The association of single nucleotide polymorphism of KCNQ1 gene rs2237895 with type 2 diabetes mellitus (T2DM) is currently controversial. It is unknown whether this association can be gene realized across different populations.

To determine the association of KCNQ1 rs2237895 with T2DM and provide reliable evidence for genetic susceptibility to T2DM.

We searched PubMed, Embase, Web of Science, Cochrane Library, Medline, Baidu Academic, China National Knowledge Infrastructure, China Biomedical Liter-ature Database, and Wanfang to investigate the association between KCNQ1 gene rs2237895 and the risk of T2DM up to January 12, 2022. Review Manager 5.4 was used to analyze the association of the KCNQ1 gene rs2237895 polymorphism with T2DM and to evaluate the publication bias of the selected literature.

Twelve case–control studies (including 11273 cases and 11654 controls) met our inclusion criteria. In the full population, allelic model [odds ratio (OR): 1.19; 95% confidence interval (95%CI): 1.09–1.29; P < 0.0001], recessive model (OR: 1.20; 95%CI: 1.11–1.29; P < 0.0001), dominant model (OR: 1.27. 95%CI: 1.14–1.42; P < 0.0001), and codominant model (OR: 1.36; 95%CI: 1.15–1.60; P = 0.0003) (OR: 1.22; 95%CI: 1.10–1.36; P = 0.0002) indicated that the KCNQ1 gene rs2237895 polymorphism was significantly correlated with susceptibility to T2DM. In stratified analysis, this association was confirmed in Asian populations: allelic model (OR: 1.25; 95%CI: 1.13–1.37; P < 0.0001), recessive model (OR: 1.29; 95%CI: 1.11–1.49; P = 0.0007), dominant model (OR: 1.35; 95%CI: 1.20–1.52; P < 0.0001), codominant model (OR: 1.49; 95%CI: 1.22–1.81; P < 0.0001) (OR: 1.26; 95%CI: 1.16–1.36; P < 0.0001). In non-Asian populations, this association was not significant: Allelic model (OR: 1.06, 95%CI: 0.98–1.14; P = 0.12), recessive model (OR: 1.04; 95%CI: 0.75–1.42; P = 0.83), dominant model (OR: 1.06; 95%CI: 0.98–1.15; P = 0.15), codominant model (OR: 1.08; 95%CI: 0.82–1.42; P = 0.60. OR: 1.15; 95%CI: 0.95–1.39; P = 0.14).

KCNQ1 gene rs2237895 was significantly associated with susceptibility to T2DM in an Asian population. Carriers of the C allele had a higher risk of T2DM. This association was not significant in non-Asian populations.

Type 2 diabetes mellitus (T2DM) is a common multifactorial, metabolic disease whose pathogenesis is influenced by a combination of genetic and environmental factors. The rise and large-scale application of genome-wide association studies have contributed to the understanding of genetic factors related to T2DM. T2DM remains a health problem that plagues the world to this day. As of January 4, 2021, the number of people with diabetes worldwide had reached 537 million. Even more alarmingly, this number is expected to increase to 643 million by 2030. The various expenditures due to diabetes have exceeded $966 billion, and this figure has grown at an annual rate of 63% since 2006[1]. The etiology of T2DM is complex and has not yet been fully elucidated. T2DM is characterized by defective insulin secretion and reduced sensitivity, leading to chronic hyperglycemia and severe metabolic dysfunction in patients[2,3]. Hyperglycemia affects the physiological function of several tissues and organs in the body, among which the most common are neuropathy and vascular complications[1].

Studies have not provided an accurate description of the etiology of T2DM, and a genome-wide scan of Japanese by Nawata et al[4] showed that KCNQ1 is a susceptibility gene for T2DM in Japan. In addition, genes such as ADRA2A, KCNJ11 and CDKAL1 may be associated with the development of T2DM[4,5]. KCNQ1 is a potassium channel subunit that is mainly found in adipose and pancreatic tissues. It was found that KCNQ1 affects the process of islet β-cell depolarization by regulating potassium channel currents, thereby limiting insulin secretion from pancreatic β-cells and leading to the development of T2DM[6].

