Regulatory Variation within 3’UTR of STAT5A Correlates with Sudden Cardiac Death in Chinese Populations

Q: What is the clinical evidence from this study?

Study design: Case-Control. Population: Sudden cardiac death (SCD) (n=827). Intervention: STAT5A 3'UTR insertion/deletion polymorphism (rs3833144) deletion allele vs. Insertion allele (ins) / ins/ins genotype of rs3833144. Primary outcome: Sudden cardiac death (SCD) susceptibility (additive model, del allele vs ins allele) (OR 1.54, 95% CI 1.18-2.01, p=0.000955).

Q: What does this research mean for the field?

The 4-bp deletion allele of the STAT5A 3'UTR polymorphism rs3833144 is significantly associated with an increased risk of sudden cardiac death in Chinese populations. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Huan Yu; Yadong Guo; Zhenzhen Yang; Qing Zhang; Jiabin Xu; Qi Yang; Yiling Qu; Rui Tan; Lijuan Li; Yan He; Chengtao Li; Suhua Zhang; Bin Luo; Yuzhen Gao

doi:10.1080/20961790.2021.1895410

July 23, 2021Forensic Sciences ResearchOpen Access

Regulatory Variation within 3’UTR of STAT5A Correlates with Sudden Cardiac Death in Chinese Populations

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Key result

STAT5A rs3833144 deletion allele linked to ~54% higher sudden cardiac death risk.

OR 1.54
95% CI 1.18-2.01
P=0.000955
n=827

Figures

Why the study?

Postmortem examination often fails to reveal an adequate cause of death in sudden cardiac death victims, making it important to uncover the inherited risk component.

Does the deletion allele of the STAT5A 3'UTR indel polymorphism rs3833144 increase susceptibility to sudden cardiac death in Han Chinese populations?

Key Points

To evaluate whether functional genetic variations within the 3’UTR of the STAT5A gene influence susceptibility to sudden cardiac death in Chinese populations.
Screened 3’UTR variants of STAT5A with minimum allele frequency > 0.01 and selected candidate insertion/deletion variant rs3833144.
Performed a case-control study enrolling 159 sudden cardiac death cases and 668 matched healthy controls in Chinese populations.
Assessed functional effects using genotype-expression eQTL analyses, in silico mRNA 3D structure prediction, Hi-C chromatin interaction data, and dual-luciferase reporter assays.
The deletion allele of rs3833144 significantly increased sudden cardiac death risk under an additive model (adjusted OR = 1.54; 95% CI = 1.18–2.01; P = 9.55 × 10^-4).
Carriers of the del/del genotype had elevated sudden cardiac death risk compared with the ins/ins genotype under a codominant model (adjusted OR = 2.53; 95% CI = 1.41–4.51; P = 6.83 × 10^-4).
Samples with the deletion allele showed lower STAT5A mRNA expression (P = 0.037), altered local 3D mRNA structure, and significant regulatory differences in luciferase transcriptional assays.

Study Design

Type

Case-Control (n=827)

Multicenter

Yes

Structured PICO

Does the deletion allele of the STAT5A 3'UTR indel polymorphism rs3833144 increase susceptibility to sudden cardiac death in Han Chinese populations?

P

Population

827 genetically unrelated Han Chinese individuals (159 sudden cardiac death victims with autopsy-confirmed coronary atherosclerosis and 668 age- and sex-matched healthy controls without cardiovascular disease history) from multiple centers in China.

E

Exposure

Carriage of the 4-bp deletion allele (or del/del, ins/del genotypes) of the insertion/deletion polymorphism rs3833144 in the 3'UTR of the STAT5A gene

C

Comparator

Carriage of the insertion allele (or ins/ins reference genotype) of rs3833144 in the 3'UTR of STAT5A

O

Outcome

Sudden cardiac death (SCD) susceptibility, defined as sudden and unexpected death or arrest attributed to a cardiovascular cause confirmed by forensic postmortem autopsyhard clinical

Main Result

Odds Ratio: 1.54 (95% CI 1.18–2.01)

Absolute Event Rate: 38.05% vs 28.29%

p-value: p=0.000955

Identifies the STAT5A 3'UTR indel polymorphism rs3833144 as a functional genetic variant associated with increased sudden cardiac death susceptibility in Chinese populations, offering a potential candidate marker for forensic molecular diagnosis and genetic risk screening.

