Genetics of type 2 diabetes (T2D) in Malaysia: a review

Abstract

Type 2 diabetes (T2D) is a significant public health concern in Malaysia, with rising prevalence across its multi-ethnic population. Genetic predisposition plays a key role in the development of T2D, but studies focusing on Malaysian populations remain limited. This review summarizes existing evidence on genetic variants associated with T2D in the Malaysian population, focusing on single-nucleotide variants and ethnic-specific risk patterns. A comprehensive literature search was conducted across major databases, identifying 31 relevant studies published between 2000 and 2024. Key findings were discussed to identify commonly implicated variants and ethnic differences in the association with T2D. These findings highlight the ethnic-specific genetic risk factors within the Malaysians, confirming the need to consider ethnic diversity and inclusion in T2D genetic study design, analysis, and clinical translation. This review offers a novel insight into the ethnic-specific effects of Malaysian T2D risks, particularly the underrepresented Malay ethnic group, which is important for the future development of precision medicine strategies for T2D in Malaysia.

Introduction

Diabetes is a fast-growing and worldwide public health issue, with 537 million people affected throughout the world, and this prevalence is suspected to increase to 643 and 783 million cases by the year 2030 and 2045, respectively [1]. Among individuals with diabetes, 90% have type 2 diabetes (T2D) [1]. Although the incidence and burden of T2D rise globally, the rates are much higher in most low- and middle-income countries [2, 3]. The Diabetes Atlas reported that 6.7 million deaths worldwide were attributable to diabetes, and diabetes remains the leading cause of blindness, chronic kidney disease (CKD), and amputation [1, 3]. Therefore, substantial efforts have been made in recent years to understand the pathophysiology of T2D and develop preventive and therapeutic measures to reduce the burden of diabetes [1, 2].

T2D is a significant burden in Southeast Asia (SEA), particularly Malaysia [1]. According to the International Diabetes Federation, Malaysia ranks third in the SEA region with the highest number of reported T2D cases (4.4 million), which accounts for 19% prevalence [1]. The recent Malaysian National Health and Morbidity Survey (NHMS) in 2023 reported a similar overall prevalence of diabetes (15.6%), which is an increase from 13.4% (year 2015) and 11.2% (year 2011) [4]. Moreover, a systematic review and meta-analysis of 15 studies also confirmed that the pooled diabetes and prediabetes prevalence in Malaysia is 14.4% and 11.6%, respectively [5], and these numbers are significantly higher compared to other SEA countries, such as Singapore and Indonesia [1]. Furthermore, during the Malaysian NHMS survey, it was reported that two out of five individuals with elevated fasting blood glucose were unaware of their conditions and had no prior clinical diagnosis [4]. This significant portion of undiagnosed diabetes is at high risk for long-term health complications due to having no early access to care and treatment. Eventually, these silent undiagnosed individuals will contribute to a greater prevalence of T2D and its related complications.

T2D is a complex disease with a significant genetic influence, and the genetic heritability is estimated to be around 20–80%, as shown by previous family- and twin-based studies [6]. Moreover, T2D is more prevalent in certain ancestral groups or ethnicities despite living in the same environment [6, 7]. Additionally, individuals with a family history of diabetes have a greater risk of diabetes [8,9,10], which further confirms there is a genetic predisposition towards T2D. Since Malaysia is a multi-ethnic and diverse population, the disparity of the T2D prevalence is also observed among the main ethnicities (Malays, Chinese, and Indians). From the recent national NHMS healthy survey, the Indian ethnic group has the highest T2D prevalence (26.4%), followed by the Malay (16.2%) and Chinese (15.1%) ethnic groups [4]. Similarly, a national health population-based cohort (The Malaysian Cohort, TMC) that consists of 106,527 Malaysians also reported that 16.6% of participants had T2D, and the disparity prevalence was also evident, with the lowest T2D prevalence being in the Chinese ethnic group compared to the Malays and Indians [11]. Consistent with this ethnic-specific trend, a significant difference was also observed in HbA1c levels, where the Malaysian Indians have the highest median HbA1c (8.3%), followed by the Malay (7.7%), and the Chinese (7.2%) ethnic groups [12]. Another study also reported that plasma adiponectin and high-density lipoprotein (HDL) were the lowest in Malaysian Indians compared to other ethnic groups [13]. Importantly, even after adjusting for clinical, dietary, and lifestyle factors, the plasma adiponectin levels remained significant with ethnicity [13], suggesting the possibility of genetics in explaining this relationship and potentially contributing to different risks in T2D.

