Variants of TCFL2 has been consistently associated with T2DM in several studies among multiple ethnic groups [16, 21, 22]. This study demonstrated the transferability of the TCF7L2 gene polymorphisms (rs12255372 and rs7903146) and their association with T2DM among a Ghanaian population. However, the associations were observed to be relevant only in a subgroup- women, patients that do not have a family history of diabetes and those with dyslipidaemia with or without elevated blood pressure and increased BMI.
This study observed that rs7903146 and rs12255372 polymorphisms have a significant effect on T2DM, however, the effect was mediated by other diabetes risk factors. In a systematic review and Meta-analysis among a Sub-Saharan Africa (SSA) population , the effect of rs7903146 was 1.75 in a recessive model and 2.27 in an additive model, which is similar to our present findings. These effects are also consistent among the Caucasian, East Asian, South Asian and other ethnicities . To the best of our knowledge, this study is currently among the few studies in SSA, that have demonstrated the transferability of rs12255372 [27, 28]. In contrast studies by Yako et al.,  and Mandour et al., , found the SNP rs12255372 to not associated with T2DM, in a South African mixed-ancestry and Egyptian population, respectively.
From a Meta-analysis by Wang et al.,  among different ethnic groups, there are significant differences in the LD structure between rs12255372 and rs7903146. From the findings of this study, weak interaction between rs12255372 and rs7903146 for T2DM was reported (in both male and female participants). This result is similar to that observed among the Yoruba population (D’= 0.075, r2 = 0.001) but unlike that of the Europeans (D’= 0.948, r2 = 0.746) and Chinese (D’= 0.479, r2 = 0.114) .
The MAF of rs7903146 observed in this study is similar to the findings of Danquah et al.,  among a Ghanaian population, where the MAF of rs7903146 was 30% in the control population and 36% in T2DM population. Among other SSA populations, the MAF of rs7903146 among T2DM vs controls has been reported at 9.5% vs 0% in Cameroonian population  and 32.2% vs 24.3% in South African mixed-ancestry . Furthermore, from the Allele Frequency Aggregator (ALFA) HapMap and 1000 Genomes project  the MAF of rs7903146 were 29.2%, 24.1% and 22.8%, respectively, which is consistent with our findings. The race-specific risk allele frequency of rs7903146 is lower among the Asian population (range: 3.1%-4.7%) and higher among Europeans (29.2%), Africans (29.5%), African American (29.7%), Latin American (34.2%) and South Asians (31.8%) . A wide population difference in the minor allele frequency of rs12255372 (Asians = 0.000 to 0.029, Europeans = 0.217-0.50 and SSA = 0.267–0.274) has been reported [17, 30, 33]. Moreover, from the results of the 1000 genomes project, the MAF of rs12255372 is 21.4% globally, 30.2% in Africa, 29.2% among Europeans and the Americans 21.9%, similar to our study.
From the findings of this study and related literature, the association between rs12255372 and rs7903146 with T2DM are similar among West African populations, Asians, Caucasians [34, 35] and other population groups . This suggests that the association of rs7903146 and rs12255372 with T2DM is moderately strong in multiple ethnicities which are likely to project a vital contribution of differences in environmental factors that confer susceptibility to T2DM.
It appears that rs12255372 and rs7903146 are not associated with T2DM among West African populations (Ghanaians and Yoruba), unlike other population groups. This finding is essential in understanding the different types and aetiology of T2DM present in SSA , and the wider population differences in T2DM prevalence. For example, as indicated in this study the association between rs12255372 with T2DM was relevant among women, obese/overweight individuals, individuals with negative family history, low HDL-C and individuals aged above 60 years. Similarly, rs7903146 was relevant among females, individuals with negative family history, elevated TG and low HDL-C but normal blood pressure. This indicated that TCF7L2 risk variants may be relevant to a subgroup of individuals with single or multiple diabetes risk factors, other than those with a positive family history .
This study observed that the risk allele rs7903146 was associated with elevated FPG and HbA1c in both the diabetic and controls. In addition to FPG and HbA1c, the risk alleles of rs12255372 were associated with elevated BMI, blood pressure, TG and reduced LDL in T2DM and controls. This finding reflects the pleiotropic role TCF7L2 polymorphisms play in T2DM (adipogenesis, incretin and insulin expression as well as beta-cell growth and development). The rs7903146 risk alleles are associated with reduced proportional control of β-cell function among newly diagnosed T2DM patients . Loos et al.,  reported that the T-allele of rs7903146 was associated with higher HbA1c concentrations and reduced β-cell function, assessed by the homeostasis model assessment of β-cell function. TCF7L2 protein was also found to be increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells  and TCF7L2 expression was required for the regulation of Wnt . High expression of TCF7L2 mRNA was identified with reduced TCF7L2 protein levels in individuals with the T-allele of rs7903146, which is associated with a downregulation of GIP- and GLP-1 receptors and impaired beta-cell function Shu et al., .
These findings imply that TCF7L2 polymorphisms rs7903146 and rs12255372 may confer T2DM susceptibility through the expression of adipocyte-insulin resistance, delayed insulin secretion (resulting from beta-cell dysfunction) and reduced intracellular energy homeostasis. Therefore, individuals with the risk alleles of TCF7L2 (rs7903146 and rs12255372) may present with obesity, elevated TG and reduced HDL-C. Also, the findings suggest that among individuals with multiple diabetes risk factors, those who do develop T2DM may have a genetic predisposition to beta-cell dysfunction which includes the SNPs rs12255372 and rs7903146 .
Some limitations of the study are worth mentioning when interpreting the findings of this study. The differences in population substructures may result in a different interpretation of risk alleles in candidate gene association studies. Also, the number of genetic roots underlying T2DM is still being investigated and could be numerous given its multifaceted nature. Therefore, the effect of the variants among the small population considered in this study may be unpredictably low, when we consider it from a larger population. Besides this limitation, the findings of this study are consistent with the recommended approach for conducting a candidate gene association study and present consistent findings with similar studies among other population groups.