Limitations

eQTL analysis mainly focused on lymphoblastoid cell lines from the 1000 Genomes Project database because RNA-seq and genotyping data of cardiomyocytes were not available.
Further functional assays are needed to verify the bioinformatic hypotheses on how rs3833144 contributes to SCD risk.
Relatively small sample size, requiring further replicated case-control studies in different or expanded populations.
SCD cases mostly suffered sudden death originating from coronary atherosclerosis, raising an unverified possibility that rs3833144 may be associated with coronary atherosclerosis susceptibility rather than SCD alone.
RNA-seq and genotyping data of cardiomyocytes were not available, so eQTL analysis was restricted to lymphoblastoid cell lines in the 1000 Genomes Project database.
Small sample size limiting statistical power (0.712 under dominant model), necessitating replication in larger or different populations.
SCD cases predominantly had underlying coronary atherosclerosis at autopsy, so the variant might be associated with coronary atherosclerosis susceptibility rather than SCD specifically.

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Supports STAT5A rs3833144 as candidate SCD marker in Chinese; hypothesis-generating and requires independent validation before forensic use.

Abstract

Definitive diagnosis to sudden cardiac death (SCD) is often challenging since the postmortem examination on SCD victims could hardly demonstrate an adequate cause of death. It is therefore important to uncover the inherited risk component to SCD. Signal transducer and activators of transcription 5 A (STAT5A) is a member of the STAT family and a transcription factor that is activated by many cell ligands and associated with various cardiovascular processes. In this study, we performed a systematic variant screening on the STAT5A to filter potential functional genetic variations. Based on the screening results, an insertion/deletion polymorphism (rs3833144) in 3’UTR of STAT5A was selected as the candidate variant. A total of 159 SCD cases and 668 SCD matched healthy controls was enrolled to perform a case-control study and evaluate the association between rs3833144 and SCD susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs3833144 had significantly increased the SCD risk (odds ratio (OR) = 1.54; 95% confidence interval (CI) = 1.18–2.01; P = 0.000955). Further genotype-expression eQTL analysis showed that samples with deletion allele appeared to lower expression of STAT5A, and in silico prediction suggested the local 3 D structure changes of STAT5A mRNA caused by the variant. On the other hand, the bioinformatic analysis presented that promoters of RARA and PTGES3L-AARSD1 could interact with rs3833144, and eQTL analysis showed the higher expression of both genes in samples with deletion allele. Dual-luciferase activity assays also suggested the significant regulatory role of rs3833144 in gene transcription. Our current data thus suggested a possible involvement of rs3833144 to SCD predisposition in Chinese populations and rs3833144 with potential function roles may become a candidate marker for SCD diagnosis and prevention.

Discussion

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Cite This Study

Yu et al. (2021) conducted a case-control in Sudden cardiac death (SCD) (n=827). STAT5A 3'UTR insertion/deletion polymorphism (rs3833144) deletion allele vs. Insertion allele (ins) / ins/ins genotype of rs3833144 was evaluated on Sudden cardiac death (SCD) susceptibility (additive model, del allele vs ins allele) (OR 1.54, 95% CI 1.18-2.01, p=0.000955). The 4-bp deletion allele of the STAT5A 3'UTR rs3833144 polymorphism was associated with a 1.54-fold increased risk of sudden cardiac death in Chinese populations (OR 1.54, 95% CI 1.18-2.01; P=0.000955).

synapsesocial.com/papers/6a842f1b22c36ed33af79678 https://doi.org/10.1080/20961790.2021.1895410

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Regulatory Variation within 3’UTR of STAT5A Correlates with Sudden Cardiac Death in Chinese Populations

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Regulatory Variation within 3’UTR of STAT5A Correlates with Sudden Cardiac Death in Chinese Populations

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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