China c Jiangbin Hospital, Nanning, Guangxi, 530021, China d Department of Medical & Human Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China Received 12 June 2003; accepted 9 July 2003
Abstract To investigate the possible involvement of the transferrin (TF) gene polymorphism in the manifestation of Alzheimer’s disease (AD), we analyzed the TF and apolipoprotein E (APOE) genotypes of 67 sporadic late-onset AD patients and 131 normal elderly controls in the Chinese population. Our data showed that the TF C1 homozygosity carriers had an increased risk of AD in subjects $75 years of age, showing that homozygosity for the TF C1 allele was associated with an approximately three-fold increased risk (OR ¼ 3:57, 95% CI, 1.24 – 10.27, P ¼ 0:014). No synergic effects were found between the APOE 14 allele and TF gene polymorphisms. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Gene polymorphisms; Alzheimer’s disease; Apolipoprotein E; Transferrin; Chinese
Alzheimer’s disease (AD) is one of the most frequent neurodegenerative disorders with heterogeneous etiologies including genetic factors. Most of the rare early-onset familial AD cases can be explained by mutations in the Presenilin 1 gene (PS-1) on chromosome 14q, the Presenilin 2 gene (PS-2) on chromosome 1q, and the amyloid b protein precursor gene (APP) on chromosome 21q. However, the etiology of the more common late-onset AD (LOAD) can only partly be explained by the apolipoprotein E (APOE) 14 allele [9]. The APOE 14 allele is neither necessary nor sufficient for the expression of AD, suggesting that there might be other genetic factors. Recently, Namekata et al. reported an association between the transferrin gene (TF) and LOAD. The TF C2 allele was demonstrated to have a higher frequency in LOAD patients than in healthy controls [8]. Since it is the major transport protein for iron and a component of senile plaques (SP), which itself is a major factor in free radical *
Corresponding author. Tel.: þ86-10-6488-0089; fax: þ 86-10-64850152. E-mail address: [email protected] (F. Jin).
generation, it might be another possible risk factor for LOAD. In the present study we examined the TF and APOE genotypes to determine whether the TF polymorphisms were associated with LOAD and their synergic effects with the APOE 14 allele in the Chinese population. All subjects were from Nanning, Guangxi, China, which included sporadic AD patients (n ¼ 67, 40 female, 27 male, age 80.0 ^ 6.6 years) and healthy controls (n ¼ 131, 41 female, 90 male, age 69.0 ^ 9.4 years). The diagnosis of dementia was based on the DSM-III-R criteria [1] and the clinical diagnosis of AD was based on the NINCDS-ADRDA with the exclusion of vascular dementia [7]. All the LOAD patients were confirmed through MRI. DNA was extracted from peripheral vein blood with standard procedures. The APOE genotype was detected using the method as previously described [3]. The TF C2 variant was detected using the method previously described by Namekata et al. [8]. Allelic and genotypic distributions were estimated by allele counting and compared in the AD and control groups by x 2 test. Logistic regression analysis was performed using Statistic Package for the Social
0304-3940/03/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00837-1
210
P. Zhang et al. / Neuroscience Letters 349 (2003) 209–211
Table 1 Allele and genotype frequencies of apolipoprotein E in LOAD patients and control subjects n
LOAD Controls
63 131
Genotypes (%)
1212
1213
0 0
6 (9) 23 (18)
Alleles (%)
1214
1313
3 (5) 37 (59) 1 (1) 91 (69) x2 ¼ 11:34, d:f: ¼ 3, P ¼ 0:01
