Frontiers in Endocrinology (Jul 2020)

MC4R Variant rs17782313 Associates With Increased Levels of DNAJC27, Ghrelin, and Visfatin and Correlates With Obesity and Hypertension in a Kuwaiti Cohort

  • Maha M. Hammad,
  • Mohamed Abu-Farha,
  • Prashantha Hebbar,
  • Preethi Cherian,
  • Irina Al Khairi,
  • Motasem Melhem,
  • Fadi Alkayal,
  • Fadi Alkayal,
  • Osama Alsmadi,
  • Thangavel Alphonse Thanaraj,
  • Fahd Al-Mulla,
  • Jehad Abubaker

DOI
https://doi.org/10.3389/fendo.2020.00437
Journal volume & issue
Vol. 11

Abstract

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Melanocortin 4 receptor (MC4R), a notable component of the melanocortin system, regulates appetite, body weight, and energy homeostasis. Genome-wide association studies have identified several MC4R variants associated with adiposity; of these, rs17782313, which is associated with increased body mass index (BMI) and overeating behavior, is of particular interest. Another gene associated with increased adiposity in global genome-wide association studies is DNAJC27, a heat shock protein known to be elevated in obesity. The detailed mechanisms underlying the role of MC4R variants in the biological pathways underlying metabolic disorders are not well-understood. To address this, we assessed variations of rs17782313 in a cohort of 282 Arab individuals from Kuwait, who are deeply phenotyped for anthropometric and metabolic traits and various biomarkers, including DNAJC27. Association tests showed that the rs17782313_C allele was associated with BMI and DNAJC27 levels. Increased levels of DNAJC27 reduced the MC4R-mediated formation of cAMP in MC4R ACTOne stable cells. In conclusion, this study demonstrated an association between the rs17782313 variant near MC4R and increased BMI and DNAJC27 levels and established a link between increased DNAJC27 levels and lower cAMP levels. We propose that regulation of MC4R activity by DNAJC27 enhances appetite through its effect on cAMP, thereby regulating obesity.

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