Previous studies have found that C allele carriers of the KCNQ1 gene rs2237895 may have an increased risk of developing T2DM[7]. rs2237895 is present in three genotypes in the population, AA, AC and CC. The A gene is wild type and the C gene is mutant, and their gene frequencies in the population are approximately 66% and 34%[8]. A study by Cui et al[7] in Kazakhs living in China showed that rs2237895 single nucleotide polymorphism (SNP) of KCNQ1 gene was not significantly associated with T2DM. A study by Afshardoost et al[9] on Iranians also showed no significant association between rs2237895 and T2DM; while in a study by Khan et al[10] on Indians, they confirmed a significant association between the SNP of rs2237895 and T2DM. Previously, a similar study has been conducted by Sun et al[11], but we consider that their inclusion criteria were more lenient and the strength of the proof may be weakened. Meanwhile, their work was > 10 years old and many new studies have been published during this period and that meta-analysis is in urgent need of updating. To address the above issues, we performed the present meta-analysis.

According to the research strategy, 323 relevant papers were retrieved from the databases. Some duplicates were found and we removed them by Endnote software. We also screened the citations of the paper to ensure the comprehensiveness of the search. After a stepwise screening process, 12 eligible papers were finally included for meta-analysis, which included 11273 patients with T2DM and 11654 controls. Five of the datasets were from China[12-16], five from the rest of Asia[7,10,17-19], one from Europe[20], and one from Africa[21]. The basic information of the studies is shown in Table 1.

The 12 datasets that met the inclusion criteria were pooled for meta-analysis, and allelic, recessive, dominant, and codominant models were used to investigate the association of rs2237895 with T2DM. Since the study population was predominantly Asian, we performed stratified analysis of Asian and non-Asian populations (Figure 2 and Figure 3).

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Figure 2 The forest plot of different model. A: Allelic model; B: Recessive model; C: Dominant model; D: Co-dominant model (CC vs AA); E: Co-dominant model (AC vs AA). T2DM: Type 2 diabetes mellitus.

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Figure 3 The forest plot for stratified analysis of different model. A: Allelic model; B: Recessive model; C: Dominant model; D: Co-dominant model (CC vs AA); E: Co-dominant model (AC vs AA). T2DM: Type 2 diabetes mellitus.

In the full population, allelic model (OR: 1.19; 95%CI: 1.09–1.29; P < 0.0001), recessive model (OR: 1.20; 95%CI: 1.11–1.29; P < 0.0001), dominant model (OR: 1.27. 95%CI: 1.14–1.42; P < 0.0001), and codominant model (OR: 1.36; 95%CI: 1.15–1.60; P = 0.0003. OR: 1.22; 95%CI: 1.10–1.36; P = 0.0002) all showed significant association between rs2237895 and T2DM. In the subgroup of the Asian population, allelic model (OR: 1.25; 95%CI: 1.13–1.37; P < 0.0001), recessive model (OR: 1.29; 95%CI: 1.11–1.49; P = 0.0007), dominant model (OR: 1.35; 95%CI: 1.20–1.52; P < 0.0001), and codominant model (OR: 1.49; 95%CI: 1.22–1.81; P < 0.0001. OR: 1.26; 95% CI: 1.16–1.36; P < 0.0001) also showed a significant association between rs2237895 and T2DM, which was consistent with the whole population. C allele carriers had an increased risk of developing T2DM. The CC and AC genotypes significantly increased the risk of T2DM compared to the AA genotype. However, in the non-Asian population subgroup, allelic model (OR: 1.06; 95%CI: 0.98–1.14; P = 0.12), recessive model (OR: 1.04; 95%CI: 0.75–1.42; P = 0.83), dominant model (OR: 1.06; 95%CI: 0.98–1.15; P = 0.15), and codominant model (OR: 1.08; 95%CI: 0.82–1.42; P = 0.60) (OR: 1.15; 95%CI: 0.95–1.39; P = 0.14) all showed no significant association between rs2237895 and T2DM.

The funnel plots showed no significant publication bias was found in the meta-analysis (Figure 4 and Figure 5). Egger’s test showed no significant publication bias for the allelic model (t = 1.84, P = 0.095), recessive model (t = 0.48, P = 0.64), dominant model (t = 1.44, P = 0.18), and codominant model (t = 1.33, P = 0.21; t = 1.79, P = 0.10).

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Figure 4 The funnel plot of different model. A: Allelic model; B: Recessive model; C: Dominant model; D: Co-dominant model (CC vs AA); E: Co-dominant model (AC vs AA). OR: Odds ratio.