Previous studies have investigated various genetic variants associated with T2D across different populations and ethnicities [6], yet the information is limited for a multi-ethnic population in Malaysia, particularly the Malay ethnic group. The genetic clustering of the Malays in Peninsular Malaysia showed that even within the Malay ethnic groups, there are sub-ethnics groups, despite sharing the same ancestral group [14, 15]. Since the Malay ethnic group is the largest ethnic group in Malaysia and one of the underrepresented in many global genetic studies, using published genetic variants to predict T2D risk may not be accurate for the Malays and would require further validation. Therefore, this mini-review aimed to discuss the existing findings on genetic variants associated with T2D and how these variants differ across ethnic groups in Malaysia. This new perspective of ethnic disparities in contributing to T2D genetic risk in Malaysia is often not addressed and overlooked in previous publications. Hence, addressing these gaps will help understand T2D and its genetic risks in Malaysia, particularly for the Malay ethnic group, paving the way for developing ethnicity-tailored approaches in T2D precision medicine.

Literature review search methodology

Three databases (PubMed, Cochrane Library, and Google Scholar) were searched extensively based on the keywords “genetics,” “Malaysia,” “diabetes,” and “Type 2 diabetes,” and only articles in the English language were considered. A total of 45 studies were relevant, and after the removal of studies with incomplete genetic information and study designs (no specific variant identifiers, sample size, or statistical measures), 31 studies were included in the discussion (Fig. 1).

Fig. 1

The flow chart showing the literature search strategy and selection. The terms used are “genetics,” “Malaysia,” “diabetes,” and “Type 2 diabetes,” focusing on the Malaysian population

Genetics of T2D in Malaysia

Candidate gene studies

Glucose homeostasis and insulin secretion-related variants

Various studies in Malaysia have reported that a few genetic variants regulating glucose metabolism and insulin secretion (Table 1). Ansari et al. [16] recently genotyped the variants from the glucokinase (GCK), glucokinase regulator (GCKR), and glucose-6-phosphatase catalytic subunit 2 (G6PC2) genes in 180 T2D Malay individuals and compared them to 180 healthy controls. Two variants (GCK rs1799884 A-allele and GCKR rs780094 T-allele) were significantly associated with the T2D risk. In contrast, there was no association with T2D for G6PC2 rs560887 A-allele [16]. Consistent with these findings, previous studies of GCK polymorphisms in Asians also reported similar associations of the GCK rs1799884 variant with higher T2D risk and fasting glucose [17, 18], which may suggest this GCK variant could have similar effects in other ethnicities in Malaysia. Since GCK is a glucose sensor enzyme responsible for the glucose-stimulated insulin release, mutations in this gene are associated with the monogenic form of diabetes (Glucokinase–maturity-onset diabetes of the young, GCK-MODY) [19]. MODY, or Maturity-Onset Diabetes of the Young, is a monogenic diabetes due to a single gene mutation causing pancreatic β-cells dysfunction. It is usually inherited in an autosomal dominant fashion, and the patients generally have heterozygous mutations [19]. Most variants that affect the GCK function are often related to insulin signalling and pancreatic β-cells insulin secretion following glucose stimulation [19]. A recent review has mapped the previously reported variants in the GCK gene and their effects on T2D pathophysiology. Even having normal or low blood glucose levels, gain-of-function (GOF) variants increase GCK activity to stimulate insulin secretion (hyperinsulinaemia). Meanwhile, the loss-of-function (LOF) variants reduce GCK activity and cause high blood glucose [20]. Therefore, previous studies of GCK rs1799884 associations showed that the A-allele was indeed associated with a consistent, sustained, and moderate increase in fasting glucose across various populations (increment of 0.03–0.05 mmol/L in rs1799884-AA genotype) [21]. However, the effect was not strong enough to cause T2D [21, 22]. These findings suggest that GCK variants, particularly the rs1799884 A-allele, may play a significant role in T2D risk in the Malaysian population, potentially through their influence on insulin secretion and glucose regulation.

