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Lack of association of APOE and tau polymorphisms with dementia in Parkinson’s disease
Neuroscience Letters 448 (2008) 20–23
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Lack of association of APOE and tau polymorphisms with dementia in Parkinson’s disease ˜ Mario Ezquerra, Jaume Campdelacreu, Carles Gaig, Yaroslau Compta, Esteban Munoz, Maria Jose Martí, Francesc Valldeoriola, Eduardo Tolosa ∗ Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
a r t i c l e
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Article history: Received 6 July 2008 Received in revised form 30 September 2008 Accepted 7 October 2008 Keywords: Parkinson’s disease Dementia with Lewy bodies tau APOE
a b s t r a c t Some APOE or tau gene polymorphisms have been associated with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Parkinson’s disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan–Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD. © 2008 Published by Elsevier Ireland Ltd.
Parkinson’s disease (PD) is frequently associated with cognitive deficits, and dementia eventually develops in a substantial number of patients. Prevalence rates of dementia in PD patients vary from 22% to 78%, depending on the population studied and the criteria used to diagnose dementia [1,3,4,9,15,16,23]. The mean duration from onset of PD to development of dementia has been reported to be around 10 years [1,18], but some PD patients may develop dementia within a few years after the onset of PD, while others became demented 20 or more years after disease onset. Age plays a major role in the development of dementia in PD; and it has been reported that it is the general effect of age, rather than the age at onset of PD, that is associated with the development of dementia [2]. Recent studies suggest that the main neuropathological substrate of dementia in PD is Lewy body (LB) type pathology in the brain cortex and limbic structures [20,25], but Alzheimer’s disease (AD) pathology frequently co-exists and may play a significant role [5,6,7,31]. The pathological changes encountered are similar if not identical to those described in dementia with Lewy bodies (DLB),
∗ Corresponding author at: Neurology Service, Hospital Clínic i Universitari de Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 93 2275785; fax: +34 93 2275783. E-mail address: [email protected] (E. Tolosa). 0304-3940/$ – see front matter © 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.neulet.2008.10.018
which suggests that most cases of PD with dementia (PDD) and DLB are likely to represent clinical presentations of the same biological process. Several tau polymorphisms have been associated with PD [29,35], and with other forms of parkinsonism that presented prominent cognitive impairment, such as PSP and CBD [8,30,32]. A recent prospective study reported that early cognitive impairment is associated with the tau H1/H1 genotype in incidental PD [13]. Several studies have established a significant association between the APOE 4 allele with AD [12,34], and a similar association has been suggested for DLB [22]. Some association studies suggest that the APOE 4 allele appears to be associated with a higher prevalence of dementia in PD [26,28], but other authors have not found this association [21,24]. Still another study found both a significantly increased frequency of the APOE 4 allele in PD patients with dementia and an increased tau H1/H1 genotype frequency in PD patients with hallucinations [27]. Hallucinations are especially common in PDD [10], and when found in non-demented PD patients, may be considered as a major predictor of subsequent development of dementia [1,33]. We analysed the APOE and tau genotypes frequencies in our clinical sample of PDD, PD with no dementia (PDND), and healthy controls in order to assess whether these polymorphisms are related to the presence of dementia in PD in our population.
M. Ezquerra et al. / Neuroscience Letters 448 (2008) 20–23 Table 1 Demographic data of the sample. PD
n Mean agea ± S.D. Mean durationb ± S.D. Males
Total
PDD
PDND
86 58.3 ± 9 16.3 ± 6.8 48%
138 56 ± 8.4 16.2 ± 5.5 58%
224 57.4 ± 8.7 16.12 ± 6.2 47.6%
Controls
91 67 ± 9.2 44%
a
Age at onset among the affected individuals and age at the inclussion of controls. S.D. = standard deviation. b Mean duration of PD until the onset of dementia or until the the last assessment of PDND patients.
