RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants in the gene may influence susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic drugs. To further investigate our previous report of association of the RGS2 gene with susceptibility to antipsychotic-induced EPS, we performed a replication study. EPS were rated in 184 US patients with schizophrenia (115 African Americans, 69 Caucasian) treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). Six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped (rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Our results indicate association of SNP rs4606 with antipsychotic-induced parkinsonism (AIP), as measured by the Simpson Angus scale, in the overall sample and in the African-American subsample, the G (minor) allele having a protective effect. ORs for AIP among rs4606 G-allele carriers were 0.23 (95% CI 0.10–0.54, P=0.001) in the overall sample, and 0.20 (0.07–0.57, P=0.003) in the African-American subsample. In the previously studied Israeli sample the OR was 0.31 (0.11–0.84, P=0.02). We completely sequenced the RGS2 gene in nine patients with AIP and nine patients without, from the Israeli sample. No common coding polymorphisms or additional regulatory variants were revealed, suggesting that association of the rs4606 C/G polymorphism with AIP is biologically meaningful and not a consequence of linkage disequilibrium with another functional variant. Taken together, the findings of the current study support the association of RGS2 with AIP and focus on a possible protective effect of the minor G allele of SNP rs4606. This SNP is located in the 3′-regulatory region of the gene, and is known to influence RGS2 mRNA levels and protein expression.
Antipsychotic (neuroleptic) drugs, the mainstay of pharmacological treatment for schizophrenia, are associated with the development of extrapyramidal symptoms (EPS), some reversible (acute dystonia, parkinsonism and akathisia) and some long-lasting (tardive dyskinesia and dystonia).1, 2 EPS are a major problem in the treatment of schizophrenia because of their negative effect on adherence.3 The majority of studies show that atypical, second-generation antipsychotics are less likely to cause EPS than typical, first-generation drugs.4 Antipsychotic-induced parkinsonism (AIP) is the most frequent manifestation of acute EPS. The incidence of AIP varies from 15 to 40%.5 AIP mimics idiopathic Parkinson's disease symptoms such as bradykinesia and rigidity, but tremor is reported to be less frequent.5 About two-thirds of the patients recover within 2 months but some may require over 6 months for their parkinsonism to resolve.1 AIP is also observed as a late onset (tardive) manifestation.6
Risk factors for AIP include older age, female gender and the use of antipsychotic drugs that block the dopamine D2 receptor with a high level of potency.5 Genetic factors may contribute to inter-individual differences in susceptibility.7 Recently, we reported association of the regulator of G-protein signaling 2 gene (RGS2) with susceptibility to AIP in patients with schizophrenia treated with antipsychotic drugs.8 Five of six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were nominally associated with development or worsening of parkinsonian symptoms in a sample of 115 Jewish, Israeli, acutely psychotic inpatients with schizophrenia. In the context of a prospective study, these patients were treated for at least 2 weeks with typical antipsychotic medication, alone or in combination with the atypical antipsychotic, risperidone. Of particular interest is the association of rs4606, a C1114G polymorphism located in the 3′-untranslated region (UTR) of the gene, which remained significant after correction for multiple testing. The minor G allele of rs4606 was associated with a lesser propensity toward development or worsening of AIP. Functionality of this polymorphism was demonstrated by Semplicini et al.,9 who showed that RGS2 expression was significantly reduced in fibroblasts carrying the rs4606 G allele in comparison with those with the CC genotype and G protein receptor-mediated signaling was significantly increased. In our study8 two haplotypes made up of tagging SNPs (including rs4606) within and flanking the gene were associated with AIP after correction for multiple testing. The haplotype that included the rs4606 G allele was associated with a lesser susceptibility to development or worsening of AIP. Association of RGS2 with akathisia was also observed but at a lesser level of significance.
