Association of Single Nucleotide Polymorphism at rs2275294 in the ZNF512B Gene with Prognosis in Amyotrophic Lateral Sclerosis

Jiang, Haixia; Yang, Baiyuan; Wang, Fang; Li, Kelu; Zhu, Yongyun; Liu, Bin; Ren, Hui; Tian, Sijia; Xu, Yanming; Pang, Ailan; Yang, Xinglong

doi:10.1007/s12017-020-08634-y

Cited by 8 publications

(12 citation statements)

References 20 publications

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“…The first allele(s) reported here is the detrimental one. All dichotomies were based on the original papers reporting the gene in ALS or subsequent studies 3,4,5,8,9 and were confirmed in our cohort (data not shown).…”

Section: Methodsmentioning

confidence: 73%

“…Genetic modifiers of ALS phenotype have been generally studied in isolation. 3,4,5,8,9 Notable exceptions are two studies reporting that the co-occurrence of the C9orf72 repeat expansion and UNC13A C/C polymorphism significantly worsened the prognosis of patients with ALS. 18,19 However, identifying the mechanisms underlying the wide phenotypic heterogeneity of ALS, which hinders the discovery of effective therapies, 2 remains one of the significant unmet goals of ALS research.…”

Section: Discussionmentioning

confidence: 99%

“…Among these, the most relevant are UNC13A (rs12608932 polymorphism), 3,4 CAMTA1 (rs2412208 polymorphism) 5 ATXN2 (intermediate polyQ repeats), 6,7 SLC11A2 (rs407135 polymorphism), 8 and ZNF512B (rs2275294 polymorphism). 9 Interestingly, UNC13A polymorphism has been demonstrated to be also a modifier of the response to drugs. 10 These observations are important from the clinical trial perspective.…”

Section: Introductionmentioning

confidence: 99%

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The additive effect of genetic modifiers on ALS prognosis: a population-based study

Chiò

Moglia

Canosa

et al. 2022

Preprint

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Objective. To determine if the co-presence of genetic polymorphisms related to ALS has additive effects on the course of the disease in a population-based cohort of Italian patients. Methods. The study population includes 1245 ALS patients identified through the Piemonte Register for ALS, diagnosed between 2007 and 2016 and not carrying SOD1, TARDBP and FUS mutations. Controls were 766 age, sex, and geographically matched Italian subjects. We considered UNC13A (rs12608932), CAMTA1 (rs2412208), SLC112A (rs407135) and ZNF512B (ZNF512B) polymorphisms, as well as ATXN2 polyQ intermediate repeats and C9ORF72 GGGGCC intronic expansion. Results. The variants in C9orf72 (p=0.016), ATXN2 (p<0.001) and UNC13A (p<0.001) were significantly related to survival in univariate analysis, while the other considered variants did not influence ALS outcome. However, in the Cox multivariable analysis, also CAMTA1 emerged to be independently related to survival. When assessing the interaction by pairs of genes, we found that the presence of both detrimental alleles/expansion was correlated with significantly shorter survival compared to subjects non-carrying both detrimental alleles/expansions. Each association of pairs of detrimental alleles was characterized by specific clinical phenotypes. Conclusions. We demonstrated that gene polymorphisms acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common polymorphism or repeat expansion, highlighting the clinical impact of our findings. In addition, the identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity and should be considered in designing and interpreting clinical trials.

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Section: Methodsmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The additive effect of genetic modifiers on ALS prognosis: a population-based study

Chiò

Moglia

Canosa

et al. 2022

Preprint

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“…Additionally, such a study has not been performed in Asian populations. Several studies in East Asian populations suggested that rs2275294 in ZNF512B 16 17 and rs9268856 in HLA-DRA/HLA-DRB5 18 affect patient survival, although these studies were retrospective analyses of one or a few SNPs in a small number of cases.…”

Section: Introductionmentioning

confidence: 99%

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Nakamura

Tohnai

Nakatochi

et al. 2023

J Neurol Neurosurg Psychiatry

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BackgroundSeveral genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS.MethodsWe enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS.ResultsThree novel loci were significantly associated with the survival of patients with sporadic ALS—FGF1at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10−9),THSD7Aat 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10−8) andLRP1at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10−8).FGF1andTHSD7Avariants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression ofFGF1andTHSD7Awas partially disrupted. The rs60565245 was not associated withLRP1mRNA expression.ConclusionsWe identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression ofFGF1andTHSD7Aand the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

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“…Among these, the most relevant are Unc-13 homolog A ( UNC13A ) (rs12608932 variant), 3,4 calmodulin binding transcription activator 1 ( CAMTA1 ) (rs2412208 variant), 5 ataxin-2 ( ATXN2 ) (intermediate polyQ repeats), 6,7 solute carrier family 11 member 2 ( SLC11A2 ) (rs407135 variant), 8 and zinc finger protein 512B ( ZNF512B ) (rs2275294 variant). 9 Interestingly, UNC13A variant has been demonstrated to be also a modifier of the response to drugs. 10 These observations are important from the clinical trial perspective.…”

mentioning

confidence: 99%

Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis

et al. 2023

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Objective.Despite recent advances, it is not clear whether the various genes/genetic variants related to ALS interact in modifying patients phenotype. The aim of this study was to determine if the co-presence of genetic variants related to ALS has interactive effects on the course of the disease.Methods.The study population includes 1,245 ALS patients identified through the Piemonte Register for ALS between 2007 and 2016 and not carryingSOD1, TARDBPandFUSpathogenic variants. Controls were 766 Italian subjects age-, sex-, and geographically-matched to cases. We consideredUNC13A (rs12608932), CAMTA1 (rs2412208), SLC11A2 (rs407135) andZNF512B (rs2275294)variants, as well asATXN2polyQ intermediate repeats (≥31) andC9orf72GGGGCC intronic expansions( ≥30).Results.The median survival time of the whole cohort was 2.67 years (IQR 1.67-5.25). In univariate analysis onlyC9orf72(2.51 years, IQR 1.74-3.82; p=0.016),ATXN2(1.82 years, IQR 1.08-2.33; p<0.001) andUNC13AC/C(2.3 years, IQR 1.3-3.9; p<0.001) significantly reduced survival. In Cox multivariable analysis, alsoCAMTA1emerged to be independently related to survival (HR 1.13, 95% c.i. 1.001-1.30, p=0.048). The co-presence of two detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients withCAMTA1G/G+G/TandUNC13AC/Calleles was 1.67 years (1.16-3.08) years compared to 2.75 years (1.67-5.26) of the patients not carrying these variants (p<0.001); the survival of patients withCAMTA1G/G+G/Talleles andATXN2≥31intermediate polyQ repeats was 1.75 years (0.84-2.18) (p<0.001); the survival of patients withATXN2≥31polyQ repeats andUNC13AC/Callele was 1.33 years (0.84-1.75) (p<0.001); the survival of patients withC9ORF72≥30andUNC13AC/Callele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes.Conclusions.We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results.

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Association of Single Nucleotide Polymorphism at rs2275294 in the ZNF512B Gene with Prognosis in Amyotrophic Lateral Sclerosis

Cited by 8 publications

References 20 publications

The additive effect of genetic modifiers on ALS prognosis: a population-based study

The additive effect of genetic modifiers on ALS prognosis: a population-based study

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis

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