Sonja W. de Jong

Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis

We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 × 10−8 in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18–1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.

ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.

Lifetime physical activity and the risk of amyotrophic lateral sclerosis

Background It has been hypothesised that physical activity is a risk factor for developing amyotrophic lateral sclerosis (ALS), fuelled by observations that professional soccer players and Gulf War veterans are at increased risk. In a population based study, we determined the relation between physical activity and risk of sporadic ALS, using an objective approach for assessing physical activity. Methods 636 sporadic ALS patients and 2166 controls, both population based, completed a semistructured questionnaire on lifetime history of occupations, sports and hobbies. To objectively compare the energy cost of a lifetime history of occupational and leisure time physical activities and to reduce recall bias, metabolic equivalent scores were assigned to each activity based on the Compendium of Physical Activities. Results ALS patients had significantly higher levels of leisure time physical activity compared with controls (OR 1.08, 95% CI 1.02 to 1.14, p=0.008). No significant difference was found between patients and controls in the level of vigorous physical activities, including marathons and triathlons, or in occupational activity. Cumulative measures of physical activity in quartiles did not show a dose–response relationship. Conclusions An increased risk of ALS with higher levels of leisure time physical activity was found in the present study. The lack of association with occupational physical activity and the absence of a dose–response relationship strengthen the hypothesis that not increased physical activity per se but rather a genetic profile or lifestyle promoting physical fitness increases ALS susceptibility.

Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis

To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design.

Smoking, Alcohol Consumption, and the Risk of Amyotrophic Lateral Sclerosis: A Population-based Study

Smoking has been posited as a possible risk factor for amyotrophic lateral sclerosis (ALS), but large population-based studies of patients with incident disease are still needed. The authors performed a population-based case-control study in the Netherlands between 2006 and 2009, including 494 patients with incident ALS and 1,599 controls. To prove the relevance of population-based incidence cohorts in case-control studies, the authors compared results with those from cohorts including patients with prevalent ALS and referral patients. Subjects were sent a questionnaire. Multivariate analyses showed an increased risk of ALS among current smokers (odds ratio = 1.38, 95% confidence interval (CI): 1.02, 1.88) in the incident patient group only. Cox regression models showed that current smoking was also independently associated with shorter survival (hazard ratio = 1.51, 95% CI: 1.07, 2.15), explaining the lack of association in the prevalent and referral patient groups. Current alcohol consumption was associated with a reduced risk of ALS (incident patient group: odds ratio = 0.52, 95% CI: 0.40, 0.75). These findings indicate that current smoking is associated with an increased risk of ALS, as well as a worse prognosis, and alcohol consumption is associated with a reduced risk of ALS, further corroborating the role of lifestyle factors in the pathogenesis of ALS. The importance of population-based incident patient cohorts in identifying risk factors is highlighted by this study.

Parental age and the risk of amyotrophic lateral sclerosis

Abstract Sporadic ALS is a multifactorial disease for which there are probably multiple genetic risk factors. An association with increased parental age might suggest there is a role for specific (epi)genetic changes. Previous studies have shown conflicting results on the association between parental age and the risk of ALS. A large, population based study might help in the search for specific (epi)genetic risk factors. We performed a population based, case-control study in the Netherlands. Date of birth of both mother and father was retrieved from the National Register. Multivariate logistic regression analysis was performed in 769 patients with sporadic ALS, 49 patients with a hexanucleotide repeat expansion in C9orf72, and 1929 age-, gender- and geographically-matched controls. Multivariate analyses showed no difference in either paternal or maternal age at delivery (adjusted for age of subject, age of other parent at delivery, and level of education) in patients with sporadic ALS, nor in patients with a hexanucleotide repeat expansion in C9orf72 compared to controls. In conclusion, parental age was not associated with an increased risk of ALS in our study. (Epi)genetic alterations that are associated with increased parental age are not, therefore, likely to contribute to the aetiology of sporadic ALS.