RGS2 encodes the RGS2 protein, a member of a large protein family defined by a common RGS domain, responsible for regulation of G protein-coupled receptors by binding to the G-α subunit, stimulating GTPase activity and terminating downstream signals.10 RGS2, a 211 amino-acid protein, influences several major receptor signaling systems in the central nervous system including dopaminergic,11 serotonergic,12 cholinergic13 and opioid14 receptors. Involvement of RGS2 in conditions, such as anxiety15 and hypertension16 has been suggested and an association of the gene with panic disorder has been reported.17
Since replication studies are essential in the field of pharmacogenetics, we report a further evaluation of our initial findings concerning the association of RGS2 with AIP in a sample of schizophrenia patients from the United States treated with typical and atypical antipsychotics drugs. We genotyped all six SNPs used in the original study, and performed a cross-sectional analysis of RGS2 as a potential candidate gene for AIP. In addition to the 3′-UTR SNP rs4606, the rs2746073 SNP is intronic, two SNPs are upstream the RGS2 locus (rs1933695 and rs2179652) and two downstream (rs1819741 and rs1152746), all within 20 000 bp flanking region. Furthermore, to determine whether functional polymorphisms in RGS2 other than rs4606 might be associated with AIP and whether the association of rs4606 might be a consequence of linkage disequilibrium (LD) with a different functional variant, we sequenced the entire RGS2 gene in 18 patients from our original Jewish-Israeli sample, selected on the basis of their AIP phenotype and rs4606 genotype status.
There were no significant differences between PARK+ (n=141) and PARK− patients (n=43) as regards demographic and clinical data, such as age, sex, ethnic origin (African-American or Caucasian) and type of antipsychotic treatment (Table 1). However, mean Positive and Negative Symptoms scale (PANSS) score was significantly higher among PARK+ than PARK− patients (P=0.00002) and PARK75% compared to PARK− patients (P=0.001). A similar difference was observed in the African-American subsample (PARK+ vs PARK−, P=0.004; PARK75% vs PARK−, P=0.015).
Two SNPs (rs1933659 and rs2746073) showed a significant (P<0.05) allele frequency difference between African Americans and Caucasians and were therefore analyzed in the African-American subsample only and not in the sample as a whole. Of the four SNPs that were suitable for association testing in the overall sample, one (rs4606) was nominally associated with AIP (P=0.033), the minor (G) allele being more frequent in the PARK− compared to the PARK+ group (Table 2), as previously reported by Greenbaum et al.8 When comparing the PARK− and the PARK75% groups, the significance level was stronger for rs4606 (P=0.016) and rs1819741 also merged as significant (P=0.026). Separate analyses were performed on the patients of African-American origin, taking into account all six SNPs genotyped. As shown in Table 2, rs4606 was associated with AIP in the African-American subsample when allele frequencies were compared in the PARK+:PARK− and PARK75%:PARK− groups (P=0.033, P=0.031). rs1819741 was significant when comparing the PARK− and PARK75% groups (P=0.046). None of these comparisons survive Bonferroni correction for multiple testing.
Haplotype analysis was performed encompassing the four SNPs that could be analyzed in the overall sample. Two of the SNPs (rs4606 and rs1819741) are in an LD block, according to the confidence interval (CI) algorithm of Gabriel et al.18 (Figure 1a). The results of the haplotype analysis are shown in Table 3 for the overall sample and the African-American sample separately; the results from the Jewish-Israeli sample8 are added for comparison. As shown in Table 3, the haplotype CCTA (made up of rs2179652-C, rs4606-C, rs1819741-T and rs1152746-A) was overrepresented among PARK+ (PARK+:PARK− ratio, 0.28:0.13, P=0.006, survives Bonferroni correction for multiple testing) and PARK75% patients (PARK75%:PARK− ratio 0.24:0.10, P=0.016). The TGCA haplotype (made up of rs2179652-T, rs4606-G, rs1819741-C and rs1152746-A) was overrepresented among PARK− patients (PARK+:PARK− ratio, 0.20:0.30, P=0.047; PARK75%:PARK− ratio, 0.16:0.31, P=0.013). The CCTG haplotype (made up of rs2179652-C, rs4606-C, rs1819741-T and rs1152746-G) was also overrepresented among PARK− patients (PARK+:PARK− ratio, 0.15:0.25, P=0.024) but the difference did not emerge as significant for the PARK75%:PARK− ratio (0.19:0.27, P=0.194). Comparing the results of the haplotype analysis across the overall US sample, the African-American subsample and the Israeli sample,8 it is noteworthy that the TGCA haplotype, which has a frequency range of 0.22–0.25, was overrepresented in the PARK− group across all samples by 10–17%. Results for the CCTA and CCTG haplotypes were less consistent among the three samples. When haplotypes derived from the nominally significant rs4606 SNP and the near-significant rs1819742 SNP were examined, the CT haplotype, which has a frequency range of 0.69–0.72, was overrepresented in the PARK+ group across all samples by 12–16%.
