Integrating publicly available genome-wide association data to study the genetic basis of metabolically healthy obese and metabolically obese but normal-weight individuals.

نویسنده

  • Ruth J F Loos
چکیده

An estimated 2.1 billion adults and children worldwide are obese (1), imposing a substantial burden on people’s personal health and on society as a whole, as excess adiposity is associated with a number of cardiometabolic complications. These include insulin resistance, dyslipidemia, and hypertension, each of which is a risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD) (2,3). However, a sizeable proportion of obese individuals does not have these cardiometabolic complications. These individuals have favorable glucose, lipid, blood pressure, liver enzyme, hormone, and inflammation levels, despite their excess adiposity. Conversely, not all normal-weight individuals are healthy, as some demonstrate one or more cardiometabolic risk factors. Although there is no consensus on the criteria to define these obese and normal-weight subtypes, an estimated 15–45% of obese individuals are considered “metabolically healthy obese” (MHO) and 5–30% of the normal-weight population is considered “metabolically obese of normal weight” (MONW) (4–10). While interest in MHO and MONW populations is growing rapidly, it remains unclear which factors determine why some obese individuals are protected, and why some normal-weight individuals are at elevated risk. Age, sex, ethnicity/race, physical activity, smoking, and alcohol intake have been identified as important correlates of MHO and MONW (6–10). However, even after accounting for these factors, the MHO population continues to be protected (longer) from the development of cardiometabolic disease compared with other obese individuals, and the MONW population remains at greater risk than healthy people of normal weight (9– 15). These observations suggest that innate physiological mechanisms underlie at least part of one’s predisposition to be MHO or MONW. Indeed, based on data from studies that were conducted mainly in rodent models, pathways implicated in adipogenesis, adipose tissue expandability, adipocyte differentiation, fat distribution, ectopic fat accumulation, lipid storage capacity, lipoatrophy, macrophage density, adipose inflammation, and responsiveness to endocrine secretions have been proposed to—at least in part—contribute to the cardiometabolic diversity observed among obese and normalweight individuals (7,16). Studies that examine these mechanisms in humans are sparse and often limited by sample size and the lack of noninvasive methods to accurately assess activity in key physiologic pathways (7,16). A study published in this issue of Diabetes by Yaghootkar et al. (17) used genetic association data from publicly available genome-wide association studies (GWAS) to gain insight into the mechanisms that link adiposity, insulin resistance, and other cardiometabolic risk factors. Nineteen genetic variants, previously shown to robustly associate with fasting insulin level (18), were examined for their association with eight adiposity and cardiometabolic traits and six disease outcomes (Fig. 1A). A cluster analysis was used to examine whether the genetic variants could be grouped based on their association signature

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عنوان ژورنال:
  • Diabetes

دوره 63 12  شماره 

صفحات  -

تاریخ انتشار 2014