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Adverse drug effects in elderly people -- a disparity between clinical examination and adverse effects self-reported by the patient.

https://arctichealth.org/en/permalink/ahliterature164731
Source
Eur J Clin Pharmacol. 2007 May;63(5):509-15
Publication Type
Article
Date
May-2007
Author
Pasi Lampela
Sirpa Hartikainen
Raimo Sulkava
Risto Huupponen
Author Affiliation
Department of Pharmacology and Toxicology, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland. Pasi.Lampela@uku.fi
Source
Eur J Clin Pharmacol. 2007 May;63(5):509-15
Date
May-2007
Language
English
Publication Type
Article
Keywords
Adverse Drug Reaction Reporting Systems - statistics & numerical data
Aged
Aged, 80 and over
Data Collection - methods
Drug-Related Side Effects and Adverse Reactions
Female
Finland
Geriatric Assessment - methods
Humans
Male
Physicians - statistics & numerical data
Polypharmacy
Reproducibility of Results
Abstract
The trend towards polypharmacy is increasing among the elderly, and associated with this trend is an increased risk of adverse drug effects and drug-drug interactions. Our objective was to assess whether drug adverse effects reported by patients are in general agreement with those identified by a physician.
We evaluated the medication of 404 randomly selected individuals aged 75 years or older by means of interviews carried out by trained nurses and examinations conducted by a physician. The medication used by these patients was recorded prior to the physician's examination and modified thereafter if considered appropriate. Adverse effects noted by the physician were compared to those self-reported by the patients.
Almost all of the patients (98.8%) were using at least one drug, and the mean total number of drugs used was 6.5. Adverse effects were self-reported by 11.4% of the patients, whereas the physician observed apparent adverse drug effects in 24.0% of the patients. No adverse effects were reported in 53.2% of the patients. There were only seven patients that had adverse effects that were both self-reported and identified by the physician, and only four of these patients reported the same adverse effect that had been identified by the physician.
There was a great disparity between the adverse effects identified by the physician and those reported by the patients themselves. Based on our results, it would appear that elderly people tend to neglect adverse drug effects and may consider them to be an unavoidable part of normal ageing. Therefore, physicians should enquire about possible adverse effects even though elderly patients may not complain of any drug-related problems.
Notes
Comment In: Eur J Clin Pharmacol. 2007 Oct;63(10):979-80; author reply 98117618426
PubMed ID
17351768 View in PubMed
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Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population.

https://arctichealth.org/en/permalink/ahliterature119431
Source
Neurobiol Aging. 2013 May;34(5):1518.e1-3
Publication Type
Article
Date
May-2013
Author
Mia Kero
Anders Paetau
Tuomo Polvikoski
Maarit Tanskanen
Raimo Sulkava
Lilja Jansson
Liisa Myllykangas
Pentti J Tienari
Author Affiliation
Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
Source
Neurobiol Aging. 2013 May;34(5):1518.e1-3
Date
May-2013
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Aging - metabolism
Amyloid beta-Protein Precursor - genetics
Female
Finland - epidemiology
Humans
Male
Mutation - genetics
Neocortex - physiology
Polymorphism, Single Nucleotide - genetics
Abstract
Pathogenic mutations of the APP gene, leading to early-onset Alzheimer's disease (AD) have been known for more than 20 years. Recently, it was discovered that APP mutations might also be protective. A rare variant A673T reportedly protects against AD and age-related cognitive impairment and might functionally inhibit proteolytic cleavage at the ß-secretase site of APP. We sequenced APP exon 16 in a population-based sample of 515 Finnish subjects aged 85 or older. Neuropathologic data were available in 274. We found the A673T variant in 1 subject (0.2%), who lived until age 104.8 years (second highest age-at-death in the cohort). Neuropathologic analysis showed little beta-amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease score 0). Some vascular amyloid was detected in meningeal arteries suggesting that vascular ß-amyloid accumulation might be less inhibited than the parenchymal. She was demented at the age of 104, most likely because of hippocampal sclerosis. The low amount of parenchymal ß-amyloid pathology at the age of 104.8 years supports the concept that the A673T variant protects the brain against ß-amyloid pathology and AD.
