Meta-analysis of insights into HHEX (rs1111875) and SLC30A8 (rs13266634) gene variants and type 2 diabetes mellitus

INTRODUCTION

Diabetes mellitus (DM) is a severe metabolic condition defined by fasting and postprandial hyperglycemia. DM is a broad category of long-term metabolic condition which impairs the regulation of blood sugar level due to insulin resistance or inadequate insulin production and the prevalence has been rising fast in low and middle-income countries.¹ According to the World Health Organization (WHO), age-standardized mortality rates due to diabetes increased by 3% between 2000 and 2019. It was estimated that the prevalence rate of diabetes among adults aged 18 years and above increased substantially from 7% in 1990 to 14% in 2022.² Type 2 diabetes mellitus (T2DM) is aggravated by inherited factors, peripheral insulin resistance and environmental factors.^3,4 The most frequent diabetes is categorized as T2DM, often known as adult-onset diabetes, which typically develops between the ages of 35 and 40.⁵ Genetic background of the individuals play an important role in the etiopathogenesis of T2DM.⁶ Genome wide association studies (GWASs) revealed more than 400 genetic loci to be associated with T2DM.⁷ Several serious ailments, including cancer, heart diseases, hypertension, and gestational diabetes mellitus, have been associated with T2DM.⁸

The haematopoietically expressed homeobox or HHEX gene (MIM: 604420), located on chromosome 10q23.33, activates hepatocyte nuclear factor (HNF)-1a, which regulates the maturation and function of beta-cells. The protein produced by HHEX gene works as transcription factor that influences the Wnt signaling pathway, which is essential for cell growth and development.⁹ The responsiveness and secretion of insulin are contingent upon HHEX expression.¹⁰ The single nucleotide variant (SNV) rs1111875 located at 3ˊ untranslated region (3ˊUTR) of HHEX gene is significantly associated with T2DM.¹¹ The impact of the HHEX gene on islet function and insulin signaling determines it as an important biological candidate.^11,12 The function of HHEX gene (rs1111875) variant and the insulin secretion response after a glucose load might impact the risk of T2DM mainly via altering pancreatic β-cell activity.¹¹ HHEX gene has been identified as a plausible candidate gene for T2DM risk by GWASs in various populations.¹³

Maintaining zinc homeostasis remains crucial for human health, and its imbalance may culminate in several conditions, such as diabetes, cancer, autoimmunity, Alzheimer's and cardiovascular diseases. The zinc transporter gene, Solute Carrier Family 30 Member 8 (SLC30A8; MIM: 611145), produces a 369-amino acid protein that is primarily expressed in pancreatic β-cells and may play a key role in insulin secretory pathway.¹⁴ Zinc carrier ZnT8, encoded by SLC30A8 (rs13266634) gene, located on chromosome 8q24.11, promotes maturation, storage and secretion of insulin by transferring zinc from the cytoplasm to insulin secretion granules in the pancreas.¹⁵ The expression level of SLC30A8 is lower in submaxillary glands, testicles and other organs, but it is robustly expressed in the alpha and beta cells of the pancreatic islet.¹⁶ Previous GWASs have demonstrated an association between SLC30A8 gene variant and predisposition to T2DM across various populations.^14,17,18

The present meta-analysis of the association between HHEX and SLC30A8 gene variants and T2DM is carried out to address disagreements and minimize the possibility of inadvertent mistakes leading to false positive or negative comparisons of the individual studies. In this analysis, HHEX A>G, HHEX C>T and SLC30A8 C>T gene variants were analyzed using published data of case-control studies.