Table 1 Summary of published genetic variants and their associations with Type 2 Diabetes in the Malaysian population

In contrast, the GCKR is a glucose disposal regulator that inhibits hepatic glycolysis and de novo lipogenesis (DNL) by binding to GCK. Therefore, genetic variants in the binding site between GCKR and GCK could result in free and active GCK [20, 23], which may partly explain the protective effects of GCKR rs780094 T-allele (OR: 0.12, P < 0.019) seen in the Malays [16]. Consistent with these findings, previous studies of GCKR rs780094 in other populations showed that the T-allele reduced the T2D risk (OR: 0.85, P = 0.05) [17], and the C-allele increased the T2D risk (OR: 1.08–1.33, P = 3.8 × 10^–6–0.039) [18, 21, 24]. However, other studies also reported no association between this variant and fasting glucose or T2D risk [22, 25], indicating the conflicting and inconsistent results of this GCKR variant. The plausible reason for such discrepancies may be due to the T-allele contrasting effect in regulating lipids. Previous studies showed that GCKR rs780094 T-allele increased plasma triglyceride levels (Beta: 0.107, P = 1.6 × 10^–16) [26, 27] and was associated with a higher risk of non-alcoholic fatty liver disease (NAFLD) (pooled OR: 1.20, 95% CI: 1.11 ~ 1.29) [28]. These contrast effects on the glucose and lipids by GCKR rs780094 suggest a complex interplay between this variant and metabolic pathways. Further insight into the biological relationship between the GCKR and GCK in glucose and lipid metabolism may also explain the contrasting effects of the T-allele on T2D risk and lipid levels. Studies suggest that the T-allele facilitates the dissociation of GCK from GCKR more efficiently in the postprandial glucose state, leading to an increased rate of glucose-stimulated glycolysis and hepatic de novo lipogenesis (DNL) [29]. Therefore, GCKR rs780094 T-allele contributes to a greater glucose metabolism (reducing the blood glucose and T2D risk), yet producing more Malonyl-CoA, a precursor for fatty acids [29]. These effects are likely more pronounced in individuals with underlying metabolic dysfunction, as the GCKR rs780094 T-allele interacted with insulin (P = 4.57 × 10^–4), HOMA‐IR (P = 1.32 × 10^–3), and triglyceride (P = 4.17 × 10^–3) traits [30]. When the level of these traits increased, the presence of GCKR rs780094 T-allele reduced the liver attenuation (LA_ivn) (Beta: -0.04), which indicates a higher fat content in the liver (steatosis) [30]. Therefore, the GCKR rs780094 T-allele is often reported as the risk variant for the NAFLD (pooled OR: 1.20, 95% CI: 1.11 ~ 1.29) [28]. Despite the slight inconsistencies of T2D risk among the ethnicities in Malaysia, the significant associations of GCK and GCKR polymorphisms with T2D in Malays [16, 31] are similar to other populations, and these associations may shed light on why high prevalence of dyslipidaemia is seen in Malaysian T2D patients, particularly in the Malays [9, 11].

