PD Risk Linked to HLA Gene

Subject: PD Risk Linked to HLA Gene

Date: 8/19/2010

A variant in a human leukocyte antigen (HLA) gene is associated with increased risk for Parkinson’s disease, according to a new study.

The HLA gene in question, HLA-DRA, is expressed by antigen-presenting cells, including microglia, and the resulting proteins interact with T-cell receptors.

The authors conducted a genome-wide association study of 2,000 PD patients from the United States, along with 1,986 controls, testing a total of over 800,000 SNPs. The mean disease duration at enrollment was 8 years, and patients were followed for 4 years afterward, to reduce the risk of misdiagnosis. Controls were an average of 12 years older than cases, reducing the risk that controls had undiagnosed PD.

The results confirmed associations between PD and variants in alpha-synuclein, tau and cyclin G–associated kinase (GAK). After correcting for sex, age, and two genetic factors based on the European and Jewish descent of the population, the authors discovered a new association between PD and a non-coding variant in intron 1 of HLA-DRA. There was no evidence of interactions between presence of the variant and known PD protective factors, including smoking, caffeine consumption, or NSAID use. The authors designated the gene as PARK18.

They next examined the combined effects of alpha-synuclein, tau, GAK and HLA-DRA. They classified subjects by the total number of risk alleles they carried (ranging from 0 to 8). “Compared to subjects who had one or zero risk alleles, the risk of Parkinson’s disease was doubled for individuals who had four risk alleles (OR = 2.49, 95% CI 1.79–3.47, P = 6.5 × 10−8) and was increased fivefold for individuals who had six or more risk alleles (OR = 4.95, 95% CI 3.20–7.64, P = 5.5 × 10−13). Thus, our data support the long-held notion that Parkinson’s disease risk is due to cumulative effects of risk factors having modest individual effects,” the authors report.

The identification of HLA-DRA as a PD risk gene “lends strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” they conclude.

Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease
TH Hamza, CP Z, A Tenesa, A Laederach, J Montimurro, D Yearout, DM Kay, KF Doheny, J Paschall, E Pugh, VI Kusel, R Collura, J Roberts, A Griffith, A Samii, WK Scott, J Nutt, SA Factor, H Payami
Nature Genetics published online 15 August 2010; doi:10.1038/ng.642