Association of ALS with head injury, cigarette smoking and APOE genotypes
Introduction
Amyotrophic lateral sclerosis (ALS) is a late-onset degenerative disease of the upper and lower motor neurons in the cortex, brain stem and spinal cord, which leads to progressive muscle weakness and is usually fatal. The incidence of ALS is 20–60% higher in men than women [1], [2]. The etiology of sporadic ALS, which accounts for 90–95% of all patients, is poorly understood and believed to involve a complex interplay of genetic and environmental risk factors. Environmental factors that have previously been associated with ALS risk include cigarette smoking [3], [4], [5], exposure to heavy metals [6], [7], [8], [9], [10], [11], [12], [13] and pesticides [9], [14], [15], intensive physical activity [16], [17], [18], [19] and head injuries [14], [20], [21], [22]. A prospective study based on ALS mortality data found that an association with cigarette smoking was restricted to women [5]. Most of these factors have not been consistently implicated, but show variation in results across different studies. This highlights the need for both individual studies with larger sample size, and for pooled or meta-analyses that combine results from multiple studies. Following reports of a potentially increased risk of ALS in US veterans [23], [24], [25], we are currently conducting a case–control study called GENEVA (Genes and Environmental Exposures in Veterans with ALS) [26]. The GENEVA cases are a subset of veterans enrolled into the “National Registry of Veterans with ALS” [27], who are compared to a sample of veteran controls. Here, we present results of an association analysis of ALS with two particular environmental exposures that are more common in military than civilian populations, and hence may contribute to an elevated risk of ALS in veterans: head injury and cigarette smoking. Common molecular pathways, which may be triggered by shared genetic and/or environmental contributions, are suspected to underlie multiple neurodegenerative disorders, and these particular two environmental factors have also been implicated in Alzheimer's (AD) and Parkinson's disease (PD). We note that the direction of the association between cigarette smoking and PD is opposite of that for AD and ALS [28].
In addition to examining the main effects of head injury and cigarette smoking, we also evaluated a specific candidate gene and its potential interaction with these environmental exposures. We selected the apolipoprotein E (APOE) gene because it has been examined in many previous genetic studies of ALS and other neurodegenerative diseases, both independently and in conjunction with head injury. It is well known that the APOE-4 (ε4) allele is a strong risk factor for AD [29]. Although the evidence for an association between AD and head injury is weaker, several studies have suggested that this association may be stronger in carriers of the APOE-4 allele [30], [31], [32]. Compared to AD, reports of the relationship between the APOE gene and either PD or ALS have been less consistent. Carriers of the APOE-4 allele may have an earlier age at onset of Parkinson's disease [33], and possibly a worse prognosis following an ALS diagnosis [34], [35], [36], [37]. In light of the extensive previous work, we examined the association between ALS and APOE genotypes in our study population, and tested whether APOE genotypes modify the association between ALS and head injury and/or cigarette smoking. In the following sections, we present the results of three sets of statistical analyses: (i) estimating the association of ALS with environmental exposures (head injury and cigarette smoking); (ii) estimating the association of ALS with APOE genotypes; (iii) conducting tests of interaction between APOE and these environmental risk factors.
Section snippets
Study population
As described previously, the “National Registry of Veterans with ALS” used both active and passive recruitment methods to enroll and review medical records of 2122 US veterans between April 2003 and September 2007 [27]. Active recruitment methods (refusal rate ∼ 6.5%) involved periodic searches of VA inpatient and outpatient databases for an ICD-9 (International Classification of Diseases, 9th Revision, Clinical Modification) code of 335.2X (motor neuron diseases). Passive recruitment was based
Clinical, demographic and exposure frequency information
Clinical and demographic information for the participants who completed the GENEVA study interview are shown in Table 1. The diagnostic distribution and the median time between symptom onset and diagnosis were very similar in the larger dataset of cases for whom APOE genotypes were available (n = 417; data not shown). The median survival from diagnosis in these genotyped cases was 19 months, slightly shorter than the 22 months for those who were also interviewed (Table 1). The latter result is
Discussion
Our predominantly male and Caucasian study population of US veterans has a higher head injury and smoking prevalence than comparable civilian cohorts and a larger sample size than most previous studies of ALS and environmental risk factors. In this population, we did not detect any evidence for an association between ALS and various measures of cigarette smoking. Since our dataset had 80% power (at α = 0.05) to detect an OR of 1.6 for an exposure prevalence of 64.2%, it is unlikely that the
Acknowledgements
We are grateful to the many ALS patients and controls who have generously given their time to participate in this research. We would like to thank the GENEVA study team (Valerie Loiacono, Catherine Stanwyck, Christina Williams, and Kristina Nord) and the ALS registry staff (Barbara Norman, Lisa DiMartino, Karen Juntilla, Laurie Marbrey, Beverly McCraw, Honore Rowe, and Priscilla Webster Williams) for their recruitment efforts and their sustained dedication to the study; Heidi Munger for
References (71)
- et al.
Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases
Mutat Res
(2009) - et al.
Association of apolipoprotein E ε4 allele with bulbar-onset motor neuron disease
Lancet
(1996) - et al.
Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis
J Neurol Sci
(Aug 1996) - et al.