METHODS

Selection of pertinent studies

The study was conducted between March 2024 and September 2024. A thorough and methodical search of published research articles related to HHEX and SLC30A8 gene variants and T2DM was carried out using PubMed, CNKI, Baidu Scholar, Google Scholar and ScienceDirect databases. The preferred reporting items for systematic reviews and meta-analyses guideline was adopted to conduct this study.¹⁹ Relevant search terms and Boolean combinations were used to identify studies examining HHEX and SLC30A8 genetic variants in relation to T2DM. The search strategy included combinations of terms such as HHEX, “hematopoietically expressed homeobox,” SLC30A8, “zinc transporter 8,” “type 2 diabetes mellitus,” “T2DM,” “genetic variant,” “polymorphism,” “single nucleotide polymorphism,” “genotype,” “allele,” “genetic susceptibility,” “genetic risk,” and “genetic association.” Database-specific search strategies were adapted according to the indexing and search functions of each database. Titles and abstracts of the retrieved records were screened to identify potentially relevant studies. The reference lists of eligible articles and relevant reviews were also examined manually to identify additional studies that might have been missed during the electronic database search. Potentially eligible articles were subsequently assessed in full text according to the predefined inclusion and exclusion criteria.

Inclusion and exclusion parameters

All articles obtained from the databases were examined manually to determine their suitability for inclusion in the analysis. The research articles with incomplete data were excluded from the analysis. The criteria for inclusion of the studies in this meta-analysis were: (i) Published articles related to HHEX and SLC30A8 gene variants and protection and/or risk to T2DM and (ii) Case-control studies having complete genotyping data on HHEX and SLC30A8 gene variants. The exclusion criteria were: (i) Review articles on association of HHEX and SLC30A8 gene variants with risk/protection to T2DM (ii) Studies that were not related to HHEX and SLC30A8 gene variants and (iii) Incomplete genotyping data or studies that did not reveal genotyping frequencies.

Data extraction

The authors reviewed each article and extracted data, addressed disputes, and confirmed all items. Selected data comprised the following information: (i) First author’s name, (ii) Publication year, (iii) Country of origin, (iv) Ethnicity, (v) Number of cases, (vi) Number of controls, (vii) genotype frequencies in case and control groups. Furthermore, the Hardy–Weinberg equilibrium (HWE) was estimated using genotyping data. The characteristics of pertinent studies that were taken into consideration for this meta-analysis are presented in Table 1.

Statistical analysis

STATA (Release 17, College Station, USA) was used to analyze the data. The 95% confidence interval (95%CI) and a pooled odds ratio (OR) were used to determine the degree of association of HHEX and SLC30A8 gene variants with T2DM risk/protection. The pooled ORs were determined for the allele (A vs G and C vs T), codominant (AA vs AG, AA vs GG and CC vs CT, CC vs TT), dominant (AA vs AG + GG and CC vs CT+TT) and recessive (AA + AG vs GG and CC+CT vs TT) inheritance models. The level of significance for pooled OR was determined using Z-test and p<0.05 was considered statistically significant. The heterogeneity among the studies was determined using Cochran’s Q statistics and I² test. The existence of heterogeneity was considered when P_{heterogeneity} <0.01.^20,21 Random effects model and Mantel-Haenszel fixed effects model were used when the I² value was greater than 50% and less than 50%, respectively.²⁰ The existence of a publication bias was determined using Egger's linear regression test, p<0.05 was considered as statistically significant.²²

RESULTS

Study characteristics

The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart describes the selection process of relevant studies for this meta-analysis and is presented in Figure 1. After completing the initial screening of HHEX A>G variant, a total of 8 studies were included with 3869 cases and 5219 controls. For HHEX C>T variant and T2DM risk/protection, a total of 11 studies comprising of 7782 cases and 13091 controls were included, while for SLC30A8 C>T variant, 53 studies comprising of 35259 cases and 35588 controls were included in the analysis.

