C77 AN INTRODUCTION TO COMPLEX GENETICS: PITFALLS IN IDENTIFYING DISEASE SUSCEPTIBILITY IN SPORADIC POPULATIONS
Merikangas K
No abstract available.
C78 EPIDEMIOLOGY AND ETHNIC DIVERSITY IN ALS
Hardiman O
Department of Neurology, Beaumont Hospital, Dublin, Ireland
E‐mail address for correspondence: [email protected]
It is generally stated that the incidence of ALS is the same throughout the world; however, there have been no well‐conducted comparative studies of ALS occurrence among different populations, ethnic groups or defined geographic areas. Epidemiological studies in regions that comprise non‐Europeans have generally yielded lower figures. An ethnic difference in susceptibility to ALS has been invoked to explain the low rate of ALS in Mexico, but restricted access to medical care among lower socio‐economic groups may also account for this finding. Similarly, small epidemiological studies in Rochester county, Minnesota, have reported variation in the presentation of ALS in different ethnic groups. More recently, Kasarskis et al. demonstrated a risk ratio for ALS of 0.61 in Blacks vs. Whites, and of 2.08 for Hispanics, Asians and Others vs. Whites, in a cohort drawn from veterans of the first Gulf war. Population‐based epidemiological studies from Asia are limited.
Mortality studies also suggest differences based on ethnicity. A study of mortality from ALS revealed lower rates among UK immigrants from the Indian subcontinent, the Caribbean, and Africa compared with the general population in England. More recent mortality data from the southern US also suggests a lower incidence of ALS in African‐Americans.
ALS is increasingly recognized as a complex genetic disease. Variations in phenotype have long been recognized, some of which correlate with specific Mendelian mediated genotypes (e.g. the autosomal recessive Scandinavian D90A mutation in SOD1). It is therefore likely that ethnic background may be important in determining the relationship between environmental risk factors and genetic susceptibility. The conflicting reports of the relative risks of various susceptibility genes including ApoE4, VEGF, SMN1 etc. may in part be due to population‐based differences. Indeed, the carrier frequency of SMN1 differs considerably among different ethnic groups, as evidenced by a recent population‐based study in Cuba.
However, it does not always follow that genetic factors necessarily underlie variations in risk between ethnic groups. Studies in Guam have implicated both genetic and environmental factors that may underlie the high risk in this group.
The definitive strategy for distinguishing genetic and environmental explanations for ethnic differences in disease risk is to study populations where there has been admixture between low‐risk and high‐risk groups.
A population‐based epidemiological study of ALS is ongoing in Cuba. The Cuban population is ethnically diverse and genetically admixed. Access to healthcare in Cuba is universal, and population‐based epidemiology is feasible as a result. Using a panel of recently developed ethnicity specific polymorphic markers it will be possible to test the hypothesis that ALS occurs less frequently in populations of African ancestry than in those of European (mainly Spanish) ancestry.
If the epidemiological observations are correct that ALS is less common in those of African descent, modern bioinformatics technology can be used to identify both ‘at risk’ and ‘protective’ genotypes that will help to elucidate disease pathogenesis.
C79 DIFFERENT DOWN UNDER? MOTOR NEURON DISEASE IN THE SOUTHERN HEMISPHERE
Pamphlett R
The University of Sydney, Sydney, Australia
E‐mail address for correspondence: [email protected]
Background: Studies of large numbers of people with MND have so far been restricted to the northern hemisphere. Epidemiological studies of disorders such as schizophrenia suggest that environmental influences on diseases can differ between the hemispheres. On the other hand, southern hemisphere data can be useful to support that of northern hemisphere studies. An island continent such as Australia is an ideal site to look for environmental factors underlying MND.
Objectives: To set up a database in Australia to enable a southern hemisphere study of environmental and genetic factors in sporadic MND.
Methods: An epidemiological and DNA database for MND was set up in Australia in 2000. Cases are recruited via motor neuron disease associations in all mainland states of Australia. The investigator travels to each state capital on a regular basis to collect blood samples from subjects. Controls are spouses, friends and relatives of MND cases. All subjects complete an eight‐page questionnaire which includes items such as ethnicity, lifetime residences and travel, employment, exposure to chemical or toxins, injuries and personal habits.
