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Genetics of Cardiovascular Risk in Obesity

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Metabolic Syndrome

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Abstract

Genetic risk assessment for cardiovascular disease (CVD) in obese patients requires considering all the background traits beginning as early as possible. Traits for both CVD and type 2 diabetes (T2D) first appear in gestation and childhood when birth weight and childhood weight gain influence; the traits and risk factors are more reversible than when they present later. Subsequently, gains in body fat leading to obesity, ectopic lipid deposition in liver and muscle, dyslipidemia, and hypertension expressed in the β-cells, hypothalamus, adipocytes, myocytes, liver, and kidney are associated with worsening insulin resistance and β-cell failure leading to both diabetes and CVD. In addition to being a central and causative factor for the metabolic syndrome, obesity is an increasingly common trait associated with energy balance under tightly regulated genetic control. Although nonalcoholic fatty liver disease (NAFLD) has an independent genetic background, it is strongly associated with obesity and is considered as a new addition to the metabolic syndrome and is also associated with dyslipidemia and CVD. Atherogenic dyslipidemia occurring in insulin-resistant states such as obesity consists of increased triglyceride, low high-density lipoprotein (HDL) cholesterol, small dense LDL particles, and dysfunctional HDL particles. It is greatly impacted by environmental and genetic effects. Like other preceding traits, the genetic background for commonly encountered hypertension is independent of that for diabetes, although it remains a predictive trait for both CVD and diabetes. Increasing evidence supports a role for the renin-angiotensin system in oxidative stress, CVD, and insulin resistance. In this review, we discuss how sequential progression of obesogenic environment leads to CVD with overlapping effects on β-cell, inflammation, and endothelial dysfunction. This review also provides current update on the discovery of novel predictive genes through genome-wide association studies and how they may illuminate novel disease pathways. Ultimately, these may help identify novel risk factors/biomarkers leading to the design of more effective treatment and/or prevention strategies.

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Acknowledgments

This work was partly supported by NIH grants R01DK082766) funded by the National Institute of Diabetes and Digestive and Kidney Diseases, NOT-HG-11-009 (DKS) funded by National Genome Research Institute (DKS), and a VPR Bridge Grant from University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA (DKS), and The Harold Hamm Diabetes Center (PRB).

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  1. Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Oklahoma City, OK, 73104, USA

    Piers R. Blackett

  2. Department of Pediatrics, Section of Genetics, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm. D317 BMSB, Oklahoma City, OK, 73104, USA

    Dharambir K. Sanghera

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  1. Piers R. Blackett
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Correspondence to Piers R. Blackett or Dharambir K. Sanghera .

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  1. Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Rexford S. Ahima

  2. Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA

    Rexford S. Ahima

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Blackett, P.R., Sanghera, D.K. (2016). Genetics of Cardiovascular Risk in Obesity. In: Ahima, R.S. (eds) Metabolic Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-319-11251-0_13

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