Among 8 studies with HHEX A>G variant, 5 were from Asian, 1 was from Arabian and 2 were from European populations.^13,23-30 Out of 11 studies with HHEX C>T variant, 6 were from Asian, 2 were from European and 1 each from Arabian, American and Mestizos populations.^3,28,31–39 Furthermore, out of 53 studies with SLC30A8 variant, 35 were from Asian, 6 were from European, 4 were from Arabian, 2 each from Iranian, Russian and African and 1 each from Turkish and Mestizos populations.^{3,10,17,23,31,32,35,38,39–77} The characteristics of the studies included in the analysis are presented in Table 1. The Hardy Weinberg equilibrium (HWE) test revealed that most of the studies were in HWE except one study related to HHEX A>G, two studies related to HHEX C>T and ten studies related to SLC30A8 C>T gene variant.^{3,9,47,78–87}

Quantitative synthesis

The findings of the tests of association and heterogeneity for HHEX and SLC30A8 gene variants and T2DM are presented in Table 2. Significant heterogeneity was found in Cochran’s Q statistics for all models tested in the current study. HHEX A>G variant showed an overall association with reduced risk of T2DM under allele (A vs G: p=0.004), codominant (AA vs GG: p=0.001), dominant (AA vs AG+GG: p=0.02) and recessive (AA+AG vs GG: p=0.002) inheritance models. However, a lack of significant association was observed between HHEX C>T variant and T2DM in all tested inheritance models. In contrast, SLC30A8 C>T gene variant was significantly associated with increased risk of T2DM under allele (C vs T: p=0.001), dominant (CC vs CT+TT: p=0.001), recessive (CC + CT vs TT: p=0.001), codominant [(CC vs CT: p=0.007) and (CC vs TT: p<0.001)] inheritance models.

When subgroup analysis by ethnicity was performed, HHEX A>G gene variant showed significant association with reduced T2DM risk in Arbian population under all tested models [allele (A vs G): p<0.001, dominant (AA vs AG + GG): p<0.001, recessive (AA + AG vs GG): p<0.001, codominant (AA vs AG): p<0.001, (AA vs GG): p<0.001], in European population under allele (A vs G: p<0.001), dominant (AA vs AG + GG: p=0.001) recessive (AA + AG vs GG: p=0.001) and codominant (AA vs GG: p<0.001) inheritance models. Further, significant association between HHEX A>G variant and reduced risk of T2DM was also observed in Asian population under recessive (AA + AG vs GG: p=0.032) inheritance model. In addition, significant association was observed between HHEX C>T gene variant and reduced risk of T2DM in American ethnic group under allele (C vs T: p=0.04), codominant (CC vs TT: p=0.021) and recessive (CC + CT vs TT: p=0.02) inheritance models. A notable association was observed between SLC30A8 C>T gene variant and increased risk of T2DM under all tested model [allele (C vs T): p=0.001, dominant (CC vs CT + TT): p=0.001, recessive (CC + CT vs TT): p=0.001, codominant (CC vs CT): p=0.007, (CC vs TT): p<0.001] inheritance models. Ethnicity wise subgroup analysis revealed an association between SLC30A8 variant with increased risk of T2DM in Asian ethnicity under allele (C vs T: p=0.002), dominant (CC vs CT+TT: p=0.018), recessive (CC + CT vs TT: p<0.001), codominant (CC vs TT: p<0.001) inheritance models, European ethnic group under allele (C vs T: p<0.001), dominant (CC vs CT+TT: p<0.001), recessive (CC + CT vs TT: p<0.001), codominant (CC vs CT: p<0.001, CC vs TT: p<0.001) inheritance models, Mestizos ethnic group under all tested inheritance models [Allele (C vs T): p<0.001, dominant (CC vs CT + TT): p<0.001, recessive (CC+CT vs TT): p<0.001, codominant (CC vs CT): p<0.001, (CC vs TT): p<0.001], Arabian ethnic group under dominant (CC vs CT + TT: P=0.043), and codominant (CC vs CT: p=0.046) inheritance models. In contrast, this gene variant was associated with reduced risk of T2DM in Russian ethnic group under allele (C vs T: p<0.001, recessive (CC+CT vs TT: p=0.002) and codominant (CC vs TT: p=0.017) inheritance models.

