Anna Håkansson

Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease

BackgroundOxidative stress is heavily implicated in the pathogenic process of Parkinsons disease. Varying capacity to detoxify radical oxygen species through induction of phase II antioxidant enzymes in substantia nigra may influence disease risk. Here, we hypothesize that variation in NFE2L2 and KEAP1, the genes encoding the two major regulators of the phase II response, may affect the risk of Parkinsons disease.MethodsThe study included a Swedish discovery case-control material (165 cases and 190 controls) and a Polish replication case-control material (192 cases and 192 controls). Eight tag single nucleotide polymorphisms representing the variation in NFE2L2 and three representing the variation in KEAP1 were chosen using HapMap data and were genotyped using TaqMan Allelic Discrimination.ResultsWe identified a protective NFE2L2 haplotype in both of our European case-control materials. Each haplotype allele was associated with five years later age at onset of the disease (p = 0.001) in the Swedish material, and decreased risk of PD (p = 2 × 10-6), with an odds ratio of 0.4 (95% CI 0.3-0.6) for heterozygous and 0.2 (95% CI 0.1-0.4) for homozygous carriers, in the Polish material. The identified haplotype includes a functional promoter haplotype previously associated with high transcriptional activity. Genetic variation in KEAP1 did not show any associations.ConclusionThese data suggest that variation in NFE2L2 modifies the Parkinsons disease process and provide another link between oxidative stress and neurodegeneration.

PITX3 polymorphism is associated with early onset Parkinson's disease

PITX3 is a transcription factor of importance for the differentiation and survival of midbrain dopaminergic neurons, the gene of which is disrupted in a putative mouse model for Parkinsons disease (PD). The A-allele of a HapMap tagging SNP (rs4919621) that was genotyped in a population of 361 PD patients, 69 of which had early onset, and in 333 controls, was significantly more common in PD patients with an early age of onset when compared either to controls (p=0.002) or to PD patients with late onset (p=0.001). In contrast, a previous finding suggesting a SNP (rs3758549) in the putative promoter region of the PITX3 gene to be associated with PD could not be replicated.

Interaction of polymorphisms in the genes encoding interleukin-6 and estrogen receptor beta on the susceptibility to Parkinson's disease.

The multifunctional cytokine interleukin‐6 (IL‐6) is involved in inflammatory processes in the central nervous system and increased levels of IL‐6 have been found in patients with Parkinsons disease (PD). It is known that estrogen inhibits the production of IL‐6, via action on estrogen receptors, thereby pointing to an important influence of estrogen on IL‐6. In a previous study, we reported an association between a G/A single nucleotide polymorphism (SNP) at position 1730 in the gene coding for estrogen receptor beta (ERbeta) and age of onset of PD. To investigate the influence of a G/C SNP at position 174 in the promoter of the IL‐6 gene, and the possible interaction of this SNP and the ERbeta G‐1730A SNP on the risk for PD, the G‐174C SNP was genotyped, by pyrosequencing, in 258 patients with PD and 308 controls. A significantly elevated frequency of the GG genotype of the IL‐6 SNP was found in the patient group and this was most obvious among patients with an early age of onset (≤50 years) of PD. When the GG genotypes of the IL‐6 and ERbeta SNPs were combined, the combination was much more robustly associated with PD, and especially with PD with an early age of onset, than respective GG genotype when analyzed separately. Our results indicate that the G‐174C SNP in the IL‐6 promoter may influence the risk for developing PD, particularly regarding early age of onset PD, and that the effect is modified by interaction of the G‐1730A SNP in the ERbeta gene.

Lack of association between the BDNF Val66Met polymorphism and Parkinson's disease in a Swedish population.

