SNPs in cytochrome P450 genes decide on the fate of individuals with genetic predisposition to Parkinson's disease

Abstract

Parkinson's disease (PD) is one of the most frequent neurological diseases affecting millions of people worldwide. While the majority of PD cases are of unknown origin (idiopathic), about 5%-10% are familial and linked to mutations in different known genes. However, there are also people with a genetic predisposition to PD who do not develop the disease. To elucidate factors leading to the manifestation of PD we compared the occurrence of single nucleotide polymorphisms (SNPs) in various cytochrome P450 (P450) genes in people with a genetic predisposition and suffering from PD (GPD) to that of people, who are genetically predisposed, but show no symptoms of the disease (GUN). We used the PPMI (Parkinson's Progression Markers Initiative) database and the gene sequences of all 57 P450s as well as their three redox partners. Corresponding odds ratios (OR) and confidence intervals (CI) were calculated to assess the incidence of the various SNPs in the two groups of individuals and consequently their relation to PD. We identified for the first time SNPs that are significantly (up to 10fold!) over- or under-represented in GPD patients compared to GUN. SNPs with OR > 5 were found in 10 P450s being involved in eicosanoid, vitamin A and D metabolism as well as cholesterol degradation pointing to an important role of endogenous factors for the manifestation of PD clinical symptoms. Moreover, 12 P450s belonging to all P450 substrate classes as well as POR have SNPs that are significantly under-represented (OR < 0.2) in GPD compared to GUN, indicating a protective role of those SNPs and the corresponding P450s regarding disease advancement. To the best of our knowledge our data for the first time demonstrate an association between known PD predisposition genes and SNPs in other genes, shown here for different P450 genes and for their redox partner POR, which promote the manifestation of the disease in familial PD. Our results thus shed light onto the pathogenesis of PD, especially the switch from GUN to GPD and might further help to advance novel strategies for preventing the development or progression of the disease.

Keywords: Adx; POR; Parkinson’s disease; cholesterol; cytochromes P450; eicosanoids; retinoic acid; vitamin D.

FIGURE 1

Overview of the effect of different SNPs in cytochromes P450 involved in various physiological pathways. Shown are P450s, which display SNPs with OR values >5 (A) and <0.2 (B) in GPD patients vs GUN individuals. Red circles: P450s participating in the biotransformation of xenobiotics; green circles: P450s involved in immune response and inflammation; blue circles: P450s involved in sterol metabolism or degradation of cholesterol; yellow circles: P450s involved in the metabolism of vitamins A and D. In addition, CYP20A1 is shown, which remains an „orphan“ P450, but is known to be involved in neurophysiological functions. P450s shown in red in (A) are those with OR values >10 (GPD/GUN). P450s shown in blue in (B) are those having SNPs found to be under-represented when considering both, GPD/HC and GPD/GUN.