Test of heterogeneity

Cochran’s Q statistics revealed the presence of overall heterogeneity for HHEX A>G (allele: I² – 87.5%, dominant: I²=82.8%, recessive: I²=75.3%, codominant: I²=73.5% and 77.6%), HHEX C>T (allele: I²=82.6%, dominant: I²=74.2%, recessive: I²=77.7%, codominant: I²=61.3% and 80.1%) and SLC30A8 C>T (allele: I²=89.3%, dominant I²⁼82.9%, recessive: I²=82.7%, codominant: I²=76.4% and 83.2%) gene variants. Subgroup analysis also revealed very high heterogeneity for HHEX A>G variant in Asian ethnic group under allele (P_{heterogeneity}=0.004, I²=73.9%) and codominant (P_{heterogeneity}=0.005, I²=73.5%) inheritance models. In addition, a significantly high heterogeneity was observed for HHEX C>T variant in Asian ethnic group under allele (P_{heterogeneity}<0.001, I²=86.1%), recessive _{(Pheterogeneity} <0.001, I²=80.4%), codominant (P_{heterogeneity}=0.001, I²=76.7% and P_{heterogeneity}<0.001, I²=82.9%) inheritance models. Furthermore, subgroup analysis of SLC30A8 C>T variant revealed very high heterogeneity in Iranian ethnic group under allele (P_{heterogeneity}=0.001, I²=91%,), recessive (P_{heterogeneity}=0.005, I²=87.2%) and codominant (P_{heterogeneity} =0.008, I²=85.9%) inheritance models, in Russian ethnic group under dominant (P_{heterogeneity}=0.003, I²=88.8%) and codominant (P_{heterogeneity}=0.004, I²=88.1%) inheritance models. Cochran’s Q statistics and heterogeneity test for all tested models are presented in Figures 2-4 and Table 2.

F – Fixed effect model; R – random effect model. OR – odds ratio, 95% CI – 95% confidence interval.

Test for publication bias

Publication bias of the studies included in this meta-analysis was determined by Egger’s regression test. Egger’s linear regression test did not reveal any publication bias for the studies analyzing HHEX A>G (AA vs GG: p=0.0873), HHEX C>T (CC vs TT: p=0.72) and SLC30A8 C>T (CC vs TT: p=0.961) variants. Sensitivity analysis did not deviate from pooled odds ratio (OR) quantitively.

DISCUSSION

Genetic and environmental factors are thought to be associated with T2DM, a chronic metabolic disorder in which genetically determined pancreatic beta (β) cells fail over time and cannot withstand the increase insulin resistance.⁸⁸ Hepatic insulin resistance results in inadequate suppression of glucose production by the liver, leading to elevated blood glucose level which supports the diminished antilipolytic action of insulin.^88,89 Genetic background is a common concern for researchers to determine the effect of altered allele distribution or expression of certain genes with T2DM susceptibility in various populations across the world. To date, several candidate genes have already been evaluated by various researchers to determine the relationship between genetic variants and T2DM risk. These include Transcription Factor 7 Like 2 (TCF7L2), Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A/2B), CDK5 Regulatory Subunit Associated Protein 1-Like 1 (CDKAL1), Melatonin Receptor 1b (MTNR1B), Peroxisome proliferator-activated receptor (PPARG), Solute Carrier Family 30 Member 8 (SLC30A8), Potassium Voltage - Gated Channel, Potassium Inwardly Rectifying Channel Subfamily J Member 11 (KCNJ11), KQT-Like Subfamily Member 1 (KCNQ1), Wolframin ER Transmembrane Glycoprotein (WFS1), Hepatocyte Nuclear Factor 1 Homeobox B (HNF1B), Insulin-Like Growth Factor 2 mRNA Binding Protein 2 (IGF2BP2), and Juxtaposed with Another Zinc Finger Protein 1 (JAZF1).^{3,9,26,27,61,70,74,76,88–99} Haematopoietically Expressed Homeobox or HHEX gene plays significant role in the development of ventral pancreas whereas SLC30A8 is involved in the maturation and storage of insulin in pancreatic beta-cells (β-cells). These are therefore considered as relevant candidate genes for investigation in T2DM risk or protection.¹⁰⁰ Previous studies carried out in the populations of Bangladesh, Japan, South India, Germany, North-East India, Iran, Hong Kong, Korea and China (Han population) have reported significant association between HHEX gene variant and T2DM.^{3,9,13,23,32,36,40,45,48,98,101} Similarly, significant association between SLC30A8 gene variant and T2DM has been reported previously in the populations of Bangladesh, North-East India, Thailand, Jordan, Hong Kong, Korea, China and Iran. ^{3,9,26,45,48,72,74,85,98}

