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Correlation of METTL4 genetic variants and severe pneumonia pediatric patients in Southern China

BMC Genomic Data volume 26, Article number: 33 (2025) Cite this article

Abstract

Background

Pneumonia is a major cause of mortality and health burden in children under five, yet its genetic etiology remains poorly understood. Methyltransferase 4, N6-adenosine (METTL4), is a methyltransferase enzyme responsible for RNA and DNA methylation and is known to be activated under hypoxic conditions. However, its potential link to susceptibility to pneumonia has not been evaluated. This study aimed to explore candidate regulatory single nucleotide polymorphisms (SNPs) within the METTL4 gene and their association with the development of severe pneumonia.

Results

In this study, we recruited a cohort of 1034 children with severe pneumonia and 8426 healthy controls. We investigated the associations of candidate regulatory single nucleotide polymorphisms (SNPs) within METTL4 polymorphisms with severe pneumonia. Our results indicated that the C allele of rs9989554 (P = 0.00023, OR = 1.21, 95% CI: 1.09–1.34) and the G allele of rs16943442 (P = 0.0026, OR = 1.22, 95% CI: 1.07–1.38) were significantly associated with an increased risk of severe pneumonia. The regulatory potential of these two SNPs in the lung was investigated using tools such as expression quantitative trait loci (eQTLs), RegulomeDB, and FORGEdb.

Conclusions

This study represents the first investigation elucidating the role of genetic variations in the METTL4 gene and their influence on susceptibility to severe pneumonia in pediatric populations. METTL4 is identified as a novel predisposing gene for severe pneumonia and a potential therapeutic target. Further research is warranted to validate this correlation and to comprehensively elucidate the biological role of the METTL4 gene in severe pneumonia.

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Background

Pneumonia is the most common lower respiratory tract infection in children and poses a significant threat to their health [1]. In 2015, community-acquired pneumonia (CAP) was responsible for 15% of deaths in children under five years old worldwide, resulting in a total of 922,000 fatalities among children of all ages globally [2]. Infections originating in the lung are the primary cause of severe pneumonia and childhood death [3]. Influenza viruses, Respiratory syncytial virus, Adenovirus, Mycoplasma, Chlamydophila, Staphylococcus aureus, etc., are the most frequently identified pathogens in severe pneumonia [4,5,6]. Pathogen invasion triggers host responses that stimulate the secretion of inflammatory cytokines such as TNF-a, IL-1b and IL-6. These cytokines impair the alveolar epithelial barrier and enhance epithelial permeability. An excessive inflammatory response is a hallmark of severe pneumonia, characterized by the presence of pulmonary edema and interstitial transparent membranes in the alveolar interstitium, which subsequently leads to clinical symptoms of fever, cough, chest pain, and dyspnea [7, 8]. Severe pneumonia may lead to the development of life-threatening syndromes, including acute respiratory distress syndrome (ARDS) [9] or respiratory failure [10]. Treatments for severe pneumonia mainly rely on antibiotics or corticosteroids, which are sometimes ineffective.

Methyltransferase 4, N6-adenosine (METTL4), belongs to the methyltransferase-like (METTL) family and methylates nucleotides, proteins, and small molecules [11]. METTL4 catalyzes the methylation of RNA (m6A) and DNA (6 mA), including internal N6-methylation of cap-adjacent N6,2′-O-dimethyladenosine of U2 small nuclear RNA (snRNA), microRNA and mammalian mitochondrial DNA [12, 13]. A recent study showed that METTL4 promotes ferroptosis by increasing BECN1 mRNA m6A modification and autophagy in hepatic stellate cells [14]. Hsu et al. showed that in mammalian tumor cells, hypoxia results in increased 6 mA levels through METTL4 via the activation of multiple metastasis-inducing genes [15]. Interestingly, in a human fibroblast cell line under hypoxic conditions, the methylated levels of the vasoactive microRNA m6A were significantly increased. Moreover, m6A modification is also present in viruses such as adenovirus [16] and SARS-CoV-2 [17]. In soft tissue sarcomas (STS), copy number variation (CNV) of the METTL4 gene could serve as a prognostic biomarker by potentially influencing mast cell infiltration and DNA methylation [18].

Given that METTL4 is activated under hypoxic conditions and that widespread m6A modification occurs during viral replication [19, 20], alterations in the METTL4 gene may correlate with the risk of developing severe pneumonia. In this study, we assembled a cohort including 1034 severe pneumonia patients and 8624 controls from a South Chinese population aged 0–15 years. First, the associations between METTL4 SNPs and severe pneumonia susceptibility were investigated. Then, haplotype-association and subtype-specific association analyses of the SNPs were conducted.

