Association of MC4R (rs17782313) with diabetes and cardiovascular disease in Korean men and women

doi:10.21203/rs.2.21680/v3

Background: Diabetes is mostly assessed by the fasting glucose level. Several studies reported that serum fasting glucose levels and cardiovascular disease are associated with MC4R.

Methods: A total of 4,294 subjects participated in this study. There were 1810 subjects with cardiovascular disease among the 4294 subjects. We used multivariate linear regression models and multiple logistic regression analysis.

Results: Individuals with the TC/CC genotype had a 1.29-fold higher risk of diabetes than did those with the TT genotype when adjusting for age, sex, and BMI (OR, 1.29; 95% CI, 1.04-1.60). For healthy subjects, the association was significant in women (OR, 1.99; 95% CI, 1.01-3.93). Men with the TC/CC genotype had a 1.21-fold higher risk of cardiovascular disease than did those with the TT genotype when adjusting for age, sex, and BMI (OR, 1.21; 95% CI, 1.04-1.41). The relationship between MC4R and cardiovascular disease was stronger in lean men (OR, 1.40; 95% CI, 1.12–1.74, p = 0.0028) than in overweight men.

Conclusions: This study suggests that the rs17782313 SNP in MC4R is related to diabetes and the SNP is also associated with cardiovascular disease in lean men.

Medical Genetics

Endocrinology & Metabolism

Cardiac & Cardiovascular Systems

fasting glucose

MC4R

polymorphisms

Diabetes is mainly assessed by the fasting blood-glucose level [1]. Several previous studies reported that the melanocortin-4 receptor (MC4R) (MIM 155541) gene is a candidate as a causal gene for type 2 diabetes [2, 3]. MC4R deficiency is related to monogenic obesity [4]. The MC4R rs17782313 SNP has also been linked with obesity in Europeans and Koreans [5, 6]. The SNP rs17782313 was also associated with diabetes in several studies [3, 7, 8]. In Korea, obesity increases the risk of death from cardiovascular disease [9].

Recent studies have reported that the MC4R gene was related to cardiovascular disease [10, 11]. In this study, we investigated the relationship between diabetes, cardiovascular disease, and the rs17782313 MC4R SNP in Korean men and women. We also evaluated modification of the relationship of MC4R and cardiovascular disease by obesity.

Study population

There were 4,294 participants who had general health examinations in University hospitals from 1994 to 2012 [12, 13]. There were 1810 subjects with Cardiovascular Disease (CVD) among the 4294 subjects. The cases were obtained by the NHIC health-insurance reimbursement data. The codes of the International classification of Disease (ICD), 10^th Revision (I00-I99), were used for the definition of CVD. Because of missing fasting blood-glucose level, body mass index (BMI), and SNP rs17782313 data, 35 subjects were excluded. Therefore, the final subjects included 4,259 people, and 1,782 subjects among them were Cardiovascular Disease (CVD) patients. Among 1782 Cardiovascular Disease (CVD) patients, 1409 individuals had ischemic heart disease and 868 had stroke. The other 2,477 subjects were the healthy subjects. The healthy subjects were defined as subjects who do not have the cardiovascular disease. This study’s protocols were approved by the Institutional Review Board of Human Research of Yonsei University, and all subjects provided written, informed consent prior to enrollment.

Data collection

The subjects were interviewed using a structured questionnaire about smoking status and demographic characteristics (age, sex, etc.). The weight and height were measured with participants lightly clothed.

Peripheral venous-blood samples taken after a 12-hour fast and stored at −70°C were used for the measure of fasting blood sugar (FBS), total cholesterol, triglycerides, and HDL-C. We used a Hitachi-7600 analyzer (Hitachi, Ltd., Tokyo, Japan) for the clinical chemistry assays.

Genotyping assays

The TaqMan reaction was used for the genotyping of the rs17782313 MC4R gene SNP [14]. Only the SNPs with a concordance rate > 99% in duplicates and a genotype success rate > 98% were included.

Statistical analysis

Data are shown as means ± standard deviation. PLINK and SAS ver. 9.4 (SAS Institute, Cary, NC, USA) were used for most statistical analyses. The linear regression under the additive genetic model was used to assess the association of MC4R rs17782313 with fasting blood glucose levels considering age and sex as covariates. We also used multiple logistic regression analysis under the recessive model to examine the association of the MC4R rs17782313 with diabetes and cardiovascular disease. Body mass index was divided by the median values. The association between the MC4R SNP, diabetes, and cardiovascular diseases were expressed by Odds ratios (ORs) with 95% confidence intervals (CIs). Diabetes was defined as fasting serum glucose ≥ 126 mg/dL or medication. All statistical tests were two-sided, and p < 0.05 was used for the statistical significance.

