Association of ALS with head injury, cigarette smoking and APOE genotypes

https://doi.org/10.1016/j.jns.2010.01.011Get rights and content

Abstract

Objective

An increased risk of ALS has been reported for US veterans, but the cause is unknown. Since head injury and cigarette smoking are two previously implicated environmental risk factors that are more common in military than civilian study populations, we tested their association with ALS in a US veteran study population.

Methods

We used logistic regression to examine the association of ALS with head injury and cigarette smoking in 241 incident cases and 597 controls. Since APOE is a plausible ALS candidate gene, we also tested its main effect and its statistical interaction with these environmental exposures.

Results

Cigarette smoking was not associated with ALS in this predominantly male and Caucasian population. Veterans who had experienced head injuries during the last 15 years before the reference date had an adjusted odds ratio of 2.33 (95% confidence interval 1.18–4.61), relative to veterans without any head injuries. This association was strongest in APOE-4 carriers.

Conclusions

Our results add to the body of evidence suggesting that head injuries may be a risk factor for multiple neurodegenerative diseases, including ALS. We hypothesize that the strength of association between head injuries and ALS may depend upon APOE genotype.

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)

  • E.D. Haasdijk et al.

    Increased apolipoprotein E expression correlates with the onset of neuronal degeneration in the spinal cord of G93A-SOD1 mice

    Neurosci Lett

    (Dec 19 2002)
  • V. McGuire et al.

    Incidence of Amyotrophic Lateral Sclerosis in three counties in western Washington state

    Neurology

    (1996)
  • B.J. Traynor et al.

    Incidence and prevalence of ALS in Ireland, 1995–1997: a population-based study

    Neurology

    (Feb 1999)
  • F. Kamel et al.

    Association of cigarette smoking with amyotrophic lateral sclerosis

    Neuroepidemiology

    (1999)
  • L.M. Nelson et al.

    Population-based case–control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption

    Am J Epidemiol

    (Jan 15 2000)
  • M.G. Weisskopf et al.

    Prospective study of cigarette smoking and amyotrophic lateral sclerosis

    Am J Epidemiol

    (Jul 1 2004)
  • A.M. Campbell et al.

    Motor neurone disease and exposure to lead

    J Neurol Neurosurg Psychiatry

    (Dec 1970)
  • C. Armon et al.

    Epidemiologic correlates of sporadic amyotrophic lateral sclerosis

    Neurology

    (Jul 1991)
  • A.M. Chancellor et al.

    Risk factors for motor neuron disease: a case–control study based on patients from the Scottish Motor Neuron Disease Register

    J Neurol Neurosurg Psychiatry

    (Nov 1993)
  • V. McGuire et al.

    Occupational exposures and amyotrophic lateral sclerosis. A population-based case–control study

    Am J Epidemiol

    (Jun 15 1997)
  • F. Kamel et al.

    Lead exposure and amyotrophic lateral sclerosis

    Epidemiology

    (May 2002)
  • M.T. Felmus et al.

    Antecedent events in amyotrophic lateral sclerosis

    Neurology

    (Feb 1976)
  • R. Pierce-Ruhland et al.

    Repeat study of antecedent events in motor neuron disease

    Ann Clin Res

    (Apr 1981)
  • L.S. Gresham et al.

    Amyotrophic lateral sclerosis and occupational heavy metal exposure: a case–control study

    Neuroepidemiology

    (1986)
  • D.M. Deapen et al.

    A case–control study of amyotrophic lateral sclerosis

    Am J Epidemiol

    (May 1986)
  • G. Savettieri et al.

    A case–control study of amyotrophic lateral sclerosis

    Neuroepidemiology

    (1991)
  • W.T. Longstreth et al.

    Risk of amyotrophic lateral sclerosis and history of physical activity: a population-based case–control study

    Arch Neurol

    (Feb 1998)
  • A. Chio et al.

    Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players

    Brain

    (Mar 2005)
  • S. Belli et al.

    Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease?

    Eur J Epidemiol

    (2005)
  • N. Scarmeas et al.

    Premorbid weight, body mass, and varsity athletics in ALS

    Neurology

    (Sep 10 2002)
  • K. Kondo et al.

    Case–control studies of motor neuron disease: association with mechanical injuries

    Arch Neurol

    (Apr 1981)
  • H. Chen et al.

    Head injury and amyotrophic lateral sclerosis

    Am J Epidemiol

    (Oct 1 2007)
  • A. Binazzi et al.

    An exploratory case–control study on spinal and bulbar forms of amyotrophic lateral sclerosis in the province of Rome

    Amyotroph Lateral Scler

    (Sep 2008)
  • R.D. Horner et al.

    Occurrence of amyotrophic lateral sclerosis among Gulf War veterans

    Neurology

    (Sep 23 2003)
  • R.W. Haley

    Excess incidence of ALS in young Gulf War veterans

    Neurology

    (Sep 23 2003)
  • Cited by (97)

    • Thoracic trauma promotes alpha-Synuclein oligomerization in murine Parkinson's disease

      2022, Neurobiology of Disease
      Citation 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 Behavior
      Citation 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 Immunity
      Citation 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.

    View all citing articles on Scopus
    1

    Present address: Institute for Medical Informatics and Statistics, Christian-Albrechts University, Kiel, Germany.

    View full text