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Figure 5 The funnel plot for stratified analysis of different models. A: Allelic model; B: Recessive model; C: Dominant model; D: Co-dominant model (CC vs AA); E: Co-dominant model (AC vs AA). OR: Odds ratio.

We performed a sensitivity analysis. After sequentially excluding one study in the allelic model, recessive model, dominant model, and codominant model, we calculated the pooled effect sizes for the remaining studies. By calculation, no qualitative change occurred between the pooled results of the remaining studies and the original results. Sensitivity analysis proved that the results of the meta-analysis were reliable.

Compared with previous studies, we increased the inclusion criteria of cases, excluded the interference of other factors (e.g., gestational diabetes), improved the strength of proof of the study, and made the results more reliable and stable. Our meta-analysis supported the findings of Khan et al[10], suggesting that the rs2237895 SNP in the KCNQ1 gene is significantly associated with the development of T2DM in Asian populations. In the study by Cui et al[7], the study population had an overall overweight problem, which increased the risk of T2DM prevalence and thus confounded the findings[22].

T2DM is a multifactorial, chronic, metabolic disease[23]. The idea that genetic factors have a significant role in the development of T2DM is now more widely accepted[23], although only a few genes have been confirmed as a risk for the development of T2DM. However, many genetic characteristics associated with T2DM, such as effect sizes and risk allele frequencies, need to be explored[24]. There is a need for researchers to identify risk genetic loci for T2DM and characterize the variation at the loci, thus providing a basis for elucidating the genetic pathogenesis of T2DM.

Previous studies have shown that the KCNQ1, miR-21, and Arg972 may be risk genes for T2DM[25,26]. KCNQ1 gene has now been shown to be located on chromosome 11p15.5, which is approximately 400 kb in length and consists of 17 exons ranging from 47 to 1122 bp in length[27]. KCNQ1 is associated with voltage-gated K⁺ channels, and mutations in the KCNQ1 gene lead to dysfunction of K⁺ channels, which would cause diseases such as QT syndrome and familial atrial fibrillation. KCNQ1 is expressed in many tissues[27,28], and the more studied about the KCNQ1 gene is expressed in cardiac and pancreatic tissues[29]. Current studies suggest that the main mechanisms of T2DM development are insulin resistance and islet β-cell dysfunction[2,23]. Variants in the KCNQ1 gene may lead to increased susceptibility to T2DM in the population by altering insulin secretion from pancreatic β-cells[30,31]. It was hypothesized that variants in the KCNQ1 gene would lead to increased expression of KCNQ1 protein on pancreatic β-cells, which in turn would alter the open state of voltage-gated potassium channels, decrease insulin secretion, and impair glucose storage and utilization[32].

This meta-analysis of the KCNQ1 gene rs2237895 SNP and T2DM association study involved 12 studies, including 11273 T2DM patients and 11654 controls. This analysis showed that the rs2237895 polymorphism was significantly associated with an elevated risk of developing T2DM in an Asian population, which is consistent with Khan et al’s[10] findings. In Asian populations, C allele carriers have an increased risk of developing T2DM. The risk of T2DM is also increased in people with the CC and AC genotypes compared to the AA genotype. This is consistent with the previous findings of Hu et al[16]. Also, their findings showed that rs2237895 was associated with hypertension, body mass index, and hypertriglyceridemia. In non-Asian populations, this association was not significant. A 2015 study by Ríos et al[33] in Europeans also showed that the KCNQ1 gene rs2237895 SNP was not significantly associated with T2DM, which is consistent with our findings. Our work provided strong evidence for the genetic pathogenesis of T2DM and helped to fully reveal the pathogenesis of T2DM.

This study showed that the rs2237895 SNP of the KCNQ1 gene was differentially associated with T2DM in different populations. The reasons for this variation may be mutations in the regulatory region of the KCNQ1 gene in particular populations[33], which interfere with the expression of the KCNQ1 gene; or it may be due to the existence of different genotypes and allele frequencies in populations with different clinical characteristics, geographical distribution and ethnic origin; or differences in the external influences associated with T2DM, such as lifestyle and behavior, in different populations[4,23-25]. The possibility of false-negative results in non-Asian populations with small study sample sizes cannot be excluded.

In the Asian population, there was a significant association between the KCNQ1 gene rs2237895 SNP and T2DM onset. C allele carriers were at increased risk of T2DM, and the CC and AC genotypes significantly increased the susceptibility to T2DM. However, in the non-Asian population, the association between rs2237895 and T2DM onset was not significant.