Polymorphism and Parkinson’s Disease in a Swedish Population Anna Håkansson, MS, Jonas Melke, MS, Lars Westberg, BS, Haydeh Niazi Shahabi, MS, Silva Buervenich, PhD, Andrea Carmine, MS, Kjell Klingborg, MD, Maj-Britt Grundell, MD, Barbara Schulhof, MD, Björn Holmberg, MD, PhD, Jarl Ahlberg, MD, Elias Eriksson, PhD, Olof Sydow, MD, PhD, Lars Olson, PhD, Bo Johnels, MD, PhD, and Hans Nissbrandt, MD, PhD

Investigation of genes coding for inflammatory components in Parkinson's disease

Several findings obtained recently indicate that inflammation may contribute to the pathogenesis in Parkinsons disease (PD). Genetic variants of genes coding for components involved in immune reactions in the brain might therefore influence the risk of developing PD or the age of disease onset. Five single nucleotide polymorphisms (SNPs) in the genes coding for interferon‐γ (IFN‐γ; T874A in intron 1), interferon‐γ receptor 2 (IFN‐γ R2; Gln64Arg), interleukin‐10 (IL‐10; G1082A in the promoter region), platelet‐activating factor acetylhydrolase (PAF‐AH; Val379Ala), and intercellular adhesion molecule 1 (ICAM‐1; Lys469Glu) were genotyped, using pyrosequencing, in 265 patients with PD and 308 controls. None of the investigated SNPs was found to be associated with PD; however, the G1082A polymorphism in the IL‐10 gene promoter was found to be related to the age of disease onset. Linear regression showed a significantly earlier onset with more A‐alleles (P = 0.0095; after Bonferroni correction, P = 0.048), resulting in a 5‐year delayed age of onset of the disease for individuals having two G‐alleles compared with individuals having two A‐alleles. The results indicate that the IL‐10 G1082A SNP could possibly be related to the age of onset of PD.

Association between the estrogen receptor beta gene and age of onset of Parkinson’s disease

The purpose of this study was to investigate the potential contribution of genetic variants in the estrogen receptor beta gene to the aetiology of Parkinsons disease (PD). Several lines of evidence from human and animal studies suggest a protective role for estrogen in PD. Recently the estrogen receptor beta subtype was reported to be an important mediator of estrogen actions in the nigrostriatal dopamine system. Two single nucleotide polymorphisms at position 1730 and 1082 in the ER beta gene were genotyped, using pyrosequencing, in 260 patients with PD and 308 controls recruited from the Swedish population. Neither of the two estrogen receptor beta polymorphisms was associated with an increased risk for PD. However, the G allele of the A1730G polymorphism was more frequent in patients with an early age of onset than in patients with a late age of onset of PD (P = 0.006). Patients carrying the GG genotype had an odds ratio of 2.2 for having an early onset of PD compared to non-carriers. In conclusion, our results indicate that genetic variation in the estrogen receptor beta gene may influence the age of onset of PD.

Association study of two genetic variants in mitochondrial transcription factor A (TFAM) in Alzheimer's and Parkinson's disease

Mitochondrial (mt) dysfunction has been implicated in Alzheimers (AD) and Parkinsons disease (PD). Mitochondrial transcription factor A (TFAM) is needed for mtDNA maintenance, regulating mtDNA copy number and is absolutely required for transcriptional initiation at mtDNA promoters. Two genetic variants in TFAM have been reported to be associated with AD in a Caucasian case-control material collected from Germany, Switzerland and Italy. One of these variants was reported to show a tendency for association with AD in a pooled Scottish and Swedish case-control material and the other variant was reported to be associated with AD in a recent meta-analysis. We investigated these two genetic variants, rs1937 and rs2306604, in an AD and a PD case-control material, both from Sweden and found significant genotypic as well as allelic association to marker rs2306604 in the AD case-control material (P=0.05 and P=0.03, respectively), where the A-allele appears to increase risk for developing AD. No association was observed for marker rs1937. We did not find any association in the PD case-control material for either of the two markers. The distribution of the two-locus haplotype frequencies (based on rs1937 and rs2306604) did not differ significantly between affected individuals and controls in the two sample sets. However, the global P-value for haplotypic association testing indicated borderline association in the AD sample set. Our data suggests that the rs2306604 A-allele could be a moderate risk factor for AD, which is supported by the recent meta-analysis.