Other variants from the genes related to insulin secretion and regulation have also been reported in T2D Malaysians (Table 1). Two studies reported the association of KQT-like subfamily, member 1 (KCNQ1) variants (rs2237892, rs2237895, and rs2283228) with the Malays [32] and Chinese [33] T2D individuals. In these studies, [32, 33], all three variants conferred a greater risk of T2D in both ethnicities (rs2237892, OR:1.45 (Malays) and 2.0 (Chinese) and rs2283228, OR:1.7 (Malays) and 1.9 (Chinese)), except for the rs2237895 (OR: 1.9 (Chinese), P < 0.05), which has no association with T2D risk in Malays. These associations are consistent with other population studies and meta-analyses [34], which reported that the KCNQ1 variants are consistently associated with T2D risk, particularly the rs2237892 [35]. The KCNQ1 gene encodes a voltage-gated potassium channel, Kv7.1, primarily expressed in cardiac cells and pancreatic islets, where it is responsible for regulating cardiomyocyte repolarization and insulin secretion [36]. Genetic variants in the KCNQ1 gene are reported to affect the voltage-dependent currents, which are important in the glucose-stimulated insulin secretion. Individuals carrying the LOF mutations in the KCNQ1 gene are shown to have hyperinsulinaemia, hypoglycaemia, and long QT syndrome [36]. For example, rs2237892 was associated with higher expression of the KCNQ1 gene, resulting in fasting hyperglycaemia and decreased glucose-stimulated insulin secretion [36]. Notably, the interaction between KCNQ1 rs2237895 and environmental factors was evident in chronic kidney disease (CKD) risk among the Malaysian T2D patients [37]. Individuals with KCNQ1 rs2237895 have a higher risk for CKD (adjusted RR:1.65, P = 0.013), and the gene–environment interaction analyses revealed that KCNQ1 rs2237895 interacted with environmental factors such as smoking and waist circumference [37]. The CKD progression rate was significantly higher in obese individuals compared to the non-obese group, but those obese individuals carrying the homozygous CC genotype had a greater risk for CKD progression. Intriguingly, the CKD progression was more prominent in non-obese individuals carrying the CC genotype than the AC and AA genotypes [37], indicating the effect of this variant on CKD progression even in a low-risk environment.

Similar to KCNQ1 variants, another study also investigated the relationship between the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) variants (rs6777038, rs16860234, and rs7651090) and T2D risk in Malaysians [38]. They found that all three variants increased the T2D risk (rs6777038 OR: 1.21, P = 0.03; rs16860234 OR: 1.36, P = 0.0004; and rs7651090 OR: 1.35, P = 0.0002) [38]. The IGF2BP2 gene, a well-known gene associated with T2D, is highly expressed in pancreatic islets and encodes the insulin-like growth factor 2 (IGF2) mRNA-binding protein (IMP2). Previous studies showed that IMP2 binds to the 5' untranslated region of the IGF2 mRNA to promote its translation [39], implicating its role in T2D. Another study also reported that IMP2 binds directly to pancreatic duodenal homeobox 1 (PDX1), an essential transcriptional factor that regulates pancreas and islet development [40], suggesting its important regulation in insulin production. Consistent with this function, previous studies have shown that genetic variants in the IGF2BP2 gene reduced insulin secretion in T2D individuals [41, 42], thus partly explaining how IGF2BP2 variants contribute to T2D pathophysiology.

Another study investigated the association of variants and haplotypes of the Solute carrier family 30 member 8 (SLC30A8) gene in Malaysian T2D subjects [43]. Three variants (rs13266634, rs1995222, and rs7002176) were genotyped in 1107 T2D individuals and compared to 973 healthy controls. Two variants, rs13266634 and rs1995222, increased the risk of T2D (OR: 1.45 and 1.29, P = 0.001 and 0.02, respectively), whereas no association was observed for rs7002176. Notably, in the sub-ethnic analysis, the rs13266634 (W325R) variant has more pronounced effects among the Indians; however, the variant effect was lost in the Chinese and Malay ethnic groups [43]. In contrast to this finding, a previous Singaporean study with a similar multi-ethnic population showed that rs13266634 was associated with T2D in the Malays [44]. These discrepancies may be due to the different sample sizes between these two studies, particularly the small sample size in the Malaysian subset analysis. Although both studies reported minimal associations (moderate odds ratios), previous studies in Jordanians [45], Iranians [46], Bangladeshis [47], and Finnish [48] reported similar associations with T2D risk, thus confirming the relevance of this genetic variant in T2D risk in Malaysia. Physiologically, the SLC30A8 gene encodes the Zinc transporter 8 (ZNT8), and previous studies have shown that the presence of the rs13266634 variant caused the accumulation of zinc and less efficient insulin packaging in the pancreatic β-cell granules [49]. Zinc plays a vital role in insulin storage within pancreatic β-cells, and disruptions in zinc transport and insulin crystallization can lead to T2D by affecting the cell’s ability to store and release insulin efficiently, ultimately impacting glucose control [50]. Another study also reported that this variant increased hepatic insulin clearance [51], resulting in low circulating insulin despite hyperinsulin secretion by the pancreatic β-cells [52], which suggests the plausible mechanism of how this variant increases the T2D risk.