Logistic regression analysis, controlling for PANSS scores (Table 4), emphasizes the significant protective effect of the rs4606 G allele against AIP in the overall US sample, the African-American subsample and the Israeli sample (although age and gender are well-known risk factors for AIP, they we not included in the regression models because there was no significant difference between PARK+ and PARK− patients regarding these two variables (Table 2)). The analysis revealed that carriers of the rs4606 G allele (as heterozygotes or homozygotes) were 3.2–5 times less likely to be in the PARK+ group than CC homozygotes. The effect of the TGCA haplotype was similar but weaker, particularly in the Israeli sample. In contrast to AIP, no association of SNPs or haplotypes in the RGS2 gene with antipsychotic-induced akathisia, as measured by the Barnes Akathisia scale (BAS), was observed.
Two rare heterozygous variants were found in gene-coding regions and UTRs in the 18 DNAs sequenced. One was an exon 5-synonymous SNP, G559A (arginine), which had a frequency of 1/18 in PARK− patients and 0 in PARK+ patients; the second was a 5′-UTR G29A SNP with a frequency of 1/18 in PARK+ patients and 0 in PARK− patients. Because of the rarity of these two variants, further genotyping in our sample was not warranted. Three intronic RGS2 SNPs with minor allele frequency >0.05 were detected in the current screen: rs3053226 (intron 3), rs10598428 (intron 4) and rs17647363 (intron 4). These SNPs are already documented in dbSNP and located in an LD block with rs4606. Since these are intronic SNPs with no putative biological function and to avoid spuriously positive results due to high LD with rs4606, we did not further study their association with AIP. Two rare (1/36 frequency), previously unknown, heterozygous intronic SNPs were found as well.
In the context of a cross-sectional replication study, we examined association of the RGS2 gene with EPS (AIP and akathisia) in a US sample of mixed ethnicity that included schizophrenic and schizoaffective patients treated for at least 1 month with a typical or atypical antipsychotic drug. We found that SNP rs4606 was associated with AIP in the overall sample and in the African-American subsample, the G allele being protective. This SNP has been shown by another research group to influence RGS2 gene expression.9 Another SNP, rs1819741 was associated with susceptibility to the extreme phenotype. Haplotypes made up of SNPs within and flanking the gene were associated with AIP in the overall sample and in the African-American subsample. Considering the current observations in conjunction with our original report,8 the most consistent finding was for SNP rs4606. The G (minor) allele of rs4606 was overrepresented in PARK− patients in the Jewish Israeli sample of Greenbaum et al.8 and also in the currently examined overall US sample and African-American subsample, indicating a protective effect. Logistic regression analysis, controlling for illness severity (PANSS total score), showed that carriers of the rs4606 G allele (as heterozygotes or homozygotes) were 3.22 (Israeli sample), 4.34 (overall US sample) and 5.0 (African-American subsample) times less likely to manifest AIP than noncarriers of the G allele. A similar pattern was observed for the TGCA haplotype but the odds ratios (ORs) were slightly weaker; the effect is most likely driven by the rs4606 G allele and the haplotype does not appear to manifest a predictive value greater than the single allele. Subject to further replication, our findings suggest that a priori analysis of genetic variation in RGS2 could contribute to prediction of risk for AIP among schizophrenia patients who are candidates for treatment with typical antipsychotic drugs, in conjunction with demographic and clinical variables and additional variants in RGS2 and other genes that have still to be identified.