The mean age in men and in women was 51.9 and 52.7 (Table 1). Diabetes patients were about 8.9% of the subjects; 37.3% in men and 3.9% in women were current smokers of the sample dataset. Cardiovascular disease patients were 44.7% of men and 35.9% of women. Table 2 shows the p values from a linear regression model for FBS levels when age and sex were included as covariates. The rs17782313 SNP in the MC4R gene was related to mean FBS level and BMI (effect per allele, 1.542 mg/dL, p = 0.0057, and 0.227 mg/dL, p = 0.0018). For healthy individuals, the rs17782313 SNP in the MC4R gene was related to mean FBS level and BMI (effect per allele, 1.477 mg/dL, p = 0.0205, and 0.237 mg/dL, p = 0.0096).

Table 1. General characteristics of the study population

Subjects		All	Men	Women
N		4259	2896	1363
		Mean ± SD	Mean ± SD	Mean ± SD
Age, year		52.2±10.2	51.9±10.3	52.7±10.1
Weight, kg		67.4±11.1	71.8±9.6	58.1±7.7
Body mass index, kg/m²		24.4±3.0	24.8±2.7	23.5±3.2
Fasting blood sugar, mg/Dl		97.0±22.6	98.8±24.0	93.1±18.7
Systolic blood pressure, mmHg		121.9±14.5	123.3±13.9	118.9±15.3
Diastolic blood pressure, mmHg		78.2±10.8	79.7±10.6	75.0±10.5
		%	%	%
Smoking status	Ex	28.4	40.1	2.4
Smoking status	Current	26.9	37.3	3.9
Cardiovascular disease		41.8	44.7	35.9
Diabetes*		8.9	10.2	6.2
Family history of diabetes		14.5	14.1	15.4

SD, standard deviation

* Diabetes was defined as fasting serum glucose ≥ 126 mg/dL or medication.

Table 2. Association between the rs17782313 single nucleotide polymorphism in the MC4R gene and fasting blood-sugar levels based on a linear regression model

	Genotypes
Phenotypes	TT	TC	CC	Effect (mg/dL)	P-value
	Mean±SD	Mean±SD	Mean±SD
All subjects	(N=2428)	(N=1578)	(N=253)
Fasting blood sugar, mg/dL	96.0±21.3	98.6±24.9	96.5±18.4	1.542	0.0057*
Body mass index, kg/m²	24.3±2.9	24.5±3.0	24.8±3.2	0.227	0.0018*
Weight, kg	67.2±11.0	67.6±11.1	68.6±11.1	0.739	0.0010*
Systolic blood pressure, mmHg	121.7±14.6	122.0±14.3	122.7±15.0	0.452	0.2032
Diastolic blood pressure, mmHg	78.2±11.0	78.2±10.4	78.4±11.2	0.061	0.8184
	%	%	%
Cardiovascular disease	40.7	44.1	38.3		0.0543
Diabetes	8.0	10.5	7.1		0.0153
Healthy subjects	(N=1439)	(N=882)	(N=156)
Fasting blood sugar, mg/dL	93.6±18.5	96.3±22.5	93.7±13.3	1.477	0.0205*
Body mass index, kg/m²	24.0±2.9	24.2±3.0	24.3±2.6	0.237	0.0096*
Weight, kg	66.5±11.2	66.9±11.5	67.8±10.6	0.839	0.0035*
Systolic blood pressure, mmHg	119.4±13.5	119.3±13.3	119.8±12.1	0.156	0.7119
Diastolic blood pressure, mmHg	78.8±10.9	78.5±10.5	78.8±10.1	-0.039	0.9068
	%	%	%
Diabetes	5.7	8.1	5.1		0.0642

Estimated effect size (β) and p values in the multiple linear regression model considered age and sex in the additive model. P values for cardiovascular disease and diabetes were obtained from chi-square test. * significant of p < 0.05.

The relationship between diabetes and the MC4R gene SNP rs17782313 was examined (Table 3). Individuals with the TC/CC genotype had a 1.29-fold higher risk of diabetes than did those with the TT genotype when adjusting for age, sex, and BMI (OR, 1.29; 95% CI, 1.04-1.60). When analyzed by sex, the relationship between MC4R and diabetes was significant only for men (OR, 1.33; 95% CI, 1.04-1.70), not women (OR, 1.10; 95% CI, 0.70-1.75). For healthy subjects, individuals with the TC/CC genotype had a 1.40-fold higher risk of diabetes than did those with the TT genotype when for adjusting age, sex, and BMI (OR, 1.40; 95% CI, 1.01-1.95). However, the association was stronger in women (OR, 1.99; 95% CI, 1.01-3.93), and the association of MC4R with diabetes was not found in men (OR, 1.24; 95% CI, 0.85-1.81).

Table 3. Odds ratios (OR) of the polymorphic rs17782313 MC4R genotypes for diabetesin the population

		Normal	Diabetes ^b
				Model 1		Model 2
Subjects	Genotype	N (%)	N (%)	OR (95% CI^a)	P-value	OR (95% CI^b)	P-value
All	TT	2233 (57.6)	195(51.5)	1.00 (reference)		1.00 (reference)
(n = 4,259)	TC /CC	1647 (42.4)	184(48.6)	1.32(1.07-1.64)*	0.0113	1.29(1.04-1.60) *	0.0218
Men	TT	1513 (58.2)	151(51.4)	1.00 (reference)		1.00 (reference)
	TC/ CC	1