Methods

Study subjects

This work was conducted with the approval of the Medical Ethics Committees of Guangzhou Women and Children’s Medical Center (No: 2016111853), with 1034 children who were diagnosed with severe pneumonia and a group of 8624 children without a history of pneumonia involved in previous studies [21]. Written informed consent to participate was obtained from the legal guardians of all participants. Data on demographic characteristics and disease severity were extracted from the electronic medical records of the patients.

Characteristics of the study participants

The clinical characteristics of the study participants were shown in Table 1. We included a severe pneumonia cohort with 1,034 patients and 8,426 healthy controls. The ages of the participants ranged from 0 to 180 months, with 37.9% being female. The control group consisted of individuals aged between 1 month and 240 months. Among the pneumonia patients, 719 (69.5%) were diagnosed with primary severe pneumonia, while 315 (31.5%) were diagnosed with secondary severe pneumonia.

Table 1 Cohort characteristics
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Criteria for severe pneumonia, primary and secondary severe pneumonia

Criteria for severe pneumonia: (a) invasive mechanical ventilation; (b) fluid refractory shock; (c) acute need for non-invasive positive-pressure ventilation; and (d) hypoxemia requiring fractional inspired oxygen (FiO2) > inspired concentration or flow feasible in the general-care area. Primary pneumonia was defined as severe pneumonia with initially diagnosed with pathogens infections. Secondary pneumonia was defined as severe pneumonia in connection with other disease such as cardiovascular disease, acute renal failure, or gastrointestinal dysfunction. The pathogen information was retrieved from the electronic medical records of the participants. Pathogen detection was performed at the central hospital diagnostic laboratories using blood, throat swab, sputum, or BAL samples.

Polymorphism selection and genotyping

The procedure for extracting and amplifying genomic DNA from venous blood samples of the included cases, following the selection criteria outlined in our published report, has been previously described [21]. The SNPs were genotyped using a MassARRAY iPLEX Gold system (Sequenom). HWE tests were performed using the goodness-of-fit χ2 test, with P < 0.05 indicating a deviation from HWE. The raw genotyping data supporting this analysis are provided in Supplementary Material 2.

SNP- and haplotype-based association analysis

All common SNPs within ± 5 kb flanking METTL4 were retrieved from the “dbSnp153Common” database by using UCSC hgTable and filtered by the minor allele frequency (MAF > 0.05) in the East Asian (EAS) population (CHS + CHB + JPT in 1000 Genomes Data). The pairwise linkage disequilibrium (LD) between SNPs was assessed in the 1000 Genome EAS population and visualized as an LD heatmap by using the R package “LDheatmap”. A R2 > 0.8 was considered to indicate high LD. Tag-SNPs were selected as the minimal set of independent SNPs that represent all SNPs in each LD block. Finally, 17 SNPs were selected for subsequent analyses. Additionally, a haplotype-specific competitive test was conducted, which compares each haplotype against all others. A P value less than 0.0045 was considered to indicate statistical significance.

Statistical analysis

The allelic association between METTL4 polymorphisms and severe pneumonia was assessed by comparing allele frequencies in patients and controls using the PLINK program (v1.9b). Age and sex were adjusted for in the multivariate logistic regression. The 95% confidence intervals (CIs) and odds ratios [22] were used to estimate the effect sizes of the SNPs. Bonferroni correction was applied to control for type 1 errors caused by multiple testing. A P value < 0.0045 was considered to indicate statistical significance. The GTEx portal was used to assess the expression quantitative trait locus (eQTL) effects of the SNPs (https://gtexportal.org/home/). The LD between SNPs was calculated by LDmatrix (https://ldlink.nci.nih.gov/?tab=home) and visualized by the R packages “LDlinkR” and “gaston”.

Potential regulatory SNPs in METTL4

The potential regulatory SNPs were subjected to comprehensive scoring analysis using the FORGEdb (https://forge2.altiusinstitute.org/files/forgedb.html) and RegulomeDB (https://regulomedb.org/regulome-search) databases. High-confidence regulatory SNPs with a RegulomeDB score less than 4 and a FORGEdb score greater than 5 were identified.

Results

Correlations of METTL4 genetic variants and the occurrences of severe pneumonia

The UCSC platform was utilized to examine common SNPs located within 5 kb upstream and downstream of the METTL4 gene. Totally 119 candidate SNPs were identified based on linkage disequilibrium (LD) patterns with an r² threshold greater than 0.8. From the gene, 11 SNPs (rs9989554, rs16943442, rs80010836, rs2138848, rs9948895, rs17534687, rs12457106, rs72857010, rs66873847, rs2644175, and rs11663148) within the METTL4 gene from 17 selected tag SNPs based on the 1000 Genomes database were screened for genotyping (Fig. 1 and Table 2). Among the selected SNPs, rs9989554 and rs16943442 showed statistical significance after Bonferroni correction for multiple comparisons when compared to control subjects. Specifically, results shown that the minor C allele frequency of rs9989554 (0.30 vs. 0.27, OR = 1.21, 95% CI = 1.09–1.34, P = 0.00023) and the G allele frequency of rs16943442 (0.16 vs. 0.14, OR = 1.22, 95% CI = 1.09–1.34, P = 0.0026) were significantly associated with an increased risk of severe pneumonia (Table 2).