Patients and controls were recruited at the Parkinson’s disease and Movement Disorders Clinics from the Neurology Service of the Hospital Clinic of Barcelona. All PD patients seen in our outpatients clinic that were demented or became demented between January-2003, and December-2005 were included into the study if they accepted to participate. Eighty-six unrelated PD patients with dementia were included in the study. They all fulfilled the accepted diagnostic clinical criteria for probable or definite PD [19], and dementia was diagnosed according to published criteria [10]. One hundred thirty eight unrelated PD patients without dementia (PDND) were recruited from the same outpatients clinic and were selected on the bases of similar age at onset of PD and duration of disease to those of the PD patients group. In addition, 91 unrelated controls without signs of neurological disease were recruited during the same time period among the spouses of patients with PD and other parkinsonian syndromes attending our outpatient clinic. Cases and controls were not matched in educational level. All patients and controls were Caucasians and from Spanish origin. Demographic and clinical data of cases and control groups are shown in Table 1. Genomic DNA was extracted from blood using standard methods. The tau H1/H2 genotype was defined by the saitohin (STH) Q7R polymorphism, which is a marker of an extended haplotype [8], and was genotyped by PCR-RFLP as previously described [11]. APOE genotyping was performed as described elsewhere [34]. Statistical analysis was performed using the SPSS for Windows release 11.0 (SPSS Inc., Chicago, IL, USA). We analysed the distribution of APOE and tau genotypic frequencies in PDND, PDD and controls by using a logistic regression model adjusting for sex. Subjects with at least one APOE 4 allele were compared to those without any APOE 4 allele. However, we excluded the 4/2 genotypes because the allele 2 could act as a confounder of the potential pathogenic effect of the allele 4. In addition, to study the possible effect of the APOE 2 allele in increasing dementia in PD, reported elsewhere [14], we compared the frequency of the 3/2 genotypes frequencies with the rest of genotypes. Subjects with the tau H1/H1 genotype were compared with the combined group of H1/H2 and H2/H2 genotype carriers. Statistical power of our sample was calculated through Quanto Beta Version 0.5.4 software (available at http://hydra.usc.edu/gxe/). The possible interaction between APOE and tau genotypes for PDD risk was tested by logistic regression analysis. Kaplan–Meier survival analysis and the Log rank test was used to compare the age at onset of PD, age at onset of dementia and duration of disease between APOE and tau genotypes. We used a p level of 0.05 as a limit for statistical significance, while 0.05 < p < 0.1 was considering as borderline significant. No statistical significant differences were detected comparing the APOE 4 genotypes frequency in total PD patients (with and without dementia) with controls (Table 2, p = 0.39), PDD patients with controls (p = 0.39), or PDD with PDND patients (p = 0.36). Assuming an expected odds ratio for PDD of carrying at least one allele APOE
21
Table 2 APOE genotypes frequencies of Parkinson’s disease without dementia patients (PDND), PD with dementia patients (PDD), and healthy controls. PDND
PDD
Controls
Genotypes 3/2 3/3 4/2 4/3 4/4
11 (8.0%) 101 (73.2%) 0 26 (18.8%) 0
7 (8.1%) 57 (66.3%) 1 (1.2%) 20 (23.2%) 1(1.2%)
7 (7.7%) 64 (70.3%) 3 (3.3%) 17 (18.7%) 0
Total n
138
86
91
4 of 2, our study had a power of 0.65 to detect statistical significant differences between PDD and controls with the present number of samples analysed, under a dominant model. Age at onset of PD, disease duration or age at onset of dementia did not correlate with the presence or absence of the APOE 4 allele (Kaplan–Meier analysis, log rank test; p = 0.32, p = 0.23 and p = 0.30, respectively). No differences were detected comparing the APOE 2 genotype frequencies in all PD patients (with and without dementia) with that of controls (p = 0.39), or PDD with PDND patients (p = 0.38). The tau H1/H1 genotype frequency was statistically increased in total PD patients (PDD plus PDND) compared with controls (Table 3, p = 0.036). This genotype frequency did not differ between PDND and PDD patients (p = 0.50) or between PDND and controls (p = 0.15). We found a borderline statistical difference in the tau H1/H1 genotype frequency between PDD patients and controls (p = 0.046; p = 0.09 with Bonferroni correction). Neither age at onset of PD, age at onset of dementia nor duration of disease were associated with the presence of the tau H1/H1 genotype (Kaplan–Meier analysis, log rank test; p = 0.40, p = 0.73 and p = 0.77, respectively). A logistic regression model did not show interaction between APOE and tau genotypes to predict dementia status (p = 0.74). A recent meta-analysis of all the available studies supports the possible involvement of the APOE polymorphism in dementia in PD, but the distribution of the data in that meta-analysis also suggested that publication bias may have confounded the data since negative results may have been under-represented [17]. Furthermore, the majority of the studies in the meta-analysis did not carefully restrict the diagnosis of PDD to those individuals in whom the onset of parkinsonian signs clearly predated the cognitive changes [10], and may therefore have studied cases with DLB wrongly diagnosed as PDD. This procedure may have affected the results, as DLB has associated with the presence of the APOE 4 allele [22]. In our study, the strict use of inclusion diagnostic criteria for PD and PDD minimized this potential problem. The statistical power in our study is limited to 0.65 due to the number of samples analysed. Other associations studies of the APOE polymorphisms on dementia in PD included fewer PDD patients [16,24,26–28]. The other published study on this subject, in which a similar number of PDD patients was included, found results similar to us [21]. As regards the APOE 2 allele, one study supports this involvement in dementia in PD [14]; our results do not support this previous finding. Table 3 Tau genotype frequencies in Parkinson’s disease without dementia (PDND), PD with dementia (PDD) and healthy controls. PDND