PubMed ID
23102935 View in PubMed
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Analgesic use among community-dwelling people aged 75 years and older: A population-based interview study.

https://arctichealth.org/en/permalink/ahliterature142226
Source
Am J Geriatr Pharmacother. 2010 Jun;8(3):233-44
Publication Type
Article
Date
Jun-2010
Author
Niina Pokela
J Simon Bell
Katri Lihavainen
Raimo Sulkava
Sirpa Hartikainen
Author Affiliation
Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland.
Source
Am J Geriatr Pharmacother. 2010 Jun;8(3):233-44
Date
Jun-2010
Language
English
Publication Type
Article
Keywords
Activities of Daily Living
Aged
Aged, 80 and over
Analgesics - therapeutic use
Analgesics, Opioid - therapeutic use
Cross-Sectional Studies
Data Collection
Depression - complications
Female
Finland
Health status
Humans
Male
Multivariate Analysis
Pain - drug therapy
Polypharmacy
Residence Characteristics - statistics & numerical data
Sex Factors
Abstract
Pain is often underrecognized and undertreated among older people. However, older people may be particularly susceptible to adverse drug reactions linked to prescription and nonprescription analgesics.
The aims of this study were to assess the prevalence of analgesic use among a random sample of community-dwelling people aged >or=75 years, and to investigate factors associated with daily and as-needed analgesic use.
A random sample of people aged >or=75 years was drawn from the population register in Kuopio, Finland, in November 2003. Data on prescription and nonprescription analgesic use were elicited during nurse interviews conducted once for each participant in 2004. Self-reported drug utilization data were verified against medical records. The interview included items pertaining to sociodemographic factors, living conditions, social contacts, health behavior, and state of health. Physical function was assessed using the Instrumental Activities of Daily Living Scale, and the 10-item Barthel Index. Self-rated mobility was assessed by asking whether respondents could walk 400 meters (yes, yes with difficulty but without help, not without help, or no). Cognitive function was assessed using the Mini-Mental State Examination. The presence of depressive symptoms was assessed using the 15-item Geriatric Depression Scale. Respondents' self-rated health was determined using a 5-point scale (very poor, poor, moderate, good, or very good).
Of the initial random sample of participants (N = 1000), 700 provided consent to participate and were community dwelling. Among the participants, 318 (45.4%) were users of >or=1 analgesic on a daily or as-needed basis. Only 23.3% of analgesic users took an analgesic on a daily basis. Factors associated with any analgesic use included female sex (odds ratio [OR], 1.78 [95 degrees % CI, 1.17-2.71]), living alone (OR, 1.46 [95 degrees % CI, 1.02-2.11]), poor self-rated health (OR, 2.6 [95% CI, 1.22-3.84]), and use of >or=10 nonanalgesic drugs (OR, 2.21 [95% CI, 1.26-3.87]). Among users of >or=1 oral analgesic, factors associated with opioid use included moderate (OR, 2.46 [95% CI, 1.175.14]) and poor (OR, 2.57 [95% CI, 1.03-6.42]) self-rated health. Opioid use (OR, 0.19 [95% CI, 0.04-0.86]) and daily analgesic use (OR, 0.16 [95% CI, 0.34-0.74]) were inversely associated with depressive symptoms. Pain in the previous month was reported by 71.4% of analgesic users and 26.4% of nonusers of analgesics.
Analgesics were used by approximately 50% of community-dwelling people aged >or=75 years. However, age was not significantly associated with increased use of analgesics in multivariate analysis. The majority of analgesic drugs were used on an as-needed rather than a daily basis (76.7% vs 23.3%, respectively). Factors most significantly associated with analgesic use were female sex, living alone, poor self-rated health, and use of >or=10 nonanalgesic drugs.