Leucine-rich repeat kinase 2 (LRRK2) mutations in a Swedish parkinson cohort and a healthy nonagenarian

Specific variants of Leucine‐rich repeat kinase 2 (LRRK2) have been shown to associate with Parkinsons disease (PD). Several mutations have been found in PD populations from different parts of the world. We investigated the occurrence of three mutations (R1441G/C/H, G2019S, and I2020T) in our Swedish case–control material and identified four carriers of the G2019S mutation in 284 PD cases and 1 95‐year‐old carrier in 305 controls. The other two variants were absent in our material. We conclude that the LRRK2 G2019S mutation constitutes a significant factor for PD in the Swedish population and that it is not completely penetrant.

Association of a polymorphism in the ABCB1 gene with Parkinson's disease.

The ATP-binding cassette, sub-family B, member 1 (ABCB1) gene encoding the protein P-glycoprotein (P-gp) has been implicated in the pathophysiology of Parkinsons disease (PD) due to its role in regulating transport of endogenous molecules and exogenous toxins. In the present study, we analyzed the ABCB1 single nucleotide polymorphisms (SNPs) 1236C/T (exon 12), 2677G/T/A (exon 21) and 3435C/T (exon 26) in 288 Swedish PD patients and 313 control subjects and found a significant association of SNP 1236C/T with disease (p=0.0159; chi(2)=8.28), whereas the distributions of wild-type and mutated alleles were similar for 2677G/T/A and 3435C/T in patients and controls. Haplotype analysis revealed significant association of the 1236C-2677G haplotype with PD (p=0.026; chi(2)=4.955) and a trend towards association with disease of the 1236C-2677G-3435C haplotype (p=0.072; chi(2)=3.229). Altered ABCB1 and/or P-pg expression was recently shown in PD patients, and impaired drug efflux across barriers such as the gastrointestinal and nasal mucosal linings or the blood-brain barrier, might result in accumulation of drugs and/or endogenous molecules in toxic amounts, possibly contributing to disease. ABCB1 polymorphisms thus constitute an example of how genetic predisposition and environmental influences may combine to increase risk of PD.

Cerebellar α-synuclein levels are decreased in Parkinson’s disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material

Alterations of brain and plasma α‐synuclein levels and SNCA gene variability have been implicated in the pathogenesis of Parkinsons disease (PD). We therefore measured α‐synuclein protein levels in postmortem PD and control cerebellum tissue using Western blot and investigated whether the levels correlated to SNCA genotype. We found markedly decreased α‐synuclein levels in PD patients (n=16) compared to gender‐and age‐matched controls (n=14; P= 0.004) normalized to α‐tubulin. We also performed an association study of the noncoding polymorphisms rs2737029 (A/G) and rs356204 (A/G) (intron 4), and of rs356219 (T/C) (34′‐region) of SNCAin a Swedish PD case‐control material. Using a two‐sided χ test, we found significant association of rs2737029 (P= 0.003; χ2 =9.07) and rs356204 (P=0.048; χ2 =3.91) with disease, strengthening the involvement of SNCA polymorphisms in sporadic PD. Stratification of the human postmortem brain material by genotype of the three investigated polymorphisms, did not indicate any influence of genotype on α‐synuclein protein levels when comparing PD with controls. Taken together, our findings demonstrate that the investigated Parkinson patients have markedly reduced levels of α‐synuclein in cerebellum, and that this reduction is general, rather then correlated to the investigated polymorphisms, although two of the polymorphisms also associated with disease in a Swedish material.—Westerlund, M., Belin, A. C., Anvret, A., Håkansson, A., Nissbrandt, H., Lind, C., Sydow, O., Olson, L., and Galter, D. Cerebellar α‐synuclein levels are decreased in Parkinsons disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material. FASEB J. 22, 3509–3514 (2008)