PDD
Controls
Genotypes H1/H1 H1/H2 H2/H2
86 (62.3%) 47 (34.1%) 5 (3.6%)
58 (67.4%) 22 (25.6%) 6 (7.0%)
48 (52.7%) 40 (44.0%) 3 (3.3%)
Total n
138
86
91
22
M. Ezquerra et al. / Neuroscience Letters 448 (2008) 20–23
Since dementia in PD has been associated with the presence of cortical synuclein pathology rather than AD changes [5], it is not surprising that our study, in accordance with others, found no association of the APOE 4 allele with PDD, and supports the notion that the biological process involved in dementia in PD is different from the one that occurs in AD. Although tau H1/H1 genotype has been associated with the presence of visual hallucinations [27] and increased cognitive decline in PD patients [13], we did not detect an increased frequency of this genotype in our set of PDD patients. However, since ethnicity could have a role in the effect of the tau H1 haplotype on PD risk [37], it is conceivable that this genetic factor could also modify the PDD risk depending of the ethnic population studied. In addition, since some tau H1 subhaplotypes have been associated with the presence of increased risk for PD [35,36], it can be hypothesised that not H1, but only a specific pathogenic tau H1 subhaplotype, could be associated with dementia in PD. Studies in a cohort of early incidental PD with appropriate prospective long-term follow up, with repeated evaluation of cognitive and motor features and eventual post-mortem diagnostic confirmation, may be needed for a more definitive evaluation of the effect of APOE and tau polymorphisms as risk factors for the development of dementia in PD. Acknowledgments This project was supported by grants from 2001SRG00387 Generalitat de Catalunya, Spain, the award “Distinció per la promoció de la Recerca Universitaria Generalitat de Catalunya”, to E. Tolosa. C, and the Fondo de Investigaciones Sanitarias to Dr Ezquerra (U2004-FS041184-O), Institut d’Investigacions Biomèdiques August Pi i Sunyer–Instituto de Salud Carlos III. We are grateful to Manel Fernandez for technical support.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Lack of association of APOE and tau polymorphisms with dementia in Parkinson’s disease ˜ Mario Ezquerra, Jaume Campdelacreu, Carles Gaig, Yaroslau Compta, Esteban Munoz, Maria Jose Martí, Francesc Valldeoriola, Eduardo Tolosa ∗ Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 6 July 2008 Received in revised form 30 September 2008 Accepted 7 October 2008 Keywords: Parkinson’s disease Dementia with Lewy bodies tau APOE
a b s t r a c t Some APOE or tau gene polymorphisms have been associated with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Parkinson’s disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan–Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD. © 2008 Published by Elsevier Ireland Ltd.
Parkinson’s disease (PD) is frequently associated with cognitive deficits, and dementia eventually develops in a substantial number of patients. Prevalence rates of dementia in PD patients vary from 22% to 78%, depending on the population studied and the criteria used to diagnose dementia [1,3,4,9,15,16,23]. The mean duration from onset of PD to development of dementia has been reported to be around 10 years [1,18], but some PD patients may develop dementia within a few years after the onset of PD, while others became demented 20 or more years after disease onset. Age plays a major role in the development of dementia in PD; and it has been reported that it is the general effect of age, rather than the age at onset of PD, that is associated with the development of dementia [2]. Recent studies suggest that the main neuropathological substrate of dementia in PD is Lewy body (LB) type pathology in the brain cortex and limbic structures [20,25], but Alzheimer’s disease (AD) pathology frequently co-exists and may play a significant role [5,6,7,31]. The pathological changes encountered are similar if not identical to those described in dementia with Lewy bodies (DLB),
∗ Corresponding author at: Neurology Service, Hospital Clínic i Universitari de Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 93 2275785; fax: +34 93 2275783. E-mail address: [email protected] (E. Tolosa). 0304-3940/$ – see front matter © 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.neulet.2008.10.018
which suggests that most cases of PD with dementia (PDD) and DLB are likely to represent clinical presentations of the same biological process. Several tau polymorphisms have been associated with PD [29,35], and with other forms of parkinsonism that presented prominent cognitive impairment, such as PSP and CBD [8,30,32]. A recent prospective study reported that early cognitive impairment is associated with the tau H1/H1 genotype in incidental PD [13]. Several studies have established a significant association between the APOE 4 allele with AD [12,34], and a similar association has been suggested for DLB [22]. Some association studies suggest that the APOE 4 allele appears to be associated with a higher prevalence of dementia in PD [26,28], but other authors have not found this association [21,24]. Still another study found both a significantly increased frequency of the APOE 4 allele in PD patients with dementia and an increased tau H1/H1 genotype frequency in PD patients with hallucinations [27]. Hallucinations are especially common in PDD [10], and when found in non-demented PD patients, may be considered as a major predictor of subsequent development of dementia [1,33]. We analysed the APOE and tau genotypes frequencies in our clinical sample of PDD, PD with no dementia (PDND), and healthy controls in order to assess whether these polymorphisms are related to the presence of dementia in PD in our population.