PubMed ID
20624613 View in PubMed
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APOE and AßPP gene variation in cortical and cerebrovascular amyloid-ß pathology and Alzheimer's disease: a population-based analysis.

https://arctichealth.org/en/permalink/ahliterature133862
Source
J Alzheimers Dis. 2011;26(2):377-85
Publication Type
Article
Date
2011
Author
Terhi Peuralinna
Maarit Tanskanen
Mira Mäkelä
Tuomo Polvikoski
Anders Paetau
Hannu Kalimo
Raimo Sulkava
John Hardy
Shiao-Lin Lai
Sampath Arepalli
Dena Hernandez
Bryan J Traynor
Andrew Singleton
Pentti J Tienari
Liisa Myllykangas
Author Affiliation
University of Helsinki, Research Program of Molecular Neurology, Biomedicum-Helsinki, Helsinki, Finland.
Source
J Alzheimers Dis. 2011;26(2):377-85
Date
2011
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Alleles
Alzheimer Disease - genetics - metabolism - pathology
Amyloid beta-Peptides - genetics - metabolism
Amyloid beta-Protein Precursor - genetics - metabolism
Apolipoproteins E - genetics - metabolism
Cerebral Amyloid Angiopathy - genetics - metabolism - pathology
Cerebral Cortex - metabolism - pathology
Female
Finland
Genetic Association Studies
Genetic Variation
Humans
Male
Middle Aged
Phenotype
Promoter Regions, Genetic
Abstract
Cortical and cerebrovascular amyloid-? (A?) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) e4 is a major genetic modulator of A? deposition and AD risk. Variants of the amyloid-? protein precursor (A?PP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and A?PP variants in cortical and cerebrovascular A? deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged = 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the e4 allele with cortical (p = 4.91 ? 10-17) and cerebrovascular (p = 9.87 ? 10-11) A? deposition as well as with NIA-RI AD (p = 1.62 ? 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the A?PP locus. In single SNP or haplotype analyses there were no statistically significant A?PP locus associations with cortical or cerebrovascular A? deposition or with NIA-RI AD. We sequenced the promoter of the A?PP gene in 40 subjects with very high A? deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular A? depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE e4 variant. Promoter mutations or common allelic variation in the A?PP gene do not have a major contribution to cortical or cerebrovascular A? deposition, or very late-onset AD in this Finnish population based study.
Notes
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PubMed ID
21654062 View in PubMed
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Association between blood pressure and survival over 9 years in a general population aged 85 and older.

https://arctichealth.org/en/permalink/ahliterature168803
Source
J Am Geriatr Soc. 2006 Jun;54(6):912-8
Publication Type
Article
Date
Jun-2006
Author
Sari Rastas
Tuula Pirttilä
Petteri Viramo
Auli Verkkoniemi
Pirjo Halonen
Kati Juva
Leena Niinistö
Kimmo Mattila
Esko Länsimies
Raimo Sulkava
Author Affiliation
Department of Neurology, Lohja Hospital, Lohja, Finland.
Source
J Am Geriatr Soc. 2006 Jun;54(6):912-8
Date
Jun-2006
Language
English
Publication Type
Article
Keywords
Activities of Daily Living
Age Factors
Aged, 80 and over
Aging - physiology
Blood pressure
Blood Pressure Monitoring, Ambulatory
Female
Finland - epidemiology
Follow-Up Studies
Humans
Male
Prospective Studies
Questionnaires
Risk factors
Sex Distribution
Survival Rate - trends
Urban Population - statistics & numerical data
Abstract
To investigate the association between blood pressure and mortality in people aged 85 and older.
Population-based prospective study with 9-year follow-up.
Department of Neuroscience and Neurology and Department of Public Health and General Practice, University of Kuopio, and Department of Clinical Neurosciences, Helsinki University Hospital.
Of all 601 people living in the city of Vantaa born before April 1, 1906, whether living at home or in institutions and alive on April 1, 1991, 521 were clinically examined and underwent blood pressure measurement.