Several limitations need to be taken into account when considering the results of this replication study. First, the design differs from that of our original study8 that was prospective. In our original study, patients were treated with typical antipsychotics (with or without risperidone) and AIP was rated at baseline and after 2 weeks of treatment. The PARK+ phenotype was defined as development or worsening of parkinsonism from the pre- to the post-treatment rating. The replication study employed a cross-sectional design with patients rated for AIP after at least a month of treatment with a single typical or atypical antipsychotic drug. The PARK+ phenotype was defined as any score exceeding 0 on the Simpson Angus scale (SAS). SAS scores were substantially higher in the Greenbaum et al.8 study (PARK+=12.2±3.1, PARK−=13.9±4.7 at baseline) than in the current study (PARK+=2.7+2.8, PARK−=0). The lower severity of parkinsonian symptoms most likely reduced the sensitivity of the current study to detect significant effects. In this context, the replicated association of SNP rs4606 is noteworthy. The very stringent 0 threshold set for defining the PARK− phenotype, necessitated by the distribution of SAS scores in the sample, allowed the protective effect of the G allele of rs4606 to be demonstrated. A second limitation of our study is that patients receiving one of four different antipsychotic drugs were studied, only one of the drugs being typical. Since atypical antipsychotics drugs are associated with a lower rate of EPS than typical drugs, this explains the low SAS scores that were observed. Nevertheless, the SAS score of the group receiving typical antipsychotics was not significantly higher than that of the other treatment groups. Third, the small sample size should be taken into account; this would limit power to detect differences and reduce the level of significance, contributing to the fact that only one of the nominally significant univariate associations survived stringent Bonferroni correction for multiple testing. At the same time, multivariate analysis of the rs4606 SNP that controlled for PANSS score showed strong ORs for a protective effect against AIP and stronger significance levels than the univariate analyses. The higher PANSS score in the PARK+ group reflects greater severity of illness, which would most likely have resulted in these patients receiving higher doses of antipsychotic drugs. It was important to take this potentially confounding variable into account, which could not be done in the univariate analyses.
The SNP most consistently associated with AIP, rs4606, is located in the 3′-UTR of the RGS2 gene. Polymorphisms in UTRs may play an important role in posttranscriptional regulation, including translation, stability and degradation, subcellular localization and other mechanisms.19 The influence of rs4606 on RGS2 mRNA and protein levels in cultured fibroblasts was described by Semplicini et al.9 RGS2 gene expression was significantly reduced in fibroblasts carrying the G allele in comparison with those with the CC genotype. Furthermore, there was higher angiotensin II-stimulated intracellular calcium increase and ERK1/2 phosphorylation, which are mediated via a G protein-coupled receptors, in fibroblasts that carry the G allele. Both processes were negatively correlated with RGS2 expression.9 Using computer modeling, Semplicini et al.9 found that the predicted secondary structure of the RGS2 mRNA is influenced by the C/G substitution, by the creation of an internal loop in the transcript structure that may cause a destabilization of the mRNA molecule. These findings indicate that rs4606 is a functional 3′-UTR SNP, which influences RGS2 mRNA expression and probably protein levels.
On sequencing gene-coding regions and UTRs two previously unknown heterozygous variants were found—a 5′-UTR SNP in a PARK+ patient and an exon 5-synonymous SNP in a PARK− patient. Given their rarity, it is unlikely that these variants influence susceptibility to AIP in our sample. Taken together with the functional role rs4606 plays in regulating RGS2 expression,9 these findings support the hypothesis that association of the s4606 C/G polymorphism with AIP is biologically meaningful. On the other hand, as yet unidentified functional variants in protein-coding regions or UTRs may be responsible, by LD, for the observed trend toward association of rs1819741, which is located outside the gene. All intronic RGS2 SNPs with MAF>0.05 detected in the current screen are already documented in dbSNP and located in an LD block with rs4606. However, the possibility that they may play a role independent of rs4606 in regulating gene expression cannot be entirely excluded. Association of additional variants in RGS2 with susceptibility to AIP was observed in our original study8 but not supported in the current study, possible due to lack of power.