Besides the SLC30A8 gene, another Malaysian study investigated the relationship between the T2D risk and organic cation transporters (OCTs) 1, 2, and 3 encoded by the SLC22A1, SLC22A2, and SLC22A3 genes, respectively [53]. In this study [53], the genetic association focused only on the Indian ethnic group, and only the SLC22A3 rs2292334 A-allele variant was associated with T2D risk, particularly in males (OR: 3.11, P = 0.006). Unfortunately, limited evidence is available from the previous studies that reported a similar effect of this rs2292334 variant [54]; thus, there is a need to assess the impact of this variant on other Malaysian ethnic groups. Since the OCTs primarily transport various small molecules or drugs and environmental toxins, their roles may be involved in the drug metabolism and treatment response [55]. A previous study reported that this rs2292334 variant influenced the pharmacokinetics of metformin, as the individuals with the A-allele had a more significant reduction of the HbA1c (0.77% reduction from baseline) levels following the metformin treatment (1000 mg/day) than those with the G-allele [56]. However, further assessments of the effect of this variant on metformin efficacy are needed, as the other two studies found no association [57, 58].

Adipocyte-related variants

Variants related to adipocytes or adipokines also influence Malaysian T2D risk. One recent study of 150 Malaysian T2D patients and 150 healthy individuals from three main ethnicities (Malays, Chinese, and Indians) genotyped the rs7799039 in the Leptin (LEP) gene [59]. This study found that this LEP rs7799039 increased the risk of T2D only in Malays and Indians (OR: 1.9 and 2.46, P = 0.042 and 0.002, respectively). Moreover, fasting serum leptin levels were significantly higher in T2D individuals compared to the non-diabetics (166.78 pg/ml compared to 101.94 pg/ml, P < 0.001), particularly in homozygous AA individuals. The elevated serum leptin, insulin levels, and BMI were all associated with the AA genotype of the rs7799039 [59]. The disparity of the significant rs7799039 association with T2D across the ethnicities was consistent with previous studies, as the rs7799039 was associated with T2D in Iranian [60], Egyptians [61], and Punjabi [62] but not in Chinese or East Asians [63]. These discrepancies may be due to the high A-allele frequency in the East Asians (73%) compared to the South Indians (51%) and Europeans (44%) [64]. Further insights on the location of the rs7799039 in the LEP gene revealed that this variant is close to the SP-1 transcription factor binding site [65], and the protein-DNA binding capacity is greater in the presence of this variant [66]. Therefore, the rs7799039 variant heightened leptin synthesis by promoting its transcription and release by adipocytes, causing higher plasma leptin levels. Besides leptin, another Malaysian study also investigated the Leptin receptor (LEPR) rs1137101 genotypes and reported that the G-allele was significantly higher in the Chinese ethnic T2D group than in healthy controls [67]; however, no association analysis was performed for T2D risk. A recent meta-analysis of nine studies showed that this G-allele predisposed individuals to T2D risk, and the biological evidence also showed that this variant influenced the LEPR binding affinity and signal transduction, contributing to insulin resistance [68], which may suggest that similar effects could be present in the Malaysians. Therefore, a larger study is needed to examine the LEP and LEPR polymorphisms in Malaysian T2D individuals.