Sciences (SPSS) software. The level of statistical significance was defined as P , 0:05. Allele and genotype frequencies for the APOE gene and TF gene are shown in Tables 1 and 2. The polymorphism distributions of APOE and TF corresponded well with Hardy – Weinberg equilibrium. The APOE 14 allele frequency in AD patients was significantly higher than that in controls (x2 ¼ 8:69, d:f: ¼ 1, P , 0:01), suggesting that our sample was representative. Although the genotype frequency of TF C1/C1 in AD patients was higher than that of controls, it did not reach statistical significance (0.64 vs. 0.56, x2 ¼ 3:199, P ¼ 0:202). The TF allele frequency between AD patients and controls was also not significantly different (P . 0:1). The C2 allele frequency in AD patients was 22%, which was slightly less than that of 28% in Japanese AD patients [8]. Neither of the frequencies of TF genotypes nor alleles were significantly different in both the APOE 14 positive subjects and APOE 14 negative subjects (P . 0:1), which was consistent with the report of Kim et al. [4] but in contrast to that of Namekata et al. [8]. Since the effects of many of the risk factors for LOAD were age-dependent and it had been reported that the effect of APOE 14 had a peak effect in the seventh decade [2,9], we stratified the population by 75 years of age in order to test whether the gene polymorphisms were associated with AD in different age groups. Our data showed that possession of TF C1 homozygosity had a significant increased
1314
1414
12
13
14
17 (27) 16 (12)
0 0
9 (7) 97 (77) 20 (16) 24 (9) 221 (84) 17 (7) x2 ¼ 8:69, d:f: ¼ 1, P , 0:01
frequency in LOAD patients as compared with controls (0.61 vs. 0.35, x2 ¼ 5:46, d:f: ¼ 1, P ¼ 0:019) in the $ 75 years age group, while the TF allele frequencies of C1 and C2 were not significantly different between the case and control in this age group (x2 ¼ 2:45, d:f: ¼ 1, P ¼ 0:118) (Table 2). Conditional logistic regression analysis was used to test the association between the TF polymorphisms and AD in the $ 75 years age group. In order to correct for significant differences in mean age and sex distribution between the AD and control, the two factors were entered as co-variants in the logistic regression analysis, along with TF C1 homozygosity and combined TF C1 homozygosity/APOE 14 carrier status. As expected, the APOE 14 effect became non-significant in the $ 75 years age group (OR ¼ 1:67, 95% CI, 0.53 –5.35, P ¼ 0:129). Homozygosity for the TF C1 allele was associated with an approximately three-fold increased risk (OR ¼ 3:57, 95% CI, 1.24 – 10.27, P ¼ 0:014), while possession of both TF C1 homozygosity and APOE 14 allele was not significantly associated with LOAD (OR ¼ 7:18, 95% CI, 0.85– 158.46, P ¼ 0:154) (Table 3). While the etiology of AD has not been clearly resolved, population and family studies showed that genetic factors played a major role in the onset of AD [9]. Iron and its binding proteins have been considered to be involved in AD pathogenesis, since iron was significantly increased in AD
Table 2 Allele and genotype frequencies of TF gene in LOAD patients and control subjects n
Genotypes (%) C1C1
LOAD Controls
Alleles (%) C1C2
C2C2
C1
C2
67 131
43 (64) 74 (56)
19 (28) 52 (40) x2 ¼ 3:199, d:f: ¼ 2, P ¼ 0:202
5 (8) 5 (4)
105 (78) 29 (22) 204 (77) 62 (23) x2 ¼ 0:14, d:f: ¼ 1, P ¼ 0:707
43 114
28 (65) 67 (59)
12 (28) 43 (38) x2 ¼ 1:908, d:f: ¼ 2, P ¼ 0:385
3 (7) 4 (3)
68 (79) 18 (21) 177 (78) 51 (22) x2 ¼ 0:08, d:f: ¼ 1, P ¼ 0:783
APOE 14 carriers LOAD Controls
20 17
12 (60) 7 (41)
6 (30) 9 (53) x2 ¼ 2:019, d:f: ¼ 2, P ¼ 0:364
2 (10) 1 (6)
30 (75) 10 (25) 23 (68) 11 (32) x2 ¼ 0:49, d:f: ¼ 1, P ¼ 0:484
Subjects $75 years of age LOAD Controls
52 29
32 (61) 10 (35)
16 (31) 18 (62) x2 ¼ 5:46, d:f: ¼ 1, P ¼ 0:019
4 (8) 1 (3)
80 (77) 24 (23) 38 (66) 20 (34) x2 ¼ 2:45, d:f: ¼ 1, P ¼ 0:118
Non-APOE 14 carriers LOAD Controls
P. Zhang et al. / Neuroscience Letters 349 (2003) 209–211 Table 3 Conditional logistic regression for the effects of TF C1 homozygosity on the risk for LOAD in subjects $75 years of age (LOAD 52, control 29) Variable
Estimated OR
95% CI
P value
APOE 14 carrier TF C1 homozygosity TF C1 homozygosity/14 carrier
1.67 3.57 7.18
0.53–5.35 1.24–10.27 0.85–158.46
0.129 0.014 0.154
Variables entered into the logistic regression model were: age, sex, APOE4 carrier status, TF C1 homozygosity, TF C1 homozygosity/14 carrier status.