The pathophysiology of AIP is unclear. Nigrostriatal pathway dopamine D2 receptor occupancy by antipsychotics is directly related to parkinsonism20 and all clinically effective antipsychotics are D2 receptor blockers.21 D2 receptor occupancy of more than 80%, as produced by typical antipsychotics, significantly increases the risk of AIP.5 D2 receptor occupancy produced by atypical antipsychotics is less than 80%, depending on specific drug type (for example, clozapine exhibits D2 occupancy less than 70%).21 Other hypotheses of AIP pathophysiology focus on the differences between typical and atypical drugs. Faster dissociation from D2 receptors and/or blockade of serotonin receptors (HT2A) by atypical antipsychotics have also been suggested as possible mechanisms.20 RGS2 (a member of the R4 subfamily of RGS proteins) may influence susceptibility to AIP in several ways. RGS2 is reported to modulate D1 and D2 dopamine receptor signal transduction pathways,11, 22, 23 and RGS2 induction by D1 receptor agonist was enhanced in hemiparkinsonian rats.24 Functional variants in the gene may contribute to susceptibility to develop AIP by influencing intracellular dopaminergic signaling. Other GPCR systems whose signaling is reported to be influenced by RGS2 may be influenced by functional variation in the gene, such as M1 and M3 muscarinic receptors.13, 25 It is noteworthy in this context that administration of muscarinic antagonists ameliorates AIP.5 RGS2 also plays a role in serotonergic signaling via 5'HT2A receptors.12 This is relevant because blockade of 5'-HT2A receptors is one of the mechanisms thought to underlie the lesser propensity of atypical antipsychotics to induce AIP. Several studies have shown significant change in RGS2 mRNA level after typical or atypical antipsychotic treatment.26, 27 Further studies of the interaction of RGS2 with other relevant signaling system genes in the context of AIP are indicated.
Notwithstanding the limitations, this replication study modestly supports the findings of our original report8 with regard to two RGS2 SNPs associated with AIP and identifies one of them (rs4606) as protective in all the samples studied. These findings render RGS2 a promising candidate gene for AIP. Further studies in larger samples are warranted. The role of the gene in idiopathic Parkinson's disease and in other pathologies related to the dopaminergic system, such as schizophrenia and ADHD, has yet to be studied.
Patients and methods
Details of the sample and study design are described in detail in a previous publication.28 In brief, this was a cross-sectional study of patients with schizophrenia or schizoaffective disorder diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edn. criteria who were hospitalized at one of three tertiary care public hospitals in the United States and had been treated with a single antipsychotic agent (clozapine, olanzapine, risperidone or a first-generation antipsychotic) for at least a month. Patients gave written informed consent for participation in the study after the purposes and procedures were explained. The protocol and consent forms were approved by the internal review board of each institution. Recruitment was consecutive and sampling procedures were continued until there were approximately 50 patients in each of the four groups. Clinical state was evaluated by the PANSS,29 parkinsonian symptoms by the SAS30 and akathisia by the BAS.31 The scales were administered on two separate occasions, separated by at least a week, by the same clinician. The mean score of the two assessments was used for data analysis. For DNA extraction, 30 cc of blood was collected in EDTA tubes. In addition, the patients were evaluated for fasting blood glucose and lipids; the results of these assays and their relationship to antipsychotic treatment are reported in Smith et al.28
The overall sample for the current study (clinical ratings and DNA available) consisted of 184 patients of whom 115 were African-American, 41 Hispanic and 28 white. Hispanic and white patients were combined as a single Caucasian group (n=69). Distribution among the antipsychotic treatment groups was as follows: typical antipsychotic drugs, n=45; risperidone, n=46; olanzapine, n=50 and clozapine, n=43. No significant difference was seen in mean SAS scores among patients in the different antipsychotic groups.
Genomic DNA was extracted from whole blood using the Puregene DNA Purification System (Gentra Systems, MA, USA). Six SNPs within or flanking RGS2 (upstream and downstream) were genotyped: rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746. These are identical to the six SNPs that were genotyped and analyzed in our original report of association of the RGS2 and EPS.8 Two SNPs (rs1933695 and rs2746073) that showed a statistically significant (P<0.05) allele frequency difference between African Americans and Caucasians were excluded from the analysis of the overall sample but were analyzed in the African-American subsample. No SNPs showed significant deviation from Hardy–Weinberg equilibrium (HWE).