Another adipocyte-related gene, Dipeptidyl Peptidase 4 (DPP4), also plays a significant role in adipose tissue and metabolic regulation in T2D [69]. DPP4 is expressed in adipose tissue and is involved in adipogenesis, insulin sensitivity, and inflammation [69, 70]. A study by Ahmed and colleagues investigated ten DPP4 genetic variants in 314 Malaysian subjects with T2D compared to 235 healthy controls [71]. Three variants (rs12617656, rs7633162, and rs4664443) significantly increased the T2D risk (OR: 1.95, 1.42, and 1.53, P = 0.008, 0.02, and 0.039, respectively). Specifically, the rs12617656 variant showed significant associations with T2D in recessive, dominant, and additive genetic models, and these associations were more prominent in the Indian ethnic group [71]. These significant associations of the DPP4 genetic variants with T2D risk are crucial, as the genetic variants of the DPP4 gene are known to influence the DPP-4 inhibitors (DPP4i) treatment response [72]. Consistent with this effect, the rs4664443 variant was associated with increased serum levels of DPP4 in T2D Malaysian individuals, and the rs7633162 variant was associated with DPP4 activity inhibition [71]. The lack of association between the other DPP4 genetic variants and T2D risk observed in this Malaysian study [71] may be partially explained by the fact that DPP4 is an adipokine released in the presence of high-fat conditions, as observed in the hypertrophic adipocytes, obese rodents, and humans [69]. Thus, only obese or overweight individuals may secrete sufficient DPP4 for the effects of the genetic variants to be apparent [73]. Unfortunately, although the T2D group had a higher BMI than controls, no sub-analysis for body fat content was performed in the Malaysians, thus potentially explaining the missing associations with other DPP4 variants [71].

Other variants

The renin–angiotensin–aldosterone system (RAAS) regulates the homeostasis of body fluids and electrolyte balance to maintain blood pressure [74]. Many studies have shown that RAAS is also involved in T2D pathophysiology, particularly in promoting oxidative stress and insulin resistance [75]. One study of 290 T2D Malaysian Malays compared to 267 healthy controls investigated the relationship of genetic variants in three RAAS genes (Angiotensin-converting enzyme (ACE), Angiotensinogen (AGT), and Angiotensin II receptor type 1 (AGTR1)) with T2D risk [76]. Only one variant, AGT rs5051, was associated with higher T2D risk (OR: 1.94, P = 0.007), and two AGT variants (rs4762 and rs699) were associated with a lower risk of T2D (OR: 0.54 and 0.47, P = 0.042 and 0.007, respectively), but these associations were only in males. However, after adjusting for diabetes-related factors, only the AGT variant, the rs699 association, remains significant. Meanwhile, the variants of ACE and AGTR1 were not associated with T2D risk in the Malays [76]. Previous studies reported that most RAAS polymorphisms were found in diabetes complications. For example, a meta-analysis of 114 studies showed that the most reported AGT variant, rs699, was associated with a lower risk of CKD (pooled OR = 0.084, P = 0.08) [77]. The other AGT variant, rs4762, was reported to be associated with diabetic nephropathy in Asians (OR = 2.8, P < 0.05), not in Caucasians [78], indicating ethnic disparity of these RAAS variants in relationship with kidney complications in diabetes.

Besides the above studies, various Malaysian studies also investigated the association between the ATP-binding cassette transporter (ABCA1) variants (rs1800977, rs2230806, and rs9282541) [79], peroxisome proliferator-activated receptor gamma (PPARG) variant (rs1801282) [80], plasminogen activator inhibitor-1 (SERPINE1) variant (rs1799889) and tissue plasminogen activator (PLAT) variant (Alu-repeat I/D) [81], and vitamin D receptor (VDR) variants (rs1544410 and rs2228570) [82] with T2D risk. However, no significant genetic association was established for these variants related to T2D risk. Since most of the genetic information for T2D risk in Malaysians is reported from small individual studies with a case–control design to validate the association of these variants reported from other populations, such an approach will not be able to uncover the actual genetic profile of T2D in Malaysians. Therefore, identifying genetic variants specific to Malaysians is crucial as the incidences and progression of T2D in Malaysians are very different.

Genome-wide association study (GWAS)