Fig. 1
figure 1

Overview of Linkage Disequilibrium (LD) within a 5-kilobase region upstream and downstream of the METTL4. The schematic representation of the physical positions of the investigated SNPs are shown in the top panel, while LD between SNPs was calculated by LDmatrix, and the LD plots were generated from the R software packages"LDlinkR” and “gaston”

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Table 2 Association between METTL4 polymorphisms and the risk of severe pneumonia
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Further haplotype-specific analyses, using the TA haplotype as a reference, showed that the CG haplotype of rs9989554 and rs16943442 is associated with a significantly increased risk of severe pneumonia (OR = 1.25, 95% CI: 1.10–1.42, P = 0.0007), while the CA haplotype demonstrated nominal significance (P = 0.0263). Thus, our findings suggest that the CG haplotype confers susceptibility to severe pneumonia (Table S2).

Associations of METTL4 SNPs with subtypes of severe pneumonia

To further investigate the correlations between METTL4 polymorphisms and subtypes of severe pneumonia, we divided our cohort into two groups: those with a primary diagnosis of severe pneumonia (mainly caused by pathogens, n = 719) and those with a secondary diagnosis of severe pneumonia (mainly caused by other diseases, n = 315). As shown in Table 3, only the minor A allele of the METTL4 rs12457106 SNP showed a statistically significant difference (p = 0.0129) between the two subtypes. No significant differences were observed for the other SNPs.

Table 3 Subgroup-specific association between METTL4 polymorphism s and the risk of severe pneumonia
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Expression quantitative trait loci (eQTLs) of METTL4 genetic variants

Next, we performed expression quantitative trait locus (eQTL) analysis to assess the regulatory effects of the METTL4 genetic variants. The results indicated that 4 SNPs were linked to elevated METTL4 mRNA expression levels in multiple organs (Table 4). Specifically, the rs9989554 and rs9948895 SNPs appear to be associated with increased METTL4 mRNA expression (indicated by effect size > 0) across different tissues. Conversely, rs2138848 and rs16943442 were shown to be associated with decreased METTL4 mRNA expression (indicated by effect size < 0) in various tissues.

Table 4 eQTL analysis of potential regulatory SNPs in METTL4 among different tissue
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Potential regulatory effects of METTL4 SNPs on pediatric severe pneumonia

Additionally, the regulatory potential of METTL4 SNPs on severe pneumonia was assessed using the RegulomeDB and FORGEdb scoring system. Our results indicated that 5 SNPs of the METTL4 gene (rs9989554, rs16943442, rs9948895, rs2138848, rs80010836) received scores ranging from 9 to 5 in the FORGEdb system and from 3a to 4 in the RegulomeDB system (Table 5). Among these SNPs, rs9989554 and rs16943442 have relatively high FORGEdb scores, suggesting that these 2 SNPs may have a stronger regulatory potential on the METTL4 gene compared to the other 3 SNPs.

Table 5 Candidate regulatory SNPs in METTL4 by forgedb and RegulomeDB resources
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FORGEdb scores suggests that the SNPs are more likely to fall within regulatory regions. We found that the METTL4 rs9989554 and rs16943442 had relatively high FORGEdb scores of 9. In addition, the FORGEdb database predicts that rs9989554 may impact H3K36me3 binding in fetal lung cells and fetal lung fibroblast lines. Collectively, these findings suggest that rs9989554 and rs16943442 may play a role in regulating the expression of the METTL4 gene.

Discussion

In this study, we identified a correlation between METTL4 gene polymorphisms and susceptibility to severe pneumonia. Specifically, the rs9989554 C allele and rs16943442 G allele of the METTL4 gene were significantly associated with an increased risk of severe pneumonia (Table 2). Additionally, the minor A allele of the rs12457106 SNP showed nominal significance when comparing patients with primary versus secondary severe pneumonia (Table 3). Furthermore, eQTL analysis of the rs9989554 C and rs16943442 G alleles suggested that these variants may influence the regulation of METTL4 mRNA expression (Table 4). Moreover, results from the FORGEdb and RegulomeDB analyses indicated that the rs9989554 C and rs16943442 G alleles might be SNPs with regulatory potentials of METTL4 gene (Table 5).