globus pallidus and frontal cortex, and transferrin was significantly increased in AD frontal cortex, compared with elderly controls [5]. It has also been reported that ionic iron, ionic zinc, and aluminum can induce the potentially toxic Ab aggregates in vitro [6]. Also iron levels affect the processing of APP to Ab. Since the first report of an association between TF C2 allele and AD, similar results have been replicated in some studies [10,11], and there has also been an opposite report [4]. The present study was the first report of the association analysis of TF polymorphism with LOAD in the Chinese population. Our data showed that the frequency of TF C1 homozygosity was associated with significantly increased risk of LOAD in the $ 75 years age group. The TF C1 and C2 allele frequencies were not significantly different between LOAD patients and controls. No synergic effects between TF polymorphisms and APOE 14 allele were found in our samples (LOAD and control populations). These results are different from those of Namekata et al. [8], who reported that the C2 allele was significantly associated with LOAD and had a synergic effect with homozygosity for the APOE 14 allele. A possible explanation could be the ethnic diversity of the different populations. Our results suggested that the frequencies of genotypes instead of alleles were significantly different between LOAD and controls. It has been reported that the total iron-binding capacity (TIBC) was significantly higher in subjects carrying TF C1/C1 than in those carrying C1/C2 or C2/C2, but was not significantly different in different TF allele carriers. Also the serum transferrin concentrations were not significantly different among subjects with different TF genotypes [12]. An increase in the TIBC might relate to a high iron level accumulation in the brain and thus more susceptibility to LOAD. In conclusion, our data revealed that TF C1 homozygosity carriers have an increased risk for LOAD in subjects $ 75 years of age. And the effect was independent of APOE 14 carrier status. However, it should be noticed that the effect of TF C1 homozygosity in our data was on the
211
borderline of significance (0:01 , P , 0:05). Further studies in a larger population and family based analysis are required, which will be helpful in clarifying whether the TF gene polymorphisms are risk factors in LOAD.
Acknowledgements This work was supported by the National “863” Program (2002AA223031), the National “973” Program (TG2000057009) and the Chinese National Natural Science Fund (30225019).
References [1] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition., American Psychiatric Association, Washington, DC, 1994. [2] D. Blacker, J.L. Haines, L. Rodes, H. Terwedow, R.C. Go, L.E. Harrell, R.T. Perry, S.S. Bassett, G. Chase, D. Meyers, M.S. Albert, R. Tanzi, ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative, Neurology 48 (1997) 139–147. [3] X.F. Hu, X.R. Zhang, A. Xuan, X.R. Cao, Association between Apolipoprotein E gene polymorphism and the patients with persistent vegetative state in the Chinese, Acta Genetica Sinica 29 (2002) 757–760. [4] K.W. Kim, J.H. Jhoo, J.H. Lee, D.Y. Lee, K.U. Lee, J.Y. Youn, J.I. Woo, Transferrin C2 variant does not confer a risk for Alzheimer’s disease in Koreans, Neurosci. Lett. 308 (2001) 45–48. [5] D.A. Loeffler, R. Connor, P.L. Juneau, B.S. Snyder, L. Kanaley, A.J. DeMaggio, H. Nguyen, C.M. Brickman, P.A. LeWitt, Transferrin and iron in normal, Alzheimer’s disease, and Parkinson’s disease brain regions, J. Neurochem. 65 (1995) 710–724. [6] P.W. Mantyh, J.R. Ghilardi, S. Rogers, E. DeMaster, C.J. Allen, E.R. Stimson, J.E. Maggio, Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide, J. Neurochem. 61 (1993) 1171–1174. [7] G. McKhamm, D. Drachman, M. Folstein, R. Datzman, D. Price, E.M. Stadlan, 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 (1984) 939–944. [8] K. Namekata, M. Imagawa, A. Terashi, S. Ohta, F. Oyama, Y. Ihara, Association of transferrin C2 allele with late-onset Alzheimer’s disease, Hum. Genet. 101 (1997) 126 –129. [9] R.E. Tanzi, A genetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders, J. Clin. Invest. 104 (1999) 1175–1179. [10] G.F. Van Landeghem, C. Sikstrom, L.E. Beckman, R. Adolfsson, L. Beckman, Transferrin C2, metal binding and Alzheimer’s disease, NeuroReport 9 (1998) 177 –179. [11] S.J. Van Rensburg, M.E. Carstens, F.C. Potocnik, A.K. Aucamp, J.J. Taljaard, Increased frequency of the transferrin C2 subtype in Alzheimer’s disease, NeuroReport 4 (1993) 1269–1271. [12] C.T. Wong, N. Saha, Effects of transferrin genetic phenotypes on total iron-binding capacity, Acta Haematol. 75 (1986) 215–218.