The influence of genetic and environmental factors on Parkinson disease in the Faroe Islands
Maria Skaalum Petersen
Deildin fyri Arbeiðs- og Almannaheilsu
Stuðul úr Granskingargrunninum:
PD occurs in the Faroese at a prevalence about twice as high as expected (Wermuth et al., 1995, 2008). In a group of selected Faroese Septuagenarians’ rather low vitamin D levels were found, thus encouraging to study the association between vitamin D and PD. Some polymorphisms in the D-vitamin receptor also seem to be overrepresented in PD patients (Kim et al., 2005). Further, NOS genetic variants are mentioned as candidate susceptibility genes for PD (Hancock et al., 2008) and interaction with both pesticides and cigarette smoking have been reported (Hancock et al., 2006, 2008; Levecque et al., 2003). Additionally, studies in the Faroe Island have shown increased incidence of diseases associated with specific gene mutations e.g. CTD (Lund et al., 2007). Thus, the high frequency of CTD, which results in a great reduction of carnitine stores, could conceivably be related to or contributory to the high prevalence of PD. In relation to this, the residents of this North Atlantic fishing community have increased exposure to seafood contaminants from traditional marine food, which may include meat and blubber form the pilot whale. In a recent case-controlled study of PD we found an association between lifetime consumption of whale meat and blubber, indicative of mercury and PCB exposure, and PD in Faroese patients. Further was a significant statistical association seen between current â-hexachlorocylclohedxane (â-HCH) levels and PD (Petersen et al., 2008)
Our main hypotheses are:
1. Low levels of D-vitamin and polymorphisms in the D-vitamin receptor (VDR) are associated with the development of PD.
2. Patients with PD have higher lifetime exposure to seafood neurotoxicants than matched population-based controls and these associations are stronger in genetically vulnerable individuals (e.g. carriers of NOS gene mutation.
3. Carnitine Transporter Deficiencies (CTD) and low levels of carnitine are associated with the development of PD.
4. Higher prevalence of known PD genes (e.g. LRRK2) exists among Faroese PD patients compared with controls.
The proposed research therefore has the following aims:
1. To study polymorphisms of the VDR gene in patients with PD in the Faroe Islands and to assess the contribution of low vitamin D concentration to the risk of developing PD.
2. To study polymorphism in the NOS genetic variants.
3. To study the mutation in the SLC22A5 gene and to assess the contribution of low carnitine levels to the risk of developing PD.
4. To study the prevalsen of the G2019S mutation in LRRK2 gene in Faroese PD patients.
The proposed study has the unique possibility to take advantage of a case control study of Faroese PD patients, conducted in 2005 with 79 PD patients and 154 controls. During 1995-2005, the average annual incidence for PD in the Faroese Islands was 21.1 per 100.000 persons. From 2005 until now, approximately 40 new PD cases probably have emerged. These new cases will be identified through the local neurology specialist Poul Joensen and invited to participate in a study identical to the former. The patients will receive a letter of invitation and one week later a follow-up telephone call. They will be examined at the Department of Occupational Medicine and Public Health in Torshavn, or if not possible, at their residence. The Faroese population Registry will be recruited pr. new PD case matched by date of birth and sex.
Blood and hair sample will be collected from the new cases and controls in order to assess the current concentrations of serum POPs’, blood and hair mercury. Blood samples from patients and controls in the already conducted study as well as from the new case and controls will be analyzed for D-vitamin level and carnitine level. Genotype analysis will also be preformed in order to clarify possible polymorphism in the D-vitamin receptor (VDR), the carnitine transporter, the nitic oxide synthases (NOS) genes and the LREK2 gene.
Despite many years of research on Parkinson’s disease (PD), the etiology remains poorly understood. The relative contribution of genetic versus environmental factors is still a matter of debate. Many different etiologic factors seem to be capable of causing PD and individual vulnerability may further complicate the picture. Genetic factors and environmental toxicants, perhaps in interaction, that cause oxidative stress in the brain are particularly relevant when studying PD risk factors and gene-environment interactions. PD occurs in the Faroese at a prevalence about twice as high as expected and the reason for this access is unknown. Mainly environmental factors have been explored in the Faroese. Thus, looking at heterogeneities causing e.g. oxidative stress and known PD genes, preferable in interaction with environmental factors, is also essential when trying to explain the high prevalence of PD in the Faroes and this was the aim of this case-control study:
1.to study polymorphisms of the VDR gene and the contribution of low vitamin D concentration to the risk of developing PD.
2.to study polymorphism in the NOS genetic variants as a risk factor for PD
3.to study polymorphism in the PON1 as a risk factor for PD
4.to study carnitine transporter mutations and the contribution of low carnitine levels to the risk of developing PD
5.to study the prevalence of PD mutations in Faroese Islands.
The study took advantage of a case-control study of Faroese PD patients, conducted in 2005 with 79 PD patients and 154 controls. During 1995-2005, the average annual incidence for PD in the Faroe Islands was 21.1 per 100,000 persons. From 2005 until the study started, we expected approximately 40 new PD cases to have emerged. The new cases were identified through different sources and invited to participate in the study, identical to the study in 2005. The patients were examined at the Department of Occupational Medicine and Public Health in Torshavn, or if not possible, at their residence. A neurology resident did examine the patients to confirm the PD diagnose. Two controls, retrieved from the Faroese Population Registry were recruited per new PD case matched by date of birth and sex. In total, 41 new cases and 82 controls were recruited. Blood and hair was collected from the new cases and controls in order to assess the current concentrations of serum POPs, blood and hair mercury and questionnaire information retrieved to assess lifestyle and environmental factors. Blood samples from patients and controls in the entire cohort were analyzed for the selected SNPs.
The statistical analyses are still ongoing but preliminary data does suggest that the chosen SNPs cannot explain the higher prevalence of PD or at least, they did not show positive. However, we cannot rule out that the examined factors may play a role in PD, but we can only say that our study did not show these associations that some studies do find and others do not. But with final analysis we can have a more conclusive conclusion and papers will be published continously.
Scientific articles, books, thesis etc.
- Petersen MS, Bech S, Christiansen DH, Schmedes AV, Halling J. The role of vitamin D levels and vitamin D receptor polymorphism on Parkinson's disease in the Faroe Islands. Neurosci Lett. 2014 Jan 3. pii: S0304-3940(13)01134-8
- Oral presentation with the title Parkinson’s disease research in the Faroe Islands at 7th GEOPD meeting in Lubeck Oct. 2013
- Poster with the title The role of serum vitamin D levels and vitamin D receptor polymorphism on Parkinson’s disease in Faroe Islands at 7th GEOPD meeting in Lubeck Oct. 2013
- Oral presentation with the title Impact of dietary exposure to food contaminants and genetic heterogeneities on the risk of Parkinson's disease at Artic Frontier 2014 in Tromsø Jan. 2014
-Ongoing publication on PON1 and carnitine results
Publications outside the scientific community, i.e. lectures, periodicals, articles in newspapers, television and radio
- interview in Góðan Morgun Føroyar about Parkinson’s research in the Faroes
- interview with Norwegian radio (NRK3) after the oral presentation at Artic Frontier
- articles written on news web pages following the oral presentation at Artic Frontier, e.g. on forskning.no