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Despite Large-Scale Efforts, Inverse Association Between Smoking and Parkinson Disease Remain Unelucidated

Valine at position 11, the most significantly associated amino acid, was found in 26% of controls and 22% of individuals with Parkinson disease.

Findings from a large-scale genome-wide association study of more than 20,000 individuals showed an inverse association between genetically predicted smoking initiation and Parkinson disease (PD) that was consistent with prior reports. Above all, the mechanisms underlying the inverse association between smoking and PD remain unknown.1

Previous studies have identified an association with the human leukocyte antigen (HLA) region, in particular with HLA-DRB1. Published in Movement Disorders, senior investigator Alexis Elbaz, MD, PhD, and colleagues performed a Mendelian randomization (MR) analysis using 182 single nucleotide polymorphisms (SNPs) associated with smoking initiation as instrumental variables in strata defined by HLA-DRB1. The final sample included 12,424 cases and 9480 controls over 26 studies with at least 50 cases or controls of European descent.

"Despite being one of the most robust findings in PD, the mechanisms underlying its inverse association with smoking remain unknown,” Elbaz et al wrote. "This work represents the first example of large-scale replication of a gene-environment interaction in PD, and allows proposing a biological mechanism to explain the inverse smoking-PD association, in the context of a larger body of work on the relationship between the immune system and PD.”

A total of 11 amino acids (AAs) were associated (9 inversely, 2 positively) with PD and were all encoded by HLA-DRB1. Following a backward stepwise selection procedure, 2 AAs, a valine at position 11 (V11) and S37, remained significantly associated with PD (OR, 0.85; 95% CI, 0.79-0.92; P = 2.2 x 10-5); although, V11 demonstrated a stronger association (OR, 1.0;7 95% CI, 1.00-1.14; P = .040).

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Previously, data from Hollenbach et al reported an inverse association of PD with the shared epitope (SE), a combination of AAs coded by HLA-DRB1, only in the presence of a V11.2 In the new study, there was no found significant interaction between SE and V11 (P = .29), as only V11 remained associated with PD (OR, 0.81; 95% CI, 0.74-0.89; P < 10-3) when both were included in the model.

In a prior meta-analysis, the strongest association was an inverse association with a histidine at position 13 (H13) in HLA-DRB1, and strongly correlated with V11.3 Additionally, a recent study by Yu et al highlighted 3 AAs—V11, H13, and H33—encoded by HLA-DRB1 inversely associated with PD.4 Similarly, Elbaz and colleagues found that the association of H13 and H33 with PD was explained by V11.1

Between genetically predicted smoking initiation and PD, investigators found an overall association OR of 0.86 (95% CI, 0.73-1.05; P = .10) without evidence of heterogeneity between SNPs (P = .40). Carriers of at least 1 V11 residue were found in 26% of controls vs 22% of the cases. Notably, inverse associations were found between genetically predicted smoking initiation and PD in the absence of V11 (ORIVW, 0.74; 95% CI, 0.59-0.93; P = .0092) but not in its presence (ORIVW, 1.25; 95% CI, 0.83-1.87; P = .29), with a positive and significant interaction (P = .03).

To examine the influence of V11 encoded by HLA-DRB1 alleles and homocitrullination (HC) of α-synuclein derived peptides on binding affinity, Elbaz et al described binding affinity for the 4 groups defined by the combination of V11 and HC. All 2 x 2 differences were tested using the Wilcoxon non-parametric test corrected for multiple comparisons. All told, compared with V11– and HC–, V11+HC– and V11–HC+ combinations were both associated with decreased affinity, with a stronger effect of HC+ than V11+. Alternatively, in the presence of HC+, V11+ increased binding affinity or had no effect (Y39).

Among 64 alleles of HLA class 2 genes, 5 were significantly and inversely associated with PD (HLA-DQA1*03:01, HLA-DQA1*03:03; HLA-DQB1*03:02; HLA-DRB1*04:01, and HLA-DRB1*04:04). Notably, the OR for the association between all HLA-DRB1*04 alleles combined with PD was of 0.84 (95% CI, 0.78-0.91; P = 3.9 x 10-6).

1. Domenighetti C, Douillard V, Sugier P, et al. The interaction between HLA-DRB1 and smoking in Parkinson disease revisited. Mov Disord. Published online July 10, 2022. doi:10.1002/mds.29133
2. Hollenbach JA, Norman PJ, Creary LE, et al. A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson's disease. Proc Natl Acad Sci U S A 2019;116:7419–7424. doi:10.1073/pnas.1821778116
3. Naito T, Satake W, Ogawa K, et al. Trans-ethnic fine-mapping of the major histocompatibility complex region linked to Parkinson's disease. Mov Disord 2021;36:1805–1814. doi:10.1002/mds.28583
4. Yu E, Ambati A, Andersen MS, et al. Fine mapping of the HLA locus in Parkinson's disease in Europeans. NPJ Parkinsons Dis 2021;7:84. doi: 10.1038/s41531-021-00231-5