M. Ezquerra et al. / Neuroscience Letters 448 (2008) 20–23 Table 1 Demographic data of the sample. PD
n Mean agea ± S.D. Mean durationb ± S.D. Males
Total
PDD
PDND
86 58.3 ± 9 16.3 ± 6.8 48%
138 56 ± 8.4 16.2 ± 5.5 58%
224 57.4 ± 8.7 16.12 ± 6.2 47.6%
Controls
91 67 ± 9.2 44%
a
Age at onset among the affected individuals and age at the inclussion of controls. S.D. = standard deviation. b Mean duration of PD until the onset of dementia or until the the last assessment of PDND patients.
Patients and controls were recruited at the Parkinson’s disease and Movement Disorders Clinics from the Neurology Service of the Hospital Clinic of Barcelona. All PD patients seen in our outpatients clinic that were demented or became demented between January-2003, and December-2005 were included into the study if they accepted to participate. Eighty-six unrelated PD patients with dementia were included in the study. They all fulfilled the accepted diagnostic clinical criteria for probable or definite PD [19], and dementia was diagnosed according to published criteria [10]. One hundred thirty eight unrelated PD patients without dementia (PDND) were recruited from the same outpatients clinic and were selected on the bases of similar age at onset of PD and duration of disease to those of the PD patients group. In addition, 91 unrelated controls without signs of neurological disease were recruited during the same time period among the spouses of patients with PD and other parkinsonian syndromes attending our outpatient clinic. Cases and controls were not matched in educational level. All patients and controls were Caucasians and from Spanish origin. Demographic and clinical data of cases and control groups are shown in Table 1. Genomic DNA was extracted from blood using standard methods. The tau H1/H2 genotype was defined by the saitohin (STH) Q7R polymorphism, which is a marker of an extended haplotype [8], and was genotyped by PCR-RFLP as previously described [11]. APOE genotyping was performed as described elsewhere [34]. Statistical analysis was performed using the SPSS for Windows release 11.0 (SPSS Inc., Chicago, IL, USA). We analysed the distribution of APOE and tau genotypic frequencies in PDND, PDD and controls by using a logistic regression model adjusting for sex. Subjects with at least one APOE 4 allele were compared to those without any APOE 4 allele. However, we excluded the 4/2 genotypes because the allele 2 could act as a confounder of the potential pathogenic effect of the allele 4. In addition, to study the possible effect of the APOE 2 allele in increasing dementia in PD, reported elsewhere [14], we compared the frequency of the 3/2 genotypes frequencies with the rest of genotypes. Subjects with the tau H1/H1 genotype were compared with the combined group of H1/H2 and H2/H2 genotype carriers. Statistical power of our sample was calculated through Quanto Beta Version 0.5.4 software (available at http://hydra.usc.edu/gxe/). The possible interaction between APOE and tau genotypes for PDD risk was tested by logistic regression analysis. Kaplan–Meier survival analysis and the Log rank test was used to compare the age at onset of PD, age at onset of dementia and duration of disease between APOE and tau genotypes. We used a p level of 0.05 as a limit for statistical significance, while 0.05 < p < 0.1 was considering as borderline significant. No statistical significant differences were detected comparing the APOE 4 genotypes frequency in total PD patients (with and without dementia) with controls (Table 2, p = 0.39), PDD patients with controls (p = 0.39), or PDD with PDND patients (p = 0.36). Assuming an expected odds ratio for PDD of carrying at least one allele APOE
21
Table 2 APOE genotypes frequencies of Parkinson’s disease without dementia patients (PDND), PD with dementia patients (PDD), and healthy controls. PDND
PDD
Controls
Genotypes 3/2 3/3 4/2 4/3 4/4
11 (8.0%) 101 (73.2%) 0 26 (18.8%) 0
7 (8.1%) 57 (66.3%) 1 (1.2%) 20 (23.2%) 1(1.2%)
7 (7.7%) 64 (70.3%) 3 (3.3%) 17 (18.7%) 0
Total n
138
86
91
