Evolutionary forces in diabetes and hypertension pathogenesis in Africans

Abstract Rates of type 2 diabetes (T2D) and hypertension are increasing rapidly in urbanizing sub-Saharan Africa (SSA). While lifestyle factors drive the increases in T2D and hypertension prevalence, evidence across populations shows that genetic variation, which is driven by evolutionary forces including a natural selection that shaped the human genome, also plays a role. Here we report the evidence for the effect of selection in African genomes on mechanisms underlying T2D and hypertension, including energy metabolism, adipose tissue biology, insulin action and salt retention. Selection effects found for variants in genes PPARA and TCF7L2 may have enabled Africans to respond to nutritional challenges by altering carbohydrate and lipid metabolism. Likewise, African-ancestry-specific characteristics of adipose tissue biology (low visceral adipose tissue [VAT], high intermuscular adipose tissue and a strong association between VAT and adiponectin) may have been selected for in response to nutritional and infectious disease challenges in the African environment. Evidence for selection effects on insulin action, including insulin resistance and secretion, has been found for several genes including MPHOSPH9, TMEM127, ZRANB3 and MC3R. These effects may have been historically adaptive in critical conditions, such as famine and inflammation. A strong correlation between hypertension susceptibility variants and latitude supports the hypothesis of selection for salt retention mechanisms in warm, humid climates. Nevertheless, adaptive genomics studies in African populations are scarce. More work is needed, particularly genomics studies covering the wide diversity of African populations in SSA and Africans in diaspora, as well as further functional assessment of established risk loci.