Genetic marker linking inflammation with sporadic Parkinson's disease.

1Departments of Neurology, Singapore General Hospital, National Neuroscience Institute 2Duke-NUS Graduate Medical School, Singapore Address for Correspondence: Assoc Prof Eng King Tan, Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608. Email: gnrtek@sgh.com. sg Parkinson’s disease (PD) is a common neurodegenerative disease which frequently leads to neurological disability.1-3 Medical and surgical therapies ameliorate the symptoms and cellular replacement is a potential therapeutic option.1-3 Numerous monogenic genes have been associated with familial forms of PD.4-7 However, these account for only 10% of the PD population. The vast majority of PD patients do not have a family history and the relative contribution of genes and environmental factors in these cases of sporadic PD4 still remains to be elucidated. A few common genetic risk variants have been found in association with PD but these are unlikely to explain the etiology for all the cases.7 In the past few years, numerous investigators have utilised the genome-wide association study (GWAS) approach to unravel risk loci for sporadic PD. As GWAS studies are not hypothesis-driven, the identifi cation of genetic markers provide an opportunity for unbiased correlation with known existing pathological processes such as mitochondrial dysfunction, proteasomal impairment, unfolded protein, oxidative stress and abnormal protein accumulation. Thus far, GWASs have provided consistent associations with alpha synuclein (SNCA) and tau (MAPT). 5,6 However, the most recent GWAS study by Hamza and colleagues8 has for the fi rst time identifi ed a genetic marker that is linked to infl ammation, providing a different perspective to the underlying pathophysiologic mechanism of PD. This GWAS study was carried out in 3986 American subjects of European ancestry (2000 PD, 1986 control subjects) with more than 800 000 genetic markers being analysed (Fig. 1). Unlike other GWA studies, the long mean disease duration of 8 years at enrollment allowed the investigators to exclude cases which had initially been misdiagnosed, thus improving the accuracy of the phenotype selection. In addition to confi rming the 2 known risk loci (SNCA, MAPT), they identifi ed a new genetic locus in the HLA region (chromosome 6p21.3), which they designated as PARK18. Among the genetic markers, rs3129882 in intron 1 of HLA-DRA showed the most robust association with disease, even after differences in population substructure were taken into account. This fi nding was replicated in 2 independent datasets, though this was statistically less robust because of the smaller sample sizes. In the meta-analysis, robust associations were observed in sporadic PD, lateonset PD and specifi cally in men (Similar demographics were observed in a majority of PD cases.). Interestingly, when the risk alleles in this HLA region were considered together with the other genetic risk regions (SNCA, MAPT, GAK) in their sample, subjects with 4 risk alleles had a 2.5-fold increased risk compared to subjects with 1 or no risk alleles. This risk increased dramatically to 5-fold in those with 6 or more risk alleles. What kind of important information does identifi cation of this genetic marker at the HLA region indicate? Based on statistical analysis, the most robustly associated marker, rs3129882 is located in the non-coding region of HLA-DRA. HLA-DR is a major histocompatibility complex, and both 2000 PD 1986 controls