Genetic studies have highlighted an overlap in risk factors for amyotrophic lateral sclerosis (ALS) and parkinsonism.1, 2 A recent study by van Es and colleagues has shown that variation in the ALS gene, Angiogenin (ANG), is more frequent in Parkinson’s disease (PD) patients than controls; the study showed that ANG variants were present in 0.46% of ALS, 0.45% of PD and 0.04% of controls.3, 4 In the present study we sequenced ANG in our PD patient-control series to assess the mutation burden in patients and risk of disease.
We employed the Mayo Clinic Florida Caucasian PD patient-control series. This series contains 630 patients with PD and 676 healthy control subjects matched by age. All patients were examined and observed longitudinally by a movement disorders neurologist and diagnosed with PD according to published criteria. Unrelated control individuals were free of personal or familial history suggestive of parkinsonism. We performed bidirectional DNA sequencing on all exons of the ANG gene. The ethical review boards at each institution approved the study, and all participants provided informed consent.
We identified four coding non-synonymous ANG variants in our patients with PD (0.63%) and zero in our controls (Table). Of the four variants, two are novel (c.70G>C; p.A-1P and c.302A>C; p.Q77P) and were not observed in the large study by van Es and colleagues. The other two known variants were p.K17I and p.K60E, after removing p.K17I from the analysis the frequency remained 0.47% which matches the findings of van Es et al. Table 1 displays variation observed in the ANG gene and the frequency of both common and rare variants. Statistical association for common variants was performed and a significant association with disease risk and rs11701 was observed (uncorrected P-value 0.01). Interestingly, association of SNP rs11701 with risk of ALS first nominated ANG as gene for ALS.5
Table 1. Angiogenin variants identified by sequencing in US case/control series.
The association between common ANG variation and PD was evaluated using a logistic regression model adjusted for age (age at diagnosis for patients and age at blood draw for controls) and gender, where odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. We examined association under an additive model. For exploratory analysis P-values ≤ 0.05 were considered statistically significant and analyses were performed using PLINK (http://pngu.mgh.harvard.edu/purcell/plink/)
| Chromosome: BP | SNP | Amino Acid | major/minor allele | US Controls | US Cases | OR (95% CI) | p value | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Major (%) | Het (%) | (%) | Total | MAF | Major (%) | Het (%) | Minor (%) | Total | MAF | ||||||
| 14:21152357 | rs117466368 | G/C | 643(95.1) | 33(4.9) | 0(0) | 676 | 0.024 | 600(95.2) | 30(4.8) | 0(0) | 630 | 0.024 | 0.87(0.52,1.46) | 0.60 | |
| 14:21152402 | rs117787610 | C/T | 652(96.4) | 24(3.6) | 0(0) | 676 | 0.018 | 608(96.5) | 22(3.5) | 0(0) | 630 | 0.017 | 0.87(0.48,1.59) | 0.66 | |
| 14:21152406 | rs117053048 | T/C | 642(95.0) | 34(5.0) | 0(0) | 676 | 0.025 | 600(95.2) | 30(4.8) | 0(0) | 630 | 0.024 | 0.85(0.51,1.42) | 0.53 | |
| 14:21152535 | rs45591635 | G/T | 644(95.3) | 31(4.6) | 1(0.1) | 676 | 0.024 | 599(95.1) | 31(4.9) | 0(0) | 630 | 0.025 | 0.91(0.55,1.51) | 0.72 | |
| 14:21152553 | rs113950902 | C/G | 676(100) | 0(0) | 0(0) | 676 | 0.000 | 629(99.8) | 1(0.2) | 0(0) | 630 | 0.001 | NA | NA | |
| 14:21152604 | rs28589507 | C/A | 531(78.6) | 128(18.9) | 17(2.5) | 676 | 0.120 | 497(78.9) | 124(19.7) | 9(1.4) | 630 | 0.113 | 0.92(0.72,1.16) | 0.47 | |
| 14:21152699 | rs45525731 | A/C | 646(95.6) | 30(4.4) | 0(0) | 676 | 0.022 | 600(95.2) | 30(4.8) | 0(0) | 630 | 0.024 | 0.95(0.56,1.61) | 0.85 | |
| 14:21152895 | rs117978329 | T/C | 644(95.3) | 32(4.7) | 0(0) | 676 | 0.024 | 600(95.2) | 30(4.8) | 0(0) | 630 | 0.024 | 0.89(0.53,1.5) | 0.66 | |
| 14:21152938 | IVS1+27 | C/T | 625(92.5) | 51(7.5) | 0(0) | 676 | 0.038 | 574(91.1) | 55(8.7) | 1(0.2) | 630 | 0.045 | 1.22(0.82,1.82) | 0.33 | |
| 14:21161794 | c.70G>C | A-1P | G/C | 676(100) | 0(0) | 0(0) | 676 | 0.000 | 629(98.8) | 1(0.2) | 0(0) | 630 | 0.001 | NA | NA |
| 14:21161844 | rs121909536 | K17I | A/T | 676(100) | 0(0) | 0(0) | 676 | 0.000 | 629(98.8) | 1(0.2) | 0(0) | 630 | 0.001 | NA | NA |
| 14:21161973 | rs17560 | K60E | A/G | 676(100) | 0(0) | 0(0) | 676 | 0.000 | 629(98.8) | 1(0.2) | 0(0) | 630 | 0.001 | NA | NA |
| 14:21162025 | c.302A>C | Q77P | A/C | 676(100) | 0(0) | 0(0) | 676 | 0.000 | 629(98.8) | 1(0.2) | 0(0) | 630 | 0.001 | NA | NA |
| 14:21162053 | rs11701 | T/G | 565(83.6) | 103(15.2) | 8(1.2) | 676 | 0.088 | 483(76.7) | 136(21.6) | 11(1.7) | 630 | 0.125 | 1.40(1.08,1.80) | 0.01 | |
| 14:21162248 | Exon2 + 81 | 3'UTR | A/C | 676(100) | 0(0) | 0(0) | 676 | 0.000 | 629(98.8) | 1(0.2) | 0(0) | 630 | 0.001 | NA | NA |
The study of van Es et al. has demonstrated the important role rare variants play in the individual risk of susceptibility to PD. Further studies are warranted to characterize patients with PD who carry rare variants in ANG and identify if there are clinicopathologic correlates that distinguish carriers from typical late-onset sporadic PD patients. As we move towards an era of individualized medicine it will be crucial to determine the frequency of rare variants and elucidate their influence on disease risk. The feasibility of genetic testing for such rare variants will need to be addressed in the long term.
Acknowledgments
We would like to thank all those who have contributed to our research, particularly the patients and families who donated DNA samples for this work. This work is supported in part by a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187), NINDS R01NS078086 and the Mayo Clinic Clinical Research Program (MCF #90052030).
Footnotes
The authors declare no financial or other conflict of interests.
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