Preeclampsia (PE) is the leading contributor to maternal and perinatal mortality globally [1]. It is responsible for an estimated 46,000 maternal deaths and roughly 500,000 fetal and newborn fatalities yearly [2]. Women in low- and middle-income countries bear a disproportionate burden of this disease [3]. The World Health Organization (WHO) has reported significantly higher numbers in developing countries than in developed ones, with approximately seven times higher figures. In Asian regions, gestational hypertensive disorders account for 9.1% of maternal deaths [4, 5]. A variety of environmental factors, including smoking habits, hypertension, diabetes mellitus, advanced maternal age, and obesity, have been linked to PE [6, 7]. However, a great deal of PE patients manifest without the presence of any of these identified risk factors, which suggests that environmental factors are not the only contributors. Genetic factors also appear to play a significant role in PE onset and progression [8, 9, 10].

Single-nucleotide polymorphisms (SNPs) represent variations in the genome that can change biological reactions and disease susceptibility. Several SNPs have been investigated in relation to PE [11, 12, 13, 14]. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a key role in the metabolism of homocysteine (HCy). It facilitates 5,10-MTHF conversion to 5-MTHF, which leads to the vitamin B12-mediated transformation of HCy to methionine [15, 16]. Decreased MTHFR levels or activity as a result of certain gene mutations can cause slight to moderate plasma HCy level elevations [17]. Several MTHFR gene mutations have been identified as potential links to PE, with the C677T and A1298C the most frequently observed. The most frequently observed mutation is the C-to-T change at nucleotide 677 (C677T) in exon 4, which leads to a substitution ofalanine with valine in the catalytic domain of the enzyme, and decreases its activity. Another mutation at position 1298 in exon 7 (A1298C) replaces glutamate with alanine at codon 429. This mutation also diminishes enzyme function in a similar way [18, 19]. The MTHFR A1298C variant shows a difference in the prevalence of its allelic distribution among different populations and ethnicities. Studies on the association between preeclampsia and this condition have been conducted among Asians, Caucasians, Africans, and Americans. Correlation with the Asian and Caucasian populations was found to be significant [20, 21].

MTHFR A1298C is linked to diminished levels of folate in serum, plasma, and red blood cells, as well as a slight elevation in plasma total homocysteine (tHcy) concentration [22]. Considering the presence of mild hyperhomocysteinemia in women with preeclampsia, the MTHFR A1298C polymorphism could potentially be a genetic factor contributing to the pathophysiology of preeclampsia [23, 24]. In cases of preeclampsia, there is a confirmed hereditary element: women born from preeclamptic pregnancies face an elevated risk of developing the condition during their own pregnancies [10]. Although genetic predisposition is a significant factor in the development of preeclampsia, efforts to establish associations between MTHFR A1298C and preeclampsia have generated inconsistent findings [25, 26, 27, 28]. As a consequence, a meta-analysis was conducted on the published case-control studies to more closely examine the relationship between the MTHFR A1298C polymorphism and PE susceptibility.

Following a meta-analysis of 11 case-control studies [17, 25, 26, 27, 28, 37, 38, 39, 40, 41, 42], a significant association was found between the MTHFR A1298C polymorphism and PE risk. In a subgroup analysis stratified by ethnicity, all the studies examined showed a significant decrease in PE risk. After the analysis was stratified by ethnicity, a notably decreased risk was identified among Asian populations for the homozygote, heterozygote, and dominant models. For mixed populations, there was also found to be a significant decrease in risk in the allele contrast, homozygote, heterozygote, and dominant models. In contrast, no significant risk was detected in Caucasian populations, there reason for this being unclear. A potential reason may be the variance in the genotype distribution of MTHFR A1298C CC among Caucasian, Mixed, and Asian populations. The studies found that the prevalence of the MTHFR A1298C CC alleles in the 3${}^{\prime }-$untranslated region stood at 12.4% for Caucasian patients [17, 26, 28, 37, 38, 40], while it was 7.4% for Asian patients [25, 42], and 15.3% for those of Mixed ethnicity [27, 41]. The variation in genotype distribution may play a role in the diverse associations that were observed between MTHFR A1298C polymorphism and PE risk in different ethnicities. Another potential factor is the restricted sample size of Asian and mixed patients in the meta-analysis. The limited representation of these Mixed patients may have diminished the statistical power, which potentially concealed the genuine associations.

In this meta-analysis, the studies included in the Asian population category are predominantly from China [25, 42]. We acknowledge that this limited representation of Asian populations, encompassing only one country, could potentially restrict the generalizability of our findings. Therefore, it is imperative to exercise caution when interpreting our results and consider the possibility of regional variations when applying these findings to other Asian populations.

The findings of this study relating to the MTHFR A1298C polymorphism deviate from those of Wu et al. [34]. In their meta-analysis, they could not successfully demonstrate a connection between PE risk and the MTHFR A1298C polymorphism in any of their analyzed models. One potential reason for this inconsistency may be the limited sample size of the earlier study. The meta-analysis of Wu et al. [34] included just six studies that examined the MTHFR A1298C polymorphism and PE risk, resulting in a less refined risk assessment.

With meta-analysis, addressing heterogeneity is a major concern, as high variability among studies can potentially cause biased outcomes. In this research, heterogeneity was identified across the studies in the heterozygote and dominant models. The Galbraith plot analysis identified one study as being the primary contributor to this heterogeneity [27]. Following the removal of this outlier study, a marked reduction in heterogeneity was noticed, although the primary findings remained consistent.

Another major concern in meta-analysis is publication bias potential as a result of the selective representation of studies. In the meta-analysis of this study, Egger’s and Begg’s [32, 33] tests were both used for evaluating this concern. The statistical outcomes, together with the symmetry of the funnel plot, indicated an absence of notable publication bias. More importantly, the results were further bolstered by sensitivity analysis, which affirmed their consistency and robustness. It should be noted that one of the studies that was considered deviated from the Hardy-Weinberg equilibrium (HWE) [41]. However, following the removal of this anomalous study and a data reassessment, the conclusions remained consistent.

There are several limitations with this study: (i) due to the limited sample size and the small number of researches that were included in the meta-analysis, the results may not adequately reflect the true associations; (ii) the analysis was reliant on unadjusted OR estimates as not all the included studies provided adjusted ORs, and where adjusted ORs were provided, the adjustments varied based on factors such as ethnicity, age, or smoking habits; (iii) the genotype distribution of the control group in one study deviated from the Hardy-Weinberg equilibrium (HWE); and (iv) in this meta-analysis, the representation of the Asian population came from two studies that were conducted in China and due to the lack of research data from other Asian populations, the findings may have limited generalizability; (v) compared to our study, the latest Whole Genome Sequencing (WGS) research has utilized a much larger study population, including participants from diverse geographical regions and ethnic backgrounds. These studies possess higher statistical power and encompass broader genetic diversity, thus enabling them to provide more accurate and comprehensive analysis results. Therefore, we anticipate these large-scale studies will offer deeper insights into the association between specific genetic variations and preeclampsia.

In conclusion, our meta-analysis suggests that the MTHFR A1298C variant holds potential as a genetic marker for PE. Nonetheless, additional comprehensive, multicenter studies are essential to solidify and validate our findings.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

KY conceived and designed the meta-analysis. YH and AW performed the literature search. AW analyzed the data. YH wrote the paper. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

Thanks to all the peer reviewers for their opinions and suggestions.

This study was supported by the Key Research and Development Program of Sichuan Province (grant no. 2022YFS0079).

The authors declare no conflict of interest.