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


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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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          Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

          Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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            Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.

            We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)).
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              The genetics of human obesity.

              Obesity is an important cause of morbidity and mortality in developed countries, and is also becoming increasingly prevalent in the developing world. Although environmental factors are important, there is considerable evidence that genes also have a significant role in its pathogenesis. The identification of genes that are involved in monogenic, syndromic and polygenic obesity has greatly increased our knowledge of the mechanisms that underlie this condition. In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase our understanding of the regulation of energy balance in humans.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                07 July 2020
                : 11
                : 437
                [1] 1Research Division, Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute , Kuwait City, Kuwait
                [2] 2Research Division, Department of Genetics and Bioinformatics, Dasman Diabetes Institute , Kuwait City, Kuwait
                [3] 3Department of Human Genetics, McGill University , Montreal, QC, Canada
                [4] 4King Hussein Cancer Center , Amman, Jordan
                Author notes

                Edited by: Pierrette Gaudreau, Université de Montréal, Canada

                Reviewed by: Ya-Xiong Tao, Auburn University, United States; Li Chan, Queen Mary University of London, United Kingdom

                *Correspondence: Thangavel Alphonse Thanaraj alphonse.thangavel@ 123456dasmaninstitute.org

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology

                †These authors have contributed equally to this work and share first authorship

                Copyright © 2020 Hammad, Abu-Farha, Hebbar, Cherian, Al Khairi, Melhem, Alkayal, Alsmadi, Thanaraj, Al-Mulla and Abubaker.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 16 February 2020
                : 03 June 2020
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 57, Pages: 10, Words: 7846
                Funded by: Kuwait Foundation for the Advancement of Sciences 10.13039/501100003286
                Award ID: RA HM-2018-023
                Award ID: RA-2015-043
                Original Research

                Endocrinology & Diabetes
                Endocrinology & Diabetes
                camp, dnajc27, ghrelin, mc4r, obesity, visfatin


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