Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014; 15: 551–556

ORIGINAL ARTICLE

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Lack of association between APOE gene polymorphisms and amyotrophic lateral sclerosis: A comprehensive meta-analysis

FLORA GOVONE*, ALESSANDRO VACCA*, ELISA RUBINO*, ANNALISA GAI, SILVIA BOSCHI, SALVATORE GENTILE, LAURA ORSI, LORENZO PINESSI & INNOCENZO RAINERO Neurology I, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, Italy

Abstract Several studies have evaluated the association between APOE gene polymorphisms and the risk for amyotrophic lateral sclerosis (ALS), with inconclusive results. The aim of our study was to further define the risk associated with carriage of the APOE alleles and development and clinical characteristics of ALS. We performed a comprehensive meta-analysis of all existing studies investigating the association between the APOE gene and ALS published up to September 2013, comprising a total of 4249 ALS patients and 10,397 controls. Pooled odds ratios (OR) were estimated using the random effect (RE) model. Results showed that the carriage of different APOE alleles had no effect on disease risk. In particular, the ε4 allele was not associated with a significantly increased disease risk (ε4 carriers vs. non-ε4 carriers: RE OR 1.18; 95% CI 0.91–1.53). In conclusion, our study suggests that the APOE gene does not have a significant effect in ALS aetiopathogenesis. Key words: Amyotrophic lateral sclerosis, APOE, gene, polymorphism, meta-analysis

Introduction Amyotrophic lateral sclerosis (ALS) is a severe, disabling disorder in which both upper and lower motor neurons degenerate, leading to a progressive muscular palsy. Death occurs within 1–5 years after disease onset, with a poorer survival rate in patients with bulbar-onset ALS compared to limb-onset ALS (1). Like other age related neurodegenerative diseases, ALS is now considered a complex disease, resulting from the interaction of several genes with poorly investigated developmental, environmental, and age related risk factors (2). Intriguingly, recent studies have shown that ALS lies on a clinical, pathological and genetic continuum with frontotemporal lobar degeneration (FTLD) (3–5). Executive dysfunction, apathy, and deficits in social cognition can be seen in patients primarily diagnosed with ALS, while approximately 30% of FTLD patients develops signs and symptoms of motor neuron disease (6,7). These two entities share a common pathological background with cytoplasmic inclusions of the ubiquitinated protein TDP-43

(8). Finally, a wide spectrum of genes has been found to be associated with both ALS and FTLD (9–12). The apolipoprotein E (APOE) gene is located on chromosome 19q13.2 and codifies for a polymorphic protein, a product of allele ε2, ε3 and ε4, that performs complex functions within the central nervous system (13–16). APOE ε4 allele is a wellknown risk factor for Alzheimer’s disease (17). In addition, APOE has also been associated with several other neurodegenerative diseases, including cerebral amyloid angiopathy (18), Lewy body dementia (19), and FTLD (20). In a recent meta-analysis investigating the role of the APOE gene in FTLD, we found a significant association between APOE ε4 allele and the disease, with a relevant gene-dosage effect (21). A role for APOE in ALS aetiopathogenesis has been investigated by several researchers, with inconclusive results. In transgenic mice carrying a familial ALS-linked superoxide dismutase-1 (G93A-SOD1) mutation, the increase in ApoE expression closely correlated with neuronal degeneration (22). In humans, association studies provided contradictory

*These authors contributed equally. Correspondence: I. Rainero, Neurology I, Department of Neuroscience, University of Turin, Via Cherasco 15 – 10126 Turin, Italy. Fax:  39 011 6638510. E-mail: [email protected] (Received 2 February 2014 ; accepted 21 April 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.918149

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F. Govone et al. able data, published either as full-length articles or letters in peer-reviewed journals, were included. Six studies did not declare the clinical or electronic criteria used for ALS diagnosis, whereas eight studies used El Escorial or El Escorial-revised criteria (27,28).

results, with some authors revealing a significant association between the carriage of APOE ε4 allele and the risk for bulbar-onset ALS, and others finding no association (23,24). Much of this disagreement is probably related to the use of relatively small studies with low statistical power. Finally, studies examining the role of the APOE gene polymorphisms on the clinical course of the disease provided also conflicting results (25,26). To further define the disease risk associated with the carriage of the APOE alleles, we performed a meta-analysis of all existing studies that evaluated allelic and genotypic frequencies of this polymorphism in patients with ALS published up to September 2013.