4 of 2, our study had a power of 0.65 to detect statistical significant differences between PDD and controls with the present number of samples analysed, under a dominant model. Age at onset of PD, disease duration or age at onset of dementia did not correlate with the presence or absence of the APOE 4 allele (Kaplan–Meier analysis, log rank test; p = 0.32, p = 0.23 and p = 0.30, respectively). No differences were detected comparing the APOE 2 genotype frequencies in all PD patients (with and without dementia) with that of controls (p = 0.39), or PDD with PDND patients (p = 0.38). The tau H1/H1 genotype frequency was statistically increased in total PD patients (PDD plus PDND) compared with controls (Table 3, p = 0.036). This genotype frequency did not differ between PDND and PDD patients (p = 0.50) or between PDND and controls (p = 0.15). We found a borderline statistical difference in the tau H1/H1 genotype frequency between PDD patients and controls (p = 0.046; p = 0.09 with Bonferroni correction). Neither age at onset of PD, age at onset of dementia nor duration of disease were associated with the presence of the tau H1/H1 genotype (Kaplan–Meier analysis, log rank test; p = 0.40, p = 0.73 and p = 0.77, respectively). A logistic regression model did not show interaction between APOE and tau genotypes to predict dementia status (p = 0.74). A recent meta-analysis of all the available studies supports the possible involvement of the APOE polymorphism in dementia in PD, but the distribution of the data in that meta-analysis also suggested that publication bias may have confounded the data since negative results may have been under-represented [17]. Furthermore, the majority of the studies in the meta-analysis did not carefully restrict the diagnosis of PDD to those individuals in whom the onset of parkinsonian signs clearly predated the cognitive changes [10], and may therefore have studied cases with DLB wrongly diagnosed as PDD. This procedure may have affected the results, as DLB has associated with the presence of the APOE 4 allele [22]. In our study, the strict use of inclusion diagnostic criteria for PD and PDD minimized this potential problem. The statistical power in our study is limited to 0.65 due to the number of samples analysed. Other associations studies of the APOE polymorphisms on dementia in PD included fewer PDD patients [16,24,26–28]. The other published study on this subject, in which a similar number of PDD patients was included, found results similar to us [21]. As regards the APOE 2 allele, one study supports this involvement in dementia in PD [14]; our results do not support this previous finding. Table 3 Tau genotype frequencies in Parkinson’s disease without dementia (PDND), PD with dementia (PDD) and healthy controls. PDND
PDD
Controls
Genotypes H1/H1 H1/H2 H2/H2
86 (62.3%) 47 (34.1%) 5 (3.6%)
58 (67.4%) 22 (25.6%) 6 (7.0%)
48 (52.7%) 40 (44.0%) 3 (3.3%)
Total n
138
86
91
22
M. Ezquerra et al. / Neuroscience Letters 448 (2008) 20–23
Since dementia in PD has been associated with the presence of cortical synuclein pathology rather than AD changes [5], it is not surprising that our study, in accordance with others, found no association of the APOE 4 allele with PDD, and supports the notion that the biological process involved in dementia in PD is different from the one that occurs in AD. Although tau H1/H1 genotype has been associated with the presence of visual hallucinations [27] and increased cognitive decline in PD patients [13], we did not detect an increased frequency of this genotype in our set of PDD patients. However, since ethnicity could have a role in the effect of the tau H1 haplotype on PD risk [37], it is conceivable that this genetic factor could also modify the PDD risk depending of the ethnic population studied. In addition, since some tau H1 subhaplotypes have been associated with the presence of increased risk for PD [35,36], it can be hypothesised that not H1, but only a specific pathogenic tau H1 subhaplotype, could be associated with dementia in PD. Studies in a cohort of early incidental PD with appropriate prospective long-term follow up, with repeated evaluation of cognitive and motor features and eventual post-mortem diagnostic confirmation, may be needed for a more definitive evaluation of the effect of APOE and tau polymorphisms as risk factors for the development of dementia in PD. Acknowledgments This project was supported by grants from 2001SRG00387 Generalitat de Catalunya, Spain, the award “Distinció per la promoció de la Recerca Universitaria Generalitat de Catalunya”, to E. Tolosa. C, and the Fondo de Investigaciones Sanitarias to Dr Ezquerra (U2004-FS041184-O), Institut d’Investigacions Biomèdiques August Pi i Sunyer–Instituto de Salud Carlos III. We are grateful to Manel Fernandez for technical support.
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