Results: So far over 900 subjects have given questionnaire data and blood samples to the Bank. One‐third have MND (70% with ALS) and two‐thirds are controls. Risk factors we are examining are parental age and number of siblings (no difference), season of birth (no difference), pesticide exposure (slightly increased in ALS) and subject and parent smoking (in progress). We have undertaken case‐control association studies on susceptibility genes for heavy metals (metallothioneins) (1), enteroviral infection (the poliovirus and other enteroviral receptors) and organophosphate toxicity (paraoxonase). The poliovirus receptor (2) and paraoxonase genes show differences in functional polymorphisms in ALS, suggesting that susceptibilities to viruses or toxins could underlie some cases.
Discussion and conclusion: This is the first epidemiological and DNA Bank in the southern hemisphere, and the first to cover an entire continent. The Bank holds the potential to uncover environmental risk factors and to look for gene‐environment interactions in MND.
References
- Morahan J, Trent RJ, Yu B, et al. Screening the metallothionein III gene in sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005, in press.
- Saunderson R, Yu B, Trent RJ, et al. A polymorphism in the poliovirus receptor gene differs in motor neuron disease. NeuroReport 2004;15:383–6.
C80 STRUCTURED INTERVIEW FOR GENETIC AND ENVIRONMENTAL RISK FACTORS IN ALS AND ITS TEST‐RETEST RELIABILITY EVALUATION
Mitsumoto H, Hillyer G, Andrews H, Thankachan A, Cruz L, Andrews L, Kaufmann P, Gordon P, Factor‐Litvac P & Ottman R
Columbia University, New York, USA
E‐mail address for correspondence: [email protected]
Background: In ALS, accurate identification of environmental exposures based on recall is a difficult but crucial methodological issue. In‐person interview is the gold standard in environmental epidemiology, but can be expensive, limits access to cases, and possibly reduces participation rates. Development of a reliable structured interview that can be administered by telephone, could improve efficiency and maximize participation rates in future studies.
Objectives: The first objective was to develop a structured interview for identifying environmental exposures and family history of neurological disorders in patients with ALS. The second objective was to evaluate the test‐retest reliability of the instrument, and specifically to assess agreement between in‐person and telephone interviews.
Methods: A structured interview instrument was developed based on literature review, a consensus obtained at an international advisory board meeting (held in February 2004), our previous experience in ALS epidemiology, and input from an environmental hygienist (LA). Test‐retest reliability was assessed by administering two interviews to each of 30 randomly selected patients with ALS from a tertiary referral center and 30 controls (mostly family members). Each subject was assigned to one of three interview modalities: in‐person to in‐person, in‐person to telephone or reversed, and telephone to telephone. First and second interviews were performed within two weeks. Kappa (a measure of agreement with desirable properties) was calculated for each interview item.
Results: The major interview domains consisted of: disease information and demographics (30 items); family composition (63); family medical history (152); lifetime residential history (29); lifetime occupational history (85); military service (54); hobbies and leisure time activities (108); lifetime exercise and sports activity (53); and tobacco and alcohol (25). The duration of the entire interview averaged approximately 2 h (range 1–3 h). The number of case‐control pairs assigned to each interview modality was 3 for in‐person to in‐person, 10 for in‐person to telephone, 10 for telephone to in‐person, and 7 for telephone to telephone. Kappas were greater than 0.8 for most items, but were lower for some exercise items before the age of 17 years, as well as for detailed residential and occupational recalls. These sections of the interview have been streamlined based on this experience. Kappas for pairs involving a telephone and an in‐person interview were not substantially lower than for other pairs. Kappas for cases did not differ markedly from those for controls.
Discussion and conclusions: These results indicate good test‐retest reliability for most items included in the instrument, suggesting that it will be useful for future epidemiologic studies. The good agreement between in‐person and telephone interviews suggests that telephone administration of this interview can be used in future epidemiologic studies in ALS.
Acknowledgement
We gratefully acknowledge the generous support from MDA Research Grant and the MDA Wings Over Wall Street Fund.