Blood pressure was measured using a standardized method in the right arm of the subject after resting for at least 5 minutes. Information on medical history for each participant was verified from a computerized database containing all primary care health records. Death certificates were obtained from the National Register; the collection of death certificates was complete.
After adjusting for age, sex, functional status, and coexisting diseases (earlier-diagnosed myocardial infarction, congestive heart failure, dementia, cancer, stroke, or hypertension), low systolic blood pressure (BP) was associated with risk of death.
Low systolic BP may be partially related to poor general health and poor vitality, but the very old may represent a select group of individuals, and the use of BP-lowering medications needs to be evaluated in this group.
Notes
Comment In: J Am Geriatr Soc. 2007 Jan;55(1):136-7; author reply 13717233706
PubMed ID
16776785 View in PubMed
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Association of polypharmacy with nutritional status, functional ability and cognitive capacity over a three-year period in an elderly population.

https://arctichealth.org/en/permalink/ahliterature137164
Source
Pharmacoepidemiol Drug Saf. 2011 May;20(5):514-22
Publication Type
Article
Date
May-2011
Author
Johanna Jyrkkä
Hannes Enlund
Piia Lavikainen
Raimo Sulkava
Sirpa Hartikainen
Author Affiliation
Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland. johanna.jyrkka@uef.fi
Source
Pharmacoepidemiol Drug Saf. 2011 May;20(5):514-22
Date
May-2011
Language
English
Publication Type
Article
Keywords
Activities of Daily Living
Aged
Aged, 80 and over
Cognition - physiology
Cohort Studies
Drug Utilization Review - statistics & numerical data
Finland
Geriatric Assessment - statistics & numerical data
Humans
Malnutrition - epidemiology
Nutrition Assessment
Nutritional Status - physiology
Polypharmacy
Prospective Studies
Psychiatric Status Rating Scales
Socioeconomic Factors
Abstract
To determine the association of polypharmacy with nutritional status, functional ability and cognitive capacity among elderly persons.
This was a prospective cohort study of 294 survivors from the population-based Geriatric Multidisciplinary Strategy for the Good Care of the Elderly (GeMS) Study, with yearly follow-ups during 2004 to 2007. Participants were the citizens of Kuopio, Finland, aged 75 years and older at baseline. Polypharmacy status was categorized as non-polypharmacy (0-5 drugs), polypharmacy (6-9 drugs) and excessive polypharmacy (10+ drugs). A linear mixed model approach was used for analysis the impact of polypharmacy on short form of mini nutritional assessment (MNA-SF), instrumental activities of daily living (IADL) and mini-mental status examination (MMSE) scores.
Excessive polypharmacy was associated with declined nutritional status (p?=?0.001), functional ability (p?
PubMed ID
21308855 View in PubMed
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Associations of instrumental activities of daily living and handgrip strength with oral self-care among home-dwelling elderly 75+.

https://arctichealth.org/en/permalink/ahliterature128053
Source
Gerodontology. 2012 Jun;29(2):e135-42
Publication Type
Article
Date
Jun-2012
Author
Kaija Komulainen
Pekka Ylöstalo
Anna-Maija Syrjälä
Piia Ruoppi
Matti Knuuttila
Raimo Sulkava
Sirpa Hartikainen
Author Affiliation
Kuopio Research Centre of Geriatric Care, Unit of Clinical Pharmacology and Geriatric Pharmacotherapy, School of Pharmacy, University of Eastern Finland, Kuopio, Finland. kaija.komulainen@uef.fi
Source
Gerodontology. 2012 Jun;29(2):e135-42
Date
Jun-2012
Language
English
Publication Type
Article
Keywords
Activities of Daily Living
Aged, 80 and over
Cognition - physiology
Cross-Sectional Studies
Dental Care - statistics & numerical data
Dental Plaque Index
Dentition
Educational Status
Female
Finland
Hand Strength - physiology
Humans
Independent living
Male
Oral Hygiene - statistics & numerical data
Population Surveillance
Toothbrushing - statistics & numerical data
Toothpastes - therapeutic use
Xerostomia - classification
Abstract
To study the associations of instrumental activities of daily living (IADL) and the handgrip strength with oral self-care among dentate home-dwelling elderly people in Finland.
