Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Hammad MM

PROVIDER: S-EPMC7358550 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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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.

Hammad Maha M MM Abu-Farha Mohamed M Hebbar Prashantha P Cherian Preethi P Al Khairi Irina I Melhem Motasem M Alkayal Fadi F Alsmadi Osama O Thanaraj Thangavel Alphonse TA Al-Mulla Fahd F Abubaker Jehad J

Frontiers in endocrinology 20200707

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 prote ...[more]

PMID: 32733386

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Project description:MC4R represents a key player involved in melanocortin-mediated control of energy balance. Recently identified near MC4R variant rs17782313 (T > C) can serve as a contributing factor for obese phenotype but its association with obesity has never been sought in a sample of the Pakistani population. The role of genetic variants as causal factors varies across populations. Association studies in a specific population can help us to distinguish global from local gene-gene and gene-environment interactions. This is the first study that investigated the association of rs17782313 with obesity and various obesity-linked anthropometric, metabolic, physical, and behavioural traits in Pakistani subjects including 306 OW/OB (overweight and obese) and 300 NW (normal weight) individuals. The comparison of various aforementioned obesity-linked continuous and categorical variables between OW/OB and NW subjects revealed that almost all variables were found significantly aberrant (p < 0.05) in OW/OB subjects as compared to their age- and gender-matched NW controls indicating greater risk of developing various cardio-metabolic disorders. The genotyping of rs17782313 showed significant association of this variant with obesity and obesity-linked anthropometric traits in females suggesting the gender-specific effect of this variant in our population. The minor allele C increased the risk of obesity by 1.55 times (95% CI = 1.1-2.18, p = 0.01) whereas homozygous CC genotype increased the risk by 2.43 times (95% CI = 1.19-4.96, p = 0.015) in females. However, no association of rs17782313 was observed with any of the obesity-linked metabolic, physical, and behavioural traits except random eating timings. In conclusion, the current study significantly contributes to the knowledge of the genetic proneness to obesity in Pakistani females. This could also be helpful for forthcoming meta-analysis studies elucidating which variants are truly associated with the susceptibility to develop an obese phenotype.

Project description:BackgroundThe melanocortin-4 receptor (MC4R) regulates metabolism by modulating eating behavior and MC4R variants (rs17782313 and rs571312) are associated with obesity in Asians and Caucasians. However, the impact of their interactions with nutritional and lifestyle factors on obesity are poorly described. Therefore, we investigated the interaction of MC4R variants and dietary patterns on the risk of obesity in Korean middle-aged adults.MethodsData collected included, genetic variations, anthropometric and biochemical measurements, dietary and lifestyle habits, and food intake. Data were obtained from the 8830 adults aged 40-69 years in the Ansung and Ansan cohort of the Korean Genome Epidemiology Study.ResultsThe MC4R rs18882313 minor allele had a higher frequency in the obese group (P < 0.01). MC4R genotypes were not associated with differences in daily energy and macronutrient intakes. However, the intakes of processed foods and fat (as percentages of energy) were significantly higher and intake of fruits were significantly lower in subjects with MC4R minor alleles (P < 0.05). Interestingly, there was a positive interaction between MC4R variants and mental stress levels that were associated with the risk of obesity after adjusting for age, gender, residence area, daily energy intake, smoking status and physical activity (interaction P = 0.0384). Only in subjects with high stress were MC4R minor alleles associated with higher BMIs after adjusting for confounders. The association was present without modulating energy and nutrient intake. In the group with energy intakes higher than estimated energy requirement (EER), subjects with MC4R minor alleles had higher BMIs than those with the major alleles (P < 0.001).ConclusionsThe interactions of mental stress and energy intakes with the MC4R minor allele genotype might be associated with increased risk of obesity in Korean adults. This research might identify subjects with a specific MC4R minor alleles as a human subset of people with a low metabolic tolerance for excessive energy intake, especially when under stress.

Dataset Information

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

Publications

<i>MC4R</i> 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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