Severe pneumonia is a major cause of childhood mortality [23]. Throughout the COVID-19 pandemic, numerous studies have indicated that host genetic risk factors may influence disease severity [24, 25]. Nonetheless, there is a scarcity of data specifically addressing genetic risk factors for childhood pneumonia that can result in adverse outcomes, such as life-threatening symptoms, clinical deterioration, and the development of complications [26]. To address this gap, we conducted a MassARRAY Genotyping to investigate genetic risk factors for childhood pneumonia in a cohort comprising 1,034 children with severe pneumonia and 8,426 healthy controls. Here, we aim to further investigate whether METTL4 polymorphisms are associated with severe pneumonia primarily caused by pathogens (primary diagnosis) or following other diseases (secondary diagnosis). As no significant difference was observed between these two groups, this suggests that the METTL4 gene may be associated with factors beyond just infections.

METTL4 mediates N6-adenosine methylation in both eukaryotic DNA and RNA [27, 28], as well as RNA splicing [12]. Recent studies have demonstrated that hypoxia induces 6 mA modification through METTL4. The activation of METTL4 promotes tumor metastasis by activating multiple metastasis-associated genes [15]. Hao et al. found that hypoxic stress leads to the accumulation of METTL4 in mitochondria, resulting in increased 6 mA methylation [13]. It is important to note that hypoxia is a common feature in all types of severe pneumonia, including COVID-19 [29], adenovirus infection [30], acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) [9, 31]. Additionally, Shen et al. (2021) reported that exposure to ferroptosis-inducing compounds elevates METTL4 levels and m6A modification, which in turn trigger autophagy and enhance ferroptosis in human hematopoietic stem cells (HSCs) [14]. Also, the autophagy pathway has been shown to play a critical role during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [32]. Notably, a recent study showed that METTL4 promotes ferroptosis in alveolar epithelial cells during sepsis-induced lung injury through N6-methyladenosine modification of ferroptosis-related genes [33], indicating a strong potential link between pulmonary dysfunction and METTL4 gene. Therefore, it is plausible that METTL4 polymorphisms influence pneumonia susceptibility by affecting the hypoxia response or regulating autophagy pathways.

It should be also noted that there are some limitations in our study. First, more clinical and microbiologic data, such as information on patients who were hospitalized more than once, should be included. Additionally, a larger sample size is needed to enhance statistical power. Second, including diverse ethnic groups would provide a more comprehensive assessment of genotype distributions. Third, the samples were heterogeneous in terms of age and putative phenotypes, especially with regard to secondary pneumonia phenotypes. Fourth, further research is needed to investigate how these SNPs affect the expressions and functions of METTL4, in order to understand how genetic variations influence the onset and progression of severe pneumonia.

Conclusions

In summary, we demonstrated that the C allele of rs9989554 and the G allele of rs16943442 are significantly associated with an increased risk of severe pneumonia. However, most SNPs of the METTL4 gene did not show significant differences between primary and secondary severe pneumonia. To our knowledge, this is the first study to establish a link between genetic variations in the METTL4 gene and susceptibility to severe pneumonia in children. These genetic variations may play a pivotal role in the development of severe pneumonia related to METTL4 dysfunction, potentially aiding in the identification of effective treatments and the development of targeted therapies. Further research is needed to elucidate the functional contributions of METTL4 gene to pneumonia development and to explore its potential for risk assessment or therapeutic intervention.

In this study, we demonstrated that METTL4 gene is a susceptibility factor for severe pneumonia. Specifically, analysis performed by eQTLs, RegulomeDB, and FORGEdb tools indicated that the representative SNPs of METTL4, rs9989554 and rs16943442, exhibit high regulatory potential and are associated with an increased risk of severe pneumonia.

Data availability

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the patients and their guardians for participating in this work and the Clinical Biological Resource Bank for assistance with cohort recruitment.

Funding

This study was supported by the National Natural Science Foundation of China (82001676 to B.L.).

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Authors and Affiliations

  1. School of Medicine, South China University of Technology, Guangzhou, 510006, China

    Liuheyi Ma & Yuxia Zhang

  2. Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, China

    Xiaoyu Zuo

  3. Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, China

    Bingtai Lu & Yuxia Zhang

  4. Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510080, China

    Bingtai Lu

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Contributions

Y.Z. conceived the ideas and supervised the project. B.L. assembled the pneumonia cohort. L.M. and B.L. performed the experiments. X.Z. performed bioinformatics analysis. L.M. and B.L. wrote the manuscript with significant input from Y.Z. and X.Z., All authors discussed and approved the manuscript.

Corresponding authors

Correspondence to Bingtai Lu or Yuxia Zhang.

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Ethics approval and consent to participate

The study was approved by the Medical Ethics Committees of Guangzhou Women and Children’s Medical Center (2016111853). Written informed consent to participate was obtained from the legal guardians of all participants.

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The authors declare no competing interests.

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Ma, L., Zuo, X., Lu, B. et al. Correlation of METTL4 genetic variants and severe pneumonia pediatric patients in Southern China. BMC Genom Data 26, 33 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12863-025-01306-5

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BMC Genomic Data

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