Until now, there has been only one genome-wide association study (GWAS) analysis to explore the genetic profile of T2D in the Malaysian population [83]. In this study [83], a total of 4986 individuals [1604 Malays (722 T2D, 882 controls), 1654 Chinese (819 T2D, 835 controls), and 1728 Indians (851 T2D, 877 controls)] were genotyped. The GWAS analysis identified 62 significant loci associated with T2D risk. A further meta-analysis of these loci across the three ethnic groups showed that seven loci were significant for T2D risk (CDKN2A rs10965250, GCK rs4607517, TCF7L2 rs7903146, FTO rs9939609, MC4R rs12970134, ADCY5 rs11708067, and PPARG rs1801282), with each variant having a small effect size (1.0–1.3) [83]. Moreover, the combined genetic risk score is strongly associated with T2D risk within and across the ancestral groups, accounting for approximately only 1.0–1.7% of the total T2D risk [83]. Notably, this GWAS study [83] did not replicate a significant portion of known T2D loci, possibly due to insufficient statistical power, a smaller sample size than other international GWAS studies, and low minor allele frequency (MAF) [84, 85]. However, the significant T2D variants observed in this study have an effect direction consistent with previous studies, confirming that T2D genetic susceptibility is mostly shared across ancestral groups or populations and is relevant for T2D risk identification in Malaysia.

Challenges and future direction

Identifying genetic factors and inferring the disease–causal relationship with T2D pathophysiology has proved challenging in Malaysia. Following the first GWAS for T2D in 2007, more than 200 T2D susceptibility loci have been discovered via independent studies from a single ancestry (primarily European) and have been extensively reviewed [84,85,86]. In recent years, the inclusion of other populations or ethnicities in the same analysis (trans-ancestry meta-analysis) has discovered an additional 500–700 T2D loci [84, 85]. One such is the recent and largest meta-analysis that analysed 428,452 T2D individuals and 2,535,601 healthy controls from six ancestral groups (European, African American, Hispanic, South Asian, South African, and East Asian) [87]. In this study [87], 145 significant loci are novel from the previously reported 318 T2D loci [88], suggesting the importance of ethnic diversity and inclusion of other multi-ethnic populations to discover novel T2D variants. Most of these new loci are commonly shared across ancestral groups, indicating they are common variants, and only a few are ancestry-specific [87, 88]. Identification of these novel loci was also possible due to the large sample size and increased statistical power to detect them, as their association effect sizes were smaller than previously reported variants [87, 88], therefore confirming that the large sample size is the primary determinant for the common variant association studies. Unfortunately, most of the published genetic studies in Malaysia are case–control studies with one or two centres sampling, small sample sizes, and often limited to a single ethnic group. These methodological and study-design issues are often constructed due to the limited budgets and resources. Consequently, these issues lead to limited statistical significance and biological interpretation, reducing the replicability, and missing the gene–environment interactions. Therefore, several improvements and solutions are needed to elucidate the comprehensive genetic profile of T2D risk in Malaysia.

One such approach is to perform a large-scale genome sequencing of the Malaysians to provide more information about the genetics of T2D. Malaysia has a diverse population, with a significant proportion of the Malay ethnic group, one of the underrepresented ethnic groups in the global genetic consortium. Previous genetic and ancestry analyses of the Peninsular Malays reported several sub-groups within the Malays [14, 15]. Two Malay sub-ethnic groups (Melayu Kelantan and Melayu Kedah) are genetically closer to each other and closely related to the Indians. Meanwhile, the Melayu Jawa ethnic group is more related to the Chinese [14, 15]. Such differential clustering reflects the region’s topographical and historical migration events, which further contribute to the diversity of the Malays. Moreover, Malaysia also has indigenous Orang Asli (aboriginal peoples) populations in the peninsula, such as the Negritos (Jahai and Kensui) and Proto-Malays (Temuan), and the indigenous populations of West Malaysia [14, 15] that further enrich the population uniqueness and diversity. However, the contribution of these ethnic groups and their genetic differences to the T2D predisposition is unknown. Therefore, large-scale studies or a national genome project are needed to unravel these potential ethnic-specific effects on T2D risk in the Malaysians. This initiative requires the participation of multiple organizations, including clinical and healthcare professionals, academics, industrial companies, local communities, funding agencies, and policymakers, to ensure the execution of the large project and sustainable funding for adequate inclusion of all ethnicities. Fortunately, with the Precision Medicine Initiative by the Academy of Sciences Malaysia [89] and the current ongoing recruitment for the national genome project (MyGenom) [90], these initiatives will help to address the limitations of the current research. Another suggestion is to strengthen local collaboration and participation in international consortia. Collaborating with local and international communities and institutions will help utilize the current resources within the individual institution and increase the existing samples or cohorts for a bigger impact, greater statistical power, better data collection and standardization, and ample grant opportunities. Furthermore, resources and knowledge sharing will empower local researchers and professionals to understand the role of genetics in contributing to T2D risk among Malaysians and within the ethnic groups.