The study analysed data for 168 dentate participants (mean age 80.6 years) in the population-based Geriatric Multidisciplinary Strategy for Good Care of the Elderly (GeMS) study. Each participant received a clinical oral examination and structured interview in 2004-2005. Functional status was assessed using the IADL scale and handgrip strength was measured using handheld dynamometry.
Study participants with high IADL (scores 7-8) had odds ratios (ORs) for brushing their teeth at least twice a day of 2.7 [95% confidence intervals (CI) 1.1-6.8], for using toothpaste at least twice a day of 2.0 (CI 0.8-5.2) and for having good oral hygiene of 2.8 (CI 1.0-8.3) when compared with participants with low IADL (scores =6). Participants in the upper tertiles of the handgrip strength had ORs for brushing the teeth at least twice a day of 0.9 (CI 0.4-1.9), for using the toothpaste at least twice a day of 0.9 (CI 0.4-1.8) and for good oral hygiene of 1.1 (CI 0.5-2.4) in comparison with the study subjects in the lowest tertile of handgrip strength.
The results of this study suggest that the functional status, measured by means of the IADL scale, but not handgrip strength, is an important determinant of oral self-care among the home-dwelling elderly.
PubMed ID
22239745 View in PubMed
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B-type natriuretic peptide as a predictor of declining cognitive function and dementia--a cohort study of an elderly general population with a 5-year follow-up.

https://arctichealth.org/en/permalink/ahliterature144288
Source
Ann Med. 2010 Apr;42(3):207-15
Publication Type
Article
Date
Apr-2010
Author
Tuomas Kerola
Tuomo Nieminen
Sirpa Hartikainen
Raimo Sulkava
Olli Vuolteenaho
Raimo Kettunen
Author Affiliation
Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland. tuomas.kerola@phsotey.fi
Source
Ann Med. 2010 Apr;42(3):207-15
Date
Apr-2010
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Cognition
Cognition Disorders - blood - epidemiology
Cohort Studies
Dementia - blood - epidemiology
Educational Status
Female
Finland - epidemiology
Follow-Up Studies
Humans
Hypertension - complications
Male
Multivariate Analysis
Natriuretic Peptide, Brain - blood
Predictive value of tests
Risk factors
Abstract
Several traditional cardiovascular risk factors assessed in the middle-aged are associated with the risk of dementia, but they are known to lose much of their prognostic value when measured in the elderly. The aim of the study was to compare B-type natriuretic peptide (BNP) with previously known risk markers for dementia in their association with cognitive decline and dementia during a follow-up.
A total of 464 subjects free of dementia aged 75 years or more were examined and followed up for 5 years in a prospective population-based stratified cohort study. The association of clinical variables to base-line Mini Mental State Examination score (MMSE), the decline of MMSE, and onset of dementia during the follow-up were examined.
The only variable to significantly associate with the decline of MMSE was BNP (beta 0.140; P = 0.019). A total of 59 new cases of dementia were diagnosed after the follow-up. Significant predictors of the occurrence of dementia over the study period were BNP (adjusted odds ratio (OR) 1.53; 95% confidence interval (CI) 1.09-2.16; P = 0.013), length of education (OR 0.50; 95% CI 0.33-0.77; P = 0.001), and diagnosis of hypertension (OR 0.53; 95% CI 0.27-0.95; P = 0.036). BNP remained as a significant predictor of dementia and the decline of MMSE even after adjustment to the base-line MMSE.
BNP is an independent harbinger of the cognitive decline and incidence of new onset of dementia in an elderly general population. This is a ground for testing the impact of antihypertensive treatment in the prevention of cognitive impairment in those with elevated BNP.