SNP genotyping was performed using the TaqMan Assay-On-Demand purchased from Applied Biosystems (Foster City, CA, USA). The assay contains two primers and two MGB-TaqMan probes. The PCR reaction was performed according to the manufacturer's instructions. In short, 10–30 ng of gDNA were added to a reaction mixture containing 0.22 μl 20 × assay reagent and 2.5 μl 2 × TaqMan Universal PCR Master Mix (Applied Biosystems) in a total volume of 5 μl in 384-well plate. PCR conditions were 2 min at 50 °C, 10 min at 90 °C and 45 cycles of 15 s at 95 °C and 1 min at 60 °C. Real-time PCR was performed and analyzed in an ABI PRISM 7900HT Sequence Detection System (Applied Biosystems) with the SDS 2.3 software. For the purpose of quality control, ∼10% of the samples were genotyped twice; the match rate was 99%.
To identify additional protein-coding or regulatory variants that might influence susceptibility to AIP, we completely sequenced the RGS2 gene in nine patients from the original sample of Greenbaum et al.8 who fulfilled criteria for parkinsonism (PARK+) and nine patients who did not (PARK−). Eight of the patients were rs4606 G-allele carriers (CG/GG genotypes, seven PARK−, one PARK+) and ten were rs4606 CC genotype carriers (eight PARK+, two PARK−). This design, taking into account both rs4606 allele status and AIP phenotype of the patients, allowed us to specifically search for variants that might be in LD with rs4606 and account for the protective effect of the G allele in PARK− G-allele carriers and for susceptibility variants in PARK+ CC genotype carriers. Primers were constructed using the Primer3 program.32 The RGS2 sequence fragments were amplified by PCR (primers sequences available on request), and the amplicons were purified using ExoSAP-IT (USB Corporation, Cleveland, OH, USA). Then the products were sequenced by an automated sequencer at the Hebrew University Center for Genomic Technologies. The sequence analysis was performed with Sequencher software (Gene Codes Corporation, USA).
Patients with an SAS score of 0 on two evaluations were grouped as null (PARK−) for the AIP phenotype and patients whose average SAS score was above 0 were grouped as positive (PARK+). To further explore association of the RGS2 gene with AIP we defined the upper quartile of patients according to SAS scores as PARK75% and compared them to PARK− patients. The same approach was used to analyze the akathisia phenotype according to the BAS. Allele and genotype frequencies were compared in PARK− vs PARK+ and PARK75% patients and in akathisia− and akathisia+ patients by χ2-tests. Bonferroni correction for multiple testing was applied. Haploview (version 3.12; Broad Institute, Cambridge, MA, USA) was used to examine LD between SNPs, to define LD blocks (according to the CI algorithm of Gabriel et al.18), to detect significant departure from HWE and to perform haplotype population frequency estimation. Individual haplotypes were extracted from the population genotype data with the program, PHASE v.2.33, 34 ORs and 95% CIs were calculated by logistic regression, controlling for PANSS scores since these were significantly higher among PARK+ compared to PARK− patients. Age, gender, ethnicity and drug treatment group did not significantly influence the model and were not included.
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This study was supported in part by internal funds from Hadassah Medical Organisation (to BL) and by an Independent Investigator Grant from Eli Lily (to RCS).
Duality of interest
The authors have no competing interests.
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Cite this article
Greenbaum, L., Smith, R., Rigbi, A. et al. Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3′-untranslated region. Pharmacogenomics J 9, 103–110 (2009). https://doi.org/10.1038/tpj.2008.6
- typical antipsychotics
- extrapyramidal symptoms
- antipsychotic-induced parkinsonism
- regulator of G-protein signaling 2
Single-Nucleotide Polymorphisms (SNPs) Both Associated with Hypertension and Contributing to Accelerated-Senescence Traits in OXYS Rats
International Journal of Molecular Sciences (2020)
Human Physiology (2018)
World Journal of Personalized Medicine (2017)
RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer’s disease: genome-wide transcriptomic profiling and bioinformatics data mining
Translational Psychiatry (2016)
A switch in G protein coupling for type 1 corticotropin-releasing factor receptors promotes excitability in epileptic brains
Science Signaling (2016)