The current review identified multiple genetic variants associated with T2D risk among the Malaysians and their ethnicities (Fig. 2). Several significant variants are shared across the three ethnicities, with some shared between the Malays and Chinese (KCNQ1 rs2283228 and rs2237892) and between the Malays and Indians (LEP rs7799039). Most of these variants have been reported before in other populations to be associated with T2D risk, with minor differences being the significant associations across the ethnic groups. Unfortunately, the variant associations and frequencies will be challenging to confirm for the Malays since the actual allele frequencies for this ethnic group are unavailable. Moreover, these significant T2D variants and their unique distributions among the ethnic groups (Fig. 2) are limited by the methodology and study design, such as focusing on one ethnic group, rather than the actual effects of those variants. Therefore, future studies should consider including all ethnicities and analysing the data based on the ethnic groups to confirm these variant effects in contributing to T2D risk. Differences in the allele frequencies and variant effects may unravel why certain ethnic groups in Malaysia have a greater risk for T2D, and importantly, their interactions with environmental factors may enhance our understanding of ethnic-specific risk in T2D and potentially its long-term health complications. Although the evidence is limited, KCNQ1 rs2237895 increased the risk of CKD and its progression rate in Malaysian T2D patients, where the effects of this variant are profound in obese individuals as well as non-obese individuals carrying the mutant genotypes. Thus, incorporating this variant with the routine clinical assessments may help to identify T2D individuals for CKD progression. However, more studies are needed to validate this relationship since only one study has provided evidence.

Fig. 2

The graphical representation of the significant variants associated with type 2 diabetes in three main ethnicities of the Malaysian population. Red wording represents variants that increase the risk, and green wording represents variants that reduce the risk

Even though ~ 800 T2D loci have been identified globally, these variants only explain 20% of the T2D genetic predisposition [84, 85], indicating a significant proportion of missing heritability and thus may have limited utility in the Malaysians. Although these identified variants are mostly common (MAF > 5%) and shared across the ancestry groups, they have small and modest effect sizes [84, 85] to be considered clinically meaningful. Moreover, most of these genetic variations are also within the noncoding regions (intergenic or intronic) [84, 85], making it challenging to infer the causal relationship with the T2D pathophysiology. Thus, the research of T2D genetics also focused on sequencing the genes located near established T2D loci to identify potential or rare coding variants [91]. A previous large study of the exome data from 81,412 T2D cases and 370,832 controls from diverse ancestral groups revealed 40 distinct coding variants associated with T2D [92]. Interestingly, five loci have a low frequency (rare), and their effect sizes were similar to the remaining common coding variants (small, modest effect) [92]. Fine-mapping these variants also showed that only 16 loci were likely to have a disease–causal relationship with T2D [92]. Therefore, without comprehensive and informative genetic and phenotype data, careful interpretations are needed to understand the biological implications of these genetic variants and how they are associated with T2D risk in Malaysians, as the genetic association does not imply a causal relationship for T2D.

Conclusion

In conclusion, genetic research on T2D in Malaysia remains limited, with most studies involving small sample sizes and focusing on candidate variants. Only one genome-wide association study (GWAS) has been conducted in the Malaysian population, highlighting a significant research gap. Although several genetic variants have been identified to associate with T2D risk, their biological relevance and interactions with environmental factors remain poorly understood. Given Malaysia’s diverse ethnic composition, there is an urgent need for extensive, multi-ethnic studies to uncover more ethnic-specific genetic risk profiles, considering there is a disparity in the T2D prevalence among the ethnic groups. Such findings could help develop ethnic-specific risk prediction tools to identify high-risk individuals and provide precise treatment. These challenges require combined efforts from all relevant players, including the healthcare professionals, local communities, funding agencies, and local government, to ensure the complete understanding of T2D genetic architecture and risk in Malaysia and their potential implementation in disease screening and assessments, precise treatments, and intervention strategies.