Data extraction and quality assessment Two investigators (AV and FG) extracted data independently and in duplicate. We obtained from each study the following data: authors, journal, year of publication, ethnicity of study population, genotyping method, allelic and genotypic frequencies of polymorphism, diagnosis of subgroups, number of patients and control subjects, age, and gender. When allelic frequencies were lacking, we calculated them using genetic standard formulae.

Methods Study selection We identified suitable studies with a literature database search (PubMed, Web of Science, Ovid, SciVerse, Science Direct, Scopus, BioMed Central) for all publications about the APOE genotype and ALS up to September 2013. Search index terms used were: APOE, apolipoprotein E in combination with ALS, amyotrophic lateral sclerosis, MND, motor neuron disease. In addition, a manual search of references cited in the retrieved articles was performed. All case-control studies with extract-

Statistical analysis Statistical analysis was carried out using Comprehensive Meta-Analysis Version 2.2.064 (Biostat, Englewood, NJ, USA) (29). The random effect (RE) model was used to calculate the pooled odds ratios (OR), according to meta-analyses guidelines in case of high heterogeneity between studies (30). To assess publication biases we used Egger’s test and Kendall’s tau with continuity test. The effect size of the different APOE alleles on the risk of developing ALS was

Table I. Clinical characteristics of the populations included in the meta-analysis. ALS

Study

Year

Mui Praline Jawaid Steenland Schmidt Zetterberg Siddique

1995 2010 2010 2010 2010 2008 1998

Country

n

M%

Age mean  SD

USA (MA) 72 – – France 1482 57,1 – USA (TX) 852 – – USA (GA) 64 54,3 65,7 USA (NC) 417 – Sweden 60 54,4* from 33 to 87* USA (IL) 363 62 52,9  13,9 (age at onset) Al-Chalabi 1996 UK 123 60,2 54 (age at onset) Moulard 1996 France 130 51,5 60,5  11 (age at onset) Gaillard

1998 France

32

Lacomblez 2002 France

403

Galasko

2002 Guam

Drory Bachus

56,2 from 42 to 76 58,3 57,1  12,9

9

40

2001 Israel

100

53

1997 Germany

151

52

59,7  10,4 (mean age) 57  12 –

Controls Diagnostic criteria

– El Escorial El Escorial SCDC El Escorial El Escorial SCDC

2000 1994 1994 1994



Bulbar Limb onset onset

M%

1209 – 955 – 7215 – 571 37,7 482 – 1265 – 351 54,7  13,3

Age mean  SD

– 464 – – – – 95

– 1018 – – – – 268

33

90

121





77

514 #





El Escorial 1994



n

161 # – 99 from 15 to 82 1091 –

– – – 60,6 – – 54

– 52,5





El Escorial Revisited 1998 SCDC

96

307





403





El Escorial Revisited 1998 –

24

76

133

70  12







1323 46,5  20





SCDC: standard clinical diagnostic criteria. *Data relative to a population of 79 ALS patients, of wich we included in our meta-analysis just 60 patients with ApoE status. # Moulard used two control groups (ECTIM 514 controls and CEPH 161 controls); we included in our meta-analisys just ECTIM controls in the fi rst comparison to avoid samples overlapping, while all controls in the subsequent subgroups analysis limb vs. bulbar onset.

APOE gene polymorphisms and ALS

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Table II. Odds ratio and heterogeneity results for apolipoprotein E polymorphism in patients with ALS vs. control subjects.

Studies, n

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Comparisons Alleles ε 2 vs. ε 3 Alleles ε4 vs. ε 3 Alleles ε 2 vs. ε4 ε 2 carriers vs. non- ε 2 carriers ε4 carriers vs. non- ε4 carriers ε 2 ε 2 vs. ε 3 ε 3 ε 2 ε 2  ε 2 ε 3 vs. ε 3 ε 3 ε4 ε4 vs. ε 3 ε 3 ε 3 ε4 vs. ε 3 ε 3 ε 3 ε4  ε4 ε4 vs. ε 3 ε 3 ε 2 ε 2 vs. ε4 ε4

9 9 9 8 13 7 8 8 8 8 7

df Q

Subjects, n

Effect size and 95% CI

ALS Control patients Subjects

Random effects OR (95% CI)

z-value

0.95 (0.77–1.18) 0.95 (0.80 –1.13) 1.03 (0.88 –1.20) 1.16 (0.81–1.66) 1.18 (0.91–1.53) 0.91 (0.44 –1.87) 0.95 (0.75 –1.20) 0.88 (0.47–1.67) 0.97 (0.87–1.10) 0.94 (0.84 –1.05) 1.30 (0.56 –3.01)

