The importance of genetic variants for type 2 diabetes established in western populations is far from being understood for sub-Saharan Africans. Here, we have investigated the role of three type 2 diabetes candidate SNPs well-known in other populations (TCF7L2 rs7903146, KCNJ11 rs5219, PPARγ rs1801282) in more than 1000 Ghanaians. Because of ambiguous findings in another West African study , we also included CAPN10 variants. More than half of the individuals carried the TCF7L2 (T) allele, which was suggestive to increase the odds for type 2 diabetes by roughly 40%. Also, in healthy controls, FPG was significantly elevated in carriers of this allele. Remarkably, the KCNJ11 (G) and PPARγ (C) alleles were practically absent. The respective minor alleles of CAPN10 variants were frequent but not associated with type 2 diabetes.
These findings need to be interpreted with caution. One study limitation is the comparatively small sample size that did not allow detecting effects of rare variants, such as of PPARγ and KCNJ11, and which may also contribute to the possibility of type I statistical errors. Clearly, larger studies purposely designed for determining the relevance of specific SNPs on a population-wide level are required. Also, extensive genetic admixture within the Ghanaian population may have obscured our findings. Ancient and recent migration from neighbouring countries and North Africa seems responsible for a highly variable genetic structure . Even though, the majority of our participants claimed to be of Akan ethnicity, and this was equally true for controls and cases with type 2 diabetes, we cannot exclude admixture from other ethnic groups. As a potential drawback, genotyping in duplicates was not done systematically. Nevertheless, all genotypes were in Hardy-Weinberg equilibrium, arguing against major typing errors. Study participants recruited in hospital may not reflect the genetic make-up of the average Ghanaian population, particularly when the ratio of cases and controls is 2:1. On the other hand, neither improved awareness of type 2 diabetes among patients nor management will influence predisposition and will therefore not affect associations of the genetic variants with type 2 diabetes. A major limitation lies in the unmatched design of our case–control study. Controls were younger, leaner, and had less hypertension as well as a higher SES than patients. Some controls may consequently show increased FBG and possibly diabetes when they become older and/or gain weight. In multivariate analysis, we have accounted for the differences in age (and gender, obesity, and hypertension) between cases and controls. Nevertheless, we cannot rule out residual attenuation by an over-representation of young participants in the control group. We are aware that the definition of type 2 diabetes by single FPG measurement and known medications is sub-optimal. However, it corresponds to general practice in resource-poor settings and IDF consensus . Glycated haemoglobin was not used for the diagnosis of type 2 diabetes as the high prevalences of hemoglobinopathies and haemolytic conditions, such as malaria, may have complicated the interpretation .
The present study provides first-time insight into the role of common polymorphisms – previously associated with type 2 diabetes in other populations – among a comparatively large and presumably non-admixed population of SSA. So far, most of the work in African populations, mainly African Americans, has focused on the TCF7L2 variant, revealing MAFs of around 0.34 and ORs for type 2 diabetes of 1.37 [8, 9, 11]. In Caucasians, these figures are 0.28-0.32 and 1.44 . Two small African studies, report MAFs of 0.26-0.48 and diverse risk estimates (ORs: Nigeria, 1.7; Ghana, 1.0, South Africa, 1.3) [9, 11]. We confirm the high frequency of the T allele in West-Africa as well as its association with type 2 diabetes and increased FPG. Indeed, these observations were independent of BMI status, supporting the concept of reduced insulin secretion via a deficiency of the gene product TCF7L2 . Interestingly, previous studies have revealed that frequencies of the T allele are lowest in North-America and Europe (with a gradient of increasing frequency from North to South), moderate in Asia, and highest in Africa [8, 9, 28].
Surprisingly, we are the first to investigate the importance of PPARγ rs1801282 and KCNJ11 rs5219 for type 2 diabetes in West Africa. Almost everybody in the present study population displayed the risk allele of PPARγ (C) while the risk allele of KCNJ11 (G) was almost absent. The protective PPARγ (G) variant has a global allele frequency of around 0.10, with highest figures in northern Europeans . In Caucasian and Asian populations, the G variant commonly protects against type 2 diabetes (OR Caucasians, 0.9; OR Asians, 0.8) [8, 10], particularly in populations with a high lipid contribution to energy intake . For SSA, associations with type 2 diabetes are conflicting [8, 10].
As for KCNJ11 rs5219, only few studies have examined the importance of the G allele in blacks: In an African American population, it was associated with reduced odds of type 2 diabetes; the frequency was 0.06 . A recent meta-analysis of eight African American cohort studies has found an increased risk for type 2 diabetes by 10% ; and the G allele was absent in a South African population of Zulu descent . Findings are inconsistent in Asian populations, while the variant is a robust marker for type 2 diabetes in Caucasians [8, 31]. The functional role of the SNP remains unclear. It is known to promote hypoinsulinemia, reduction of body weight and physical endurance . However, activation of the gene product depends on several other co-factors that may outweigh the importance of the SNP [33, 34]. The near absence of the G allele in our study population and its contradictory influence in other regions argue for alternative variants influencing the population-wide variation in type 2 diabetes risk in SSA.
CAPN10 polymorphisms are associated with diabetic status in Mexican Americans (OR, 2.8), Botnian Fins (OR, 2.5) and Germans (OR, 5.0) . Subsequent studies, however, could not replicate the strength of association in Caucasians , and the role in African populations is unclear [12, 13, 37]. Here, we replicated the allele frequencies of the most prominent CAPN10 variants in West Africans. These were neither associated with type 2 diabetes nor with diabetic traits in this urban Ghanaian population. The co-existence of susceptibility variants and protective haplotypes, previously reported from Caucasian and Indian populations [36, 38], may be responsible for these findings. Indeed, some CAPN10 haplotypes nominally confer a protection against type 2 diabetes in our study population (ORs, 0.45-0.72). However, the figures contrast previous findings from two ethnic groups in Ghana, where the 221 haplotype showed no association with type 2 diabetes (OR, 0.9) . Clearly, further investigations are warranted to understand the role of CAPN10 variants and their interplay for the risk of type 2 diabetes in SSA.