PubMed ID
20384435 View in PubMed
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Change in psychotropic drug use among community-dwelling people aged 75 years and older in Finland: repeated cross-sectional population studies.

https://arctichealth.org/en/permalink/ahliterature134674
Source
Int Psychogeriatr. 2011 Oct;23(8):1278-84
Publication Type
Article
Date
Oct-2011
Author
Franciska Desplenter
Charlotte Caenen
Jolein Meelberghs
Sirpa Hartikainen
Raimo Sulkava
J Simon Bell
Author Affiliation
Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland.
Source
Int Psychogeriatr. 2011 Oct;23(8):1278-84
Date
Oct-2011
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Anti-Anxiety Agents - therapeutic use
Antidepressive Agents - therapeutic use
Antipsychotic Agents - therapeutic use
Chi-Square Distribution
Cross-Sectional Studies
Female
Finland - epidemiology
Health status
Humans
Hypnotics and Sedatives - therapeutic use
Independent Living - psychology - statistics & numerical data
Logistic Models
Male
Odds Ratio
Physician's Practice Patterns - statistics & numerical data
Psychotropic Drugs - therapeutic use
Socioeconomic Factors
Statistics, nonparametric
Abstract
Older people are at high risk of experiencing psychotropic-related adverse drug events. The objective of this study was to compare and contrast the use of psychotropic drugs among community-dwelling people aged = 75 years in 1998 and 2004.
Comparable random samples of people aged = 75 years were extracted from the population register in Kuopio, Finland, in 1998 (n = 700) and 2003 (n = 1000). In 1998 and 2004, 523 and 700 community-dwelling people respectively participated in nurse interviews, during which demographic, diagnostic and drug use data were elicited. Logistic regression was used to compute unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of psychotropic drug use in 2004 compared to 1998.
The unadjusted prevalence of total psychotropic (37.3% and 38.4%, OR 1.05; 95% CI 0.83-1.33), anxiolytic, hypnotic and sedative (29.6% and 31.3%, OR 1.08, 95% CI 0.85-1.38), and antidepressant (10.7% and 11.9%, OR 1.12, 95% CI 0.78-1.61) use were similar in 1998 and 2004. There was a decrease in the unadjusted prevalence of antipsychotic use (9.2% and 5.7%, OR 0.60; 95% CI 0.39-0.93). After adjusting for socioeconomic and health status differences, there was an increase in the prevalence of total psychotropic (adjusted OR 1.31, 95% CI 1.01-1.70) and antidepressant (OR 1.59, 95% CI 1.06-2.40) use.
The unadjusted prevalence of psychotropic drug use remained stable between 1998 and 2004. However, in adjusted analyses there was a small increase in the prevalence of any psychotropic drug use and antidepressant use specifically.
PubMed ID
21554797 View in PubMed
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Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.

https://arctichealth.org/en/permalink/ahliterature141194
Source
Lancet Neurol. 2010 Oct;9(10):978-85
Publication Type
Article
Date
Oct-2010
Author
Hannu Laaksovirta
Terhi Peuralinna
Jennifer C Schymick
Sonja W Scholz
Shaoi-Lin Lai
Liisa Myllykangas
Raimo Sulkava
Lilja Jansson
Dena G Hernandez
J Raphael Gibbs
Michael A Nalls
David Heckerman
Pentti J Tienari
Bryan J Traynor
Author Affiliation
Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland.
Source
Lancet Neurol. 2010 Oct;9(10):978-85
Date
Oct-2010
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis - enzymology - epidemiology - genetics
Chromosomes, Human, Pair 9 - genetics
Cohort Studies
Female
Finland - epidemiology
Genetic Loci - genetics
Genetic Predisposition to Disease - epidemiology - genetics
Genome-Wide Association Study - methods
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide - genetics
Superoxide Dismutase - genetics
Young Adult
Abstract
The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population.
We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.
We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318?167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1).
The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.
National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
Notes
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PubMed ID
20801718 View in PubMed
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