Genetic or non-genetic factors: which ones are the main determinants of type 2 diabetes? This is the question

This editorial refers to ‘Cardiovascular health, genetic predisposition, and lifetime risk of type 2 diabetes’, by K. Wang et al. pp. 1850–1857. Type 2 diabetes (T2D), is a metabolic disease, characterized by disturbances in glucose and insulin metabolism, widespread in the world: it is estimated that ∼9.3% of adults aged 20–79 years, ∼463 million people, are living with diabetes. These figures are expected to increase significantly: the prevalence will reach 578 million adults by 2030, and 700 million by 2045.1 Diabetes increases the risk of early death: ∼4.2 million adults’ deaths in 2019 have been due to diabetes and its complications. This is equivalent to one death every 8 s.1 Cardiovascular (CV) diseases are responsible for one-third to a half of all diabetes related deaths; diabetes and elevated blood glucose confer a two-fold excess risk of vascular outcomes (coronary heart disease, ischaemic stroke, and vascular deaths), independent of other CV risk factors.2 The pathogenesis of T2D is driven by genetic and non-genetic factors, such as obesity, an unhealthy diet, and physical inactivity, and great emphasis has been given by the international literature for the identification of which of these two groups of risk factors represents the main determinant for the development of T2D. Two independent Asian cohorts (the China Kadoorie Biobank Study and the Singapore Chinese Health Study) reported that a healthy lifestyle was associated with a significantly lower risk of T2D than an unhealthy lifestyle regardless of genetic risk category (49 related genetic variants) among the Chinese population.3 In the UK Biobank Study, genetic composition and combined health behaviours and factors demonstrated a log-additive effect on the risk of developing CV disease. The relative effects of poor lifestyle were comparable between genetic risk groups (38 related genetic variants) for developing of T2D.4 On the other hand, the Finnish study reported that a polygenic risk score could improve reclassification of incident T2D over a combination of traditional risk factors extrapolated from American Diabetes Association's diabetes risk test.5 The evidence also shows that women would have more years of survival free of T2D than men after the age of 45, with the same lifestyle.6,7 Wang et al. in the manuscript ‘Cardiovascular health, genetic predisposition, and lifetime risk of type 2 diabetes’ evaluated the lifetime risk for incident T2D across different cardiovascular health (CVH) categories and the role of T2D genetic variants on the risk of incident T2D across different CVH categories, in a population free of T2D at baseline embedded within the Rotterdam Study, a prospective cohort study of the community-dwelling population aged 55 years and older in Rotterdam, the Netherlands.8 The concept of CVH was introduced by the American Heart Association (AHA) in 2010, to define goals for promoting CVH and reducing deaths from CV disease.9 Some authors have already shown an inverse association between CVH and the risk of T2D: the better the CVH, the lower the risk of developing T2D.10,11 Unlike the score developed by the AHA, the CVH score used in the study of Wang et al. did not consider glucose levels since diabetes was the outcome of interest. The metrics evaluated were body mass index (BMI), smoking behaviour, blood pressure, total cholesterol, physical activity, and diet, all measured at baseline, then grouped to form behavioural CVH (BMI, smoking, diet, and physical activity) and biological CVH (blood pressure and total cholesterol) scores, divided into three categories: poor, intermediate, and ideal. A total of 5993 subjects free of T2D at baseline [mean (standard deviation) age: 69.1 (8.5) years, and 3475 (58%) were women], enrolled in two steps, the first between 1990 and 1993 and the second in 2000, were followed until the occurrence of incident T2D, death, or until the end of the study period (1 January 2015), for a total 14 (8–15) years. The genetic risk score (GRS) was calculated as the sum of the products of single-nucleotide polymorphism allele dosages of the 403 genetic variants associated with T2D based on a recent genome-wide association studies on European ancestry individuals.12 According to T2D-related GRS, population was stratified into low, intermediate, and high genetic risk categories. Then, the joint contribution of genetic predisposition and CVH profile on the T2D pathogenesis, by calculating lifetime risks of T2D in the population, was calculated. While the baseline risk profile showed no significant differences in the distribution of individual CVH metrics between GRS tertiles, substantial gradients of lifetime T2D risk were observed within hierarchical CVH categories regardless of the indexed age, sex, and genetic predisposition: the lifetime risk of incident T2D was the lowest for ideal CVH when compared to intermediate and poor CVH categories. The pattern of lifetime risk of T2D remained similar when participants were stratified based on biological and behaviour CVH scores. Behavioural factors, especially BMI, have the most influence on the risk of incident T2D. Participants benefit more from decreasing lifetime T2D risk from adhering to an ideal behavioural CVH than adhering to an ideal biological CVH. The results show us that lifestyle has the main effect on the risk of developing T2D, beyond the genetic predisposition, in middle-aged subjects (Figure 1). The figure illustrates the contribution of genetic and non-genetic factors to the pathophysiology of type 2 diabetes mellitus: non-genetic factors (body mass index, smoking behaviour, blood pressure, total cholesterol, physical activity, and diet) have the main effect on the risk of developing type 2 diabetes, beyond the genetic predisposition, in middle-aged subjects according to the manuscript of Wang et al. ‘Cardiovascular health, genetic predisposition, and lifetime risk of type 2 diabetes’. T2D, type 2 diabetes. To reduce the risk of developing T2D, it is possible to act both on behavioural risk factors (BMI, smoking, diet, and physical activity) through the lifestyle correction, both on biological risk factors (blood pressure and total cholesterol), through pharmacological intervention and lifestyle correction at a younger age. The genetic predisposition to diabetes must not represent an alibi, attenuating the intensity of lifestyle correction process for both the physician and the patient. In conclusion, through very simple tools, such as education for a correct lifestyle, we can significantly contribute to the prevention of T2D and its complications. Efforts in this regard must be made not only by health professionals, but also and above all, by schools, including these issues in the ordinary education of children from the earliest years of age, and at the level of advertising campaigns through the main communication channels. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.