0.44 0.56 0.36 0.79 1.23 0.26 0.44 0.38 0.44 1.07 0.61

8 8 8 7 12 6 7 7 7 7 6

6052 6431 1333 3448 4249 2246 2643 2288 2929 2981 66

12270 13107 2915 7898 10397 4210 4998 4347 5526 5698 207

expressed for each study in terms of OR and 95% confidence interval (CI). Results We found 33 articles with electronic database search, and two additional articles with manual search of the retrieved articles. Data from 14 articles met the inclusion criteria (23–26,31–40). Table I summarizes the clinical characteristics of the populations included in our meta-analysis. In the first analysis we included 13 case-control studies comparing allelic information about carrying or not carrying the ε4 allele in ALS patients and control subjects (23–26,31–35,37–40). These studies included 4249 ALS patients and 10,558 control subjects genotyped for APOE. After taking into account duplication of controls because of overlapping samples (38,39), the population included in this first analysis comprised 10,397 healthy individuals. In the second analysis we compared genotypic distribution of all APOE alleles in patients and controls, using data provided by nine studies (24,25,31,33–36,38,39). Finally, we performed a subgroup analysis using five studies (23,26,31,37,39) to determine if there was an association between ε4 allele and risk of limb-onset or bulbar-onset ALS. The genotypic distribution in control subjects was in Hardy-Weinberg equilibrium in all studies, except for the study by Schmidt et al. (33), in which the Hardy-Weinberg χ2 p-value was 0.047.

Test of null (two-tail)

Heterogeneity

p- value Q-value p -value 0.66 0.58 0.72 0.43 0.22 0.79 0.66 0.70 0.66 0.28 0.54

16.17 18.15 5.69 40.29 74.53 5.61 13.93 22.06 4.20 5.93 6.39

0.04 0.02 0.67 0.00 0.00 0.47 0.05 0.00 0.76 0.55 0.38

I2 50.52 55.92 0.00 82.63 83.90 0.00 49.74 68.27 0.00 0.00 6.09

Tables II and III show the OR and heterogeneity results for APOE polymorphisms in patients with ALS versus control subjects. We found no significant difference when comparing ε4 vs. non-ε4 carriers in ALS patients and controls (RE OR 1.18; 95% CI 0.91–1.53; p  0.22; I2 83.90%) (Figure 1). There was no association between carrying an ε2 allele and the risk of developing ALS, compared with the ε3 allele (RE OR 0.95; 95% CI 0.77–1.18; p  0.66; I2 50.52). Also, when comparing the ε4 allele vs. the ε3 allele, the pooled OR was not significant (OR 0.95; 95% CI 0.80–1.13; p  0.58; I2 55.92%). When we compared the ε2 allele vs. the ε4 allele, the pooled OR was not significant (RE OR 1.03; 95% CI 0.88–1.20; p  0.72; I2 0%). Comparing ε2 carriers vs. non-ε2 carriers, the pooled RE OR was 1.16 (95% CI 0.81–1.66; p  0.43; I2 82.63%). In the genotype comparisons using ε3ε3 as reference genotype there was also no difference between ALS patients and controls. In particular, the genotype comparisons between ε2ε2 vs. ε3ε3 and ε2ε2-ε2ε3 vs. ε3ε3 showed no difference. During the comparison between subjects with the ε3ε4 genotype vs. the ε3ε3 genotype, the pooled RE OR was 0.98 (95% CI 0.87–1.10; p  0.66; I2 0%). When we compared ε4ε4 vs. ε3ε3, the RE OR was not significant (RE OR 0.88; 95% CI 0.47–1.67; p  0.70; I2 68.27%). When comparing ε3ε4  ε4ε4 vs. ε3ε3, the OR was 0.94 (95% CI 0.84–1.05; p  0.28; I2 0%).

Table III. Odds ratio and heterogeneity results for apolipoprotein E ε4 carriers vs. non- ε4 carriers in patients with bulbar-onset ALS, limb-onset ALS and control subjects.

Comparison ε4 carriers vs. non- ε4 carriers Limb vs. bulbar onset Limb onset vs. controls Bulbar onset vs. controls

Subjects, n

Effect size and 95% CI

Test of null (two-tail)

Studies, n

df, Q

ALS patients

Control subjects

Random effects OR (95% CI)

z- value

4 4 5

3 3 4

645 1453 669

1453 2102 2202

1.52 (0.87–2.63) 0.88 (0.64 –1.20) 1.25 (0.91–1.71)

1.48 0.81 1.37

Heterogeneity

p- value

Q-value

p-value

I2

0.14 0.42 0.17

10.30 6.31 6.34

0.02 0.10 0.18

70.87 52.47 36.90

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F. Govone et al.

