..."The finding that genetic variants in immune response affect risk of developing PD, firmly grounds, at the DNA level, the long held notion that the immune system and inflammation play a significant role in PD [2]."...


[poster insertion: HLA-DR is a MHC (major histocompatibility complex ) class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 ...human leukocyte antigens were originally defined as cell surface antigens that mediate graft-versus-host disease, which resulted in the rejection of tissue transplants in HLA-mismatched donors. Identification of these antigens has led to greater success and longevity in organ transplant.

HLA-DR is also involved in several autoimmune conditions, disease susceptibility and disease resistance. It is also closely linked to HLA-DQ and this linkage often makes it difficult to resolve the more causative factor in disease.

HLA-DR molecules are upregulated in response to signalling. In the instance of an infection, the peptide (such as the staphylococcal enterotoxin I peptide) is bound into a DR molecule and presented to a few of a great many T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation.

http://en.wikipedia.org/wiki/HLA-DR


DISCUSSION: It is intriguing that different GWAS's (genome-wide association study) have identified different SNPs as their top PD associated SNP in the HLA region. We questioned whether they tag the same susceptibility locus. In this study, we demonstrated that the top hits from different studies are not strongly correlated with each other. Low correlation among PD-associated SNPs does not rule out the possibility that they tag the same locus, but it does raise the possibility that there may be more than one PD signal in HLA. Using step-wise conditional analyses on the NGRC data we uncovered four seemingly independent signals for PD within the HLA region.

There was no correlation and no detectable interaction among the four NGRC SNPs. Two of the four NGRC SNPs, rs3129882 (SNP1) and rs9268515 (SNP4), were replicated in an independent dataset. We have therefore demonstrated that there are at least two HLA-PD associations that cannot be explained by LD. These signals may indicate different PD-associated alleles at a single susceptibility gene, or different PD susceptibility loci. In support of the different alleles in the same gene hypothesis, there are known examples of multiple disease-associated alleles at the same gene for HLA-associated diseases including type1 diabetes [13] and multiple sclerosis [14], as well as multiple association signals for PD within one gene, notably, SNCA [8], [15].

Alternatively, the signals may represent different genes. SNP1, rs3129882, the original genome-wide significant finding in NGRC, is an expression quantitative trait locus (eQTL). It is in intron 1 of HLA-DRA and is associated with expression levels of HLA-DRA, DRB5 and DQA2 genes [3], [4]. SNP4, rs9268515, is highly correlated (r2 = 0.95) with three eQTL SNPs (rs3793127, rs3763309, rs3763312) that are associated with expression levels of HLA-DQA2 [4]. SNP4 also correlates with the top SNP of IPDGC (r2 = 0.60), which maps between DRA and DRB5, and could be tagging any of the classical HLA genes in the DR-DQ region due to their high LD.This raises the intriguing possibility that PD may be associated with both regulatory elements that influence HLA class II gene expression, and with a classical HLA class II allele

The allele frequency for SNP1 varies significantly in Caucasian Americans according to the European country from which their ancestors immigrated to the US [1]. Furthermore, SNP1 is more strongly associated with sporadic PD than familial PD [1]. Therefore, depending on subject selection, a study may find a positive association (as reported in NGRC), no association, or even an inverse association between SNP1 and PD. We used principal components to correct for ethnic and geographic variability. The subpopulations that differed were the Jewish and the Irish (defined by self-report and verified by principal components [1]). SNP1 and SNP4 remained significant when we excluded the Jewish and the Irish individuals. A recent study showed an inverse association between SNP1 and PD in a mixed Irish and Polish population [16]. It is noteworthy that in the original NGRC GWAS report [1], the Americans of Irish-descent also showed an inverse association between SNP1 and PD, while all other European-descent subpopulations showed a positive association (number of individuals of Polish-descent were few). The Irish/Polish study found the association using a recessive model, as compared to additive model used in NGRC. This is also in agreement with the NGRC data, because the recessive model projects a larger effect size than additive model because it compares individuals who are homozygous for the risk allele to all others.

SNP2 and SNP3 are more than 800 kb away from SNP1 and SNP4. SNP2 had a low minor allele frequency and thus could not be studied in any detail. SNP3 indicated a potential third signal in the NGRC data (NeuroGenetics Research Consortium
(see:http://www.ncbi.nlm.nih.gov/projects...hs000196.v1.p1) ,
but it did not replicate. Much larger sample sizes will be required to determine if and how SNP2 and SNP3 affect susceptibility to PD.

SNP4 was the last of the four seemingly independent SNPs to show up in the conditional analysis of the NGRC data with a modest P = 0.025; and it was the only one of the four NGRC SNPs( that showed any correlation with the top HLA hit of IPDGC. The direction of the SNP4 effect was the same as the IPDGC SNP; they reported reduced risk with the minor allele, we report increased risk with the major allele (we used the risk alleles throughout the text and the main tables to keep the ORs consistently in the positive direction). We used a liberal P<0.05 given the exploratory nature of the study and that we would follow with a replication study.

That our last significant HLA SNP tagged the most significant HLA SNP in IPDGC ( International Parkinson's Disease Genomics Consortium) gives credence to SNP4 being a true association rather than a false positive signal due to a relaxed significance threshold. SNP4 was genotyped in NGRC and imputed in the replication study. The Impute Information score was 0.95, suggesting relatively high reliability. Cases and controls were imputed together under the same conditions, using the same method, and independently of NGRC, and the results showed significantly different allele frequencies between cases and controls for SNP4, in line with the original observation in NGRC. Thus it is unlikely that the results for replication were severely skewed by the fact that SNP4 was imputed; however, replication by other studies will help clarify further.

We do not know if HLA plays a larger role for PD risk for certain individuals and perhaps little or no role for others. HLA may be involved in a subtype of PD; for example, some cases of PD may be due to infection [17] or autoimmunity [18]. Alternatively, HLA may have a ubiquitous role in all PD perhaps via inflammatory response to a variety of causes [19]. The two possibilities are not mutually exclusive; i.e., it is possible that HLA and the immune system affect PD pathogenesis in more than one way.

Our results illustrate the utility of conditional analyses and examination of LD structure in replication studies. These exploratory studies can be used to investigate the possibility of more than one disease association in a region. They can also help understand the differences in the results across association studies. We acknowledge the exploratory nature of this study and the difficulty of deciphering HLA-disease association due to the complex structure of the region. At this point, we have probably identified markers and not the true risk alleles. Not only is it critical to understand the nature of the association(s) of PD with HLA, it is equally important to understand the interrelationship between PD and other HLA-associated disorders, particularly multiple sclerosis which like PD is a neurodegenerative disorder14], [20], [21], [22]. Solving this evolving story will take open collaboration to amass large datasets with genotype, sequence, expression and epigenetic data.

Madelyn,

Girlfriend, you are on fire with the research these days! Keep them coming...this one states outright that PD can result as reaction to a viral or bacterial infection. I have thought this might be a more common cause of "idiopathic" pd since we are all exposed.

So looks like in using good old fashioned common sense, we're now finding that some of of our theories have kept step with the research.

Laura