In this meta-analysis, deviation of Hardy-Weinberg equilibrium (HWE) was detected in several studies for HHEX and SLC30A8 gene variants.^{3,9,47,77-79,81–84,86,87} The deviation from the HWE might be attributed to various factors such as assortative mating, natural selection, genetic drift, distribution of allele frequencies among populations and sample size. This current study revealed a significant association between HHEX A>G variant and reduced risk of T2DM under allele (A vs G: p=0.004), codominant (AA vs GG: p=0.001), dominant (AA vs AG+GG: p=0.02) and recessive (AA+AG vs GG: p=0.002) except under codominant (AA vs AG: p=0.092) inheritance model. Further, positive association was observed between SLC30A8 C>T variant and T2DM risk under allele (C vs T: p=0.001), dominant (CC vs CT+TT: p=0.001), recessive (CC + CT vs TT: p=0.001) and codominant (CC vs CT: p=0.007 and (CC vs TT: p<0.001) inheritance models. This is the first study, in which both the HHEX A>G and HHEX C>T variants for SNV rs1111875 were analyzed. HHEX A>G variant was associated with reduced T2DM risk in Arabian ethnic group under all tested models and in European ethnic group under allele, dominant, recessive and codominant inheritance models. HHEX C>T gene variant was significantly associated with reduced T2DM risk in American ethnic group under allele, codominant and recessive inheritance models. In contrast, SLC30A8 C>T variant was associated with increased T2DM risk in Asian, Arabian, Russian, European and Mestizos populations. Prior meta-analysis of SLC30A8 C>T variant and T2DM lacks data for Russian, Arabian and Mestizos populations.¹⁰²

The present meta-analysis demonstrated a substantial degree of heterogeneity across the pooled analyses, as reflected by the I² statistics. The highest overall heterogeneity was observed for SLC30A8 C>T variant under the allelic model (I²=89.3%), followed by HHEX A>G (I²=87.5%) and HHEX C>T (I²=82.6%) variants. Ethnicity-specific analyses also demonstrated considerable heterogeneity, particularly among Asian populations for HHEX variants and Iranian and Russian populations for SLC30A8 C>T variant. This considerable heterogeneity indicates that the degree of the association between these genetic variants and T2DM was not consistent across the included studies. The variability in I² values across populations may reflect differences in genetic background, allele frequencies, demographic characteristics or sample size. Publication bias for the pertinent studies was assessed by Egger’s linear regression test.²² Overall, there was absence of publication bias for all selected studies.

The pathogenesis of T2DM is regulated by multiple genes such as CDKL1, LOC387761, CDKN2A/2B, TCF7L2, IGF2BP2, KCNJ11, MTNR1B.^{26,39,49,89,92} However, in this meta-analysis, only HHEX and SLC30A8 gene variants were evaluated for their possible association with T2DM risk or protection. Furthermore, the demographic variables were not considered as the confounding factors in evaluation of association between genetic variants and T2DM.

CONCLUSION

The results of this meta-analysis demonstrated significant association of HHEX A>G and SLC30A8 C>T variants with reduced risk and increased risk of T2DM, respectively. The findings indicate that these gene variants may contribute to the genetic predisposition to T2DM.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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