Figure 1. Forest plot of estimated odds ratio for apolipoprotein E (APOE) ε4 allele carriers in patients with ALS.

Subsequently, we performed the subgroups analysis: we compared the number of ε4 carriers in limb-onset patients vs. controls using four studies (23,31,37,39) involving 1453 patients and 2102 healthy subjects. The calculated RE OR was not significant (RE OR 0.88; 95% CI 0.64–1.20; p  0.42); ε4 frequency in bulbar ALS patients resulted not significantly different compared with controls (669 patients and 2202 controls) (23,26,31,37,39): RE OR was 1.25 (95% CI 0.91–1.71; p  0.17). The comparison between patients with bulbar vs. limb onset OR also resulted not significant (23,31,37,39) (RE OR 1.52; 95% CI 0.87–2.63; p  0.14). Graphical analysis of the funnel plot (Figure 2) did not provide evidence for selection and publication bias. Furthermore, there was no significant publication bias as evidenced by the Egger’s test

(t-value 2.06, p two-tailed 0.06). Both the I2 statistic and the Q-value highlighted a high percentage of heterogeneity for most of the comparisons between ALS patients and control subjects. Discussion In this comprehensive meta-analysis, the APOE gene polymorphisms did not show a significant association with amyotrophic lateral sclerosis. Multiple comparisons showed that the carriage of different alleles or genotype had no significant effect on disease risk and did not modify the examined clinical characteristics. Taken together, our data do not support a role for APOE in ALS aetiopathogenesis. The results of our study are in accord with recent genome-wide studies that, providing new insight into the genetic structure

Figure 2. Funnel plot of Standard Error of comparison of E4 carriers vs. non-E4 carriers to determine publication bias. MH log odds ratio: Mantel-Haenszel log odds ratio.

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APOE gene polymorphisms and ALS of ALS, excluded that variation in the APOE gene may contribute to disease risk (41,42). There are some limitations to our study. First, the present meta-analysis was performed on a large number of small sample-sized studies. There is evidence in literature that the magnitude of the genetic effect differs significantly in larger versus smaller studies (43). Secondly, in 2000, the El-Escorial diagnostic criteria for ALS were revised; as a consequence, the diagnostic criteria of the disease differ between older and more recent studies. Finally, publication bias may explain the lack of association between APOE gene polymorphisms and ALS. The results of our study do not rule out a role for APOE gene polymorphisms in the development of cognitive impairment in amyotrophic lateral sclerosis. The carriage of APOE ε4 allele is now considered a genetic risk factor for cognitive impairment in several neurodegenerative disorders. Intriguingly, Vossel et al. recently reported the case of two siblings with C9orf72-linked familial FTLD-ALS. One patient was an APOE e4 homozygote and the other an ε3 homozygote (44). The former presented worse cognitive-behavioural symptoms and more severe cortical atrophy. These findings are consistent with a worse cortical pathology in ALS patients carrying one or two copies of the APOE ε4 allele. Furthermore, a syndromic heterogeneity, even within the same family, is common in patients with FTLD-MND, in particular when carrying the C9orf72 expansion. Investigating the APOE gene in FTLD, we found a significant association between APOE ε4 allele and the disease, with a relevant gene-dosage effect (21). These findings suggest that APOE may play a role, as cofactor, in the phenotypic expression of the FTLD-MND spectrum of disease. Unfortunately, the studies involved in the meta-analysis did not distinguish ALS patients with or without cognitive impairment, since the majority of the studies included in the present meta-analysis were realized before the mid-2000s, in a period in which less relevance was given to cognitive symptoms in ALS. In future, it could be of interest to analyse the influence of APOE ε4 on the cognitive impairment and neurodegeneration severity in patients with ALS. In the literature, cognitively impaired ALS patients have shorter survival than cognitively normal ALS patients (45) and, as suggested also by other authors, APOE ε4 could influence brain pathology and consequently the survival effect, aggravating TDP-43 pathology by forming toxic apoE-TDP-43 complexes or impairing cells survival through unknown mechanisms. In conclusion, our study provides additional evidence that the APOE gene is not a major genetic risk factor for ALS. However, possible involvement of this gene in the development of cognitive symptoms during the course of this devastating disease deserves further studies.

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Lack of association between APOE gene polymorphisms and amyotrophic lateral sclerosis: a comprehensive meta-analysis.

Several studies have evaluated the association between APOE gene polymorphisms and the risk for amyotrophic lateral sclerosis (ALS), with inconclusive...
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