Apolipoprotein E epsilon 4 in bulbar-onset motor neuron disease
Lancet
(Aug 3 1996) El Escorial World Federation of Neurology Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” Workshop Contributors
J Neurol Sci
(1994 Jul)- et al.
The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III)
J Neurol Sci
(Oct 31 1999) - et al.
Millennium cohort: enrollment begins a 21-year contribution to understanding the impact of military service
J Clin Epidemiol
(Feb 2007) - et al.
Amyotrophic lateral sclerosis and soccer: a different epidemiological approach strengthen the previous findings
J Neurol Sci
(Jun 15 2008) - et al.
Neurotrauma/neurodegeneration and mitochondrial dysfunction
Prog Brain Res
(2002) - et al.
Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury
Neuroscience
(Apr 10 2009)
Increased apolipoprotein E expression correlates with the onset of neuronal degeneration in the spinal cord of G93A-SOD1 mice
Neurosci Lett
Incidence of Amyotrophic Lateral Sclerosis in three counties in western Washington state
Neurology
Incidence and prevalence of ALS in Ireland, 1995–1997: a population-based study
Neurology
Association of cigarette smoking with amyotrophic lateral sclerosis
Neuroepidemiology
Population-based case–control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption
Am J Epidemiol
Prospective study of cigarette smoking and amyotrophic lateral sclerosis
Am J Epidemiol
Motor neurone disease and exposure to lead
J Neurol Neurosurg Psychiatry
Epidemiologic correlates of sporadic amyotrophic lateral sclerosis
Neurology
Risk factors for motor neuron disease: a case–control study based on patients from the Scottish Motor Neuron Disease Register
J Neurol Neurosurg Psychiatry
Occupational exposures and amyotrophic lateral sclerosis. A population-based case–control study
Am J Epidemiol
Lead exposure and amyotrophic lateral sclerosis
Epidemiology
Antecedent events in amyotrophic lateral sclerosis
Neurology
Repeat study of antecedent events in motor neuron disease
Ann Clin Res
Amyotrophic lateral sclerosis and occupational heavy metal exposure: a case–control study
Neuroepidemiology
A case–control study of amyotrophic lateral sclerosis
Am J Epidemiol
A case–control study of amyotrophic lateral sclerosis
Neuroepidemiology
Risk of amyotrophic lateral sclerosis and history of physical activity: a population-based case–control study
Arch Neurol
Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players
Brain
Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease?
Eur J Epidemiol
Premorbid weight, body mass, and varsity athletics in ALS
Neurology
Case–control studies of motor neuron disease: association with mechanical injuries
Arch Neurol
Head injury and amyotrophic lateral sclerosis
Am J Epidemiol
An exploratory case–control study on spinal and bulbar forms of amyotrophic lateral sclerosis in the province of Rome
Amyotroph Lateral Scler
Occurrence of amyotrophic lateral sclerosis among Gulf War veterans
Neurology
Excess incidence of ALS in young Gulf War veterans
Neurology
Cited by (97)
Sex biology in amyotrophic lateral sclerosis
2024, Ageing Research ReviewsThoracic trauma promotes alpha-Synuclein oligomerization in murine Parkinson's disease
2022, Neurobiology of DiseaseCitation Excerpt :However, TXT trauma exposed PD mice showed an elevation of asyn oligomers in comparison to sham treated mice, suggesting that peripheral injury influences protein aggregation in the brain of PD mice. A direct link between physical trauma and neurodegeneration has long been discussed and traumatic injuries have been shown to increase the risk of developing neurodegenerative diseases (Fleminger et al., 2003) (Rugbjerg et al., 2008) (Schmidt et al., 2010) (Wang et al., 2015). This link has been reported mainly in the context of traumatic brain injuries for which it has been shown to significantly increase the risk of developing Parkinson's disease (PD) (Jafari et al., 2013).
Inhibition of microRNA-203 protects against traumatic brain injury induced neural damages via suppressing neuronal apoptosis and dementia-related molecues
2021, Physiology and BehaviorCitation Excerpt :So TBI is a potential risk factor for subsequent dementia. Interestingly, a history of TBI has been reported to increase the incidence of Alzheimer's disease (AD) [7] and other neurodegenerative diseases, including Parkinson's disease (PD) [8], amyotrophic lateral cord-sclerosis (ALS) [9] and frontotemporal dementia (FTD) [6]. One histopathological manifestation of AD is the presence of nerve fiber masses containing hyperphosphorylated Tau [10].
The influence of immunological stressors on traumatic brain injury
2018, Brain, Behavior, and ImmunityCitation Excerpt :Depending on the nature and severity of the injury (i.e., focal versus diffuse; mild versus severe), outcomes from TBI range from transient to long-term neurological deficits (e.g., cognitive, emotional, and motor abnormalities) that can involve significant grey and white matter damage (Blennow et al., 2012). TBI is also linked to the later development of other neurological conditions, including posttraumatic epilepsy (Webster et al., 2017), Alzheimer’s disease (AD) (Jellinger, 2004), amyotrophic lateral sclerosis (Chen et al., 2007; Schmidt et al., 2010), and chronic traumatic encephalopathy (McKee et al., 2009, 2015). The brain damage induced by TBI is generally categorized as being caused by either primary or secondary injury mechanisms.
- 1
Present address: Institute for Medical Informatics and Statistics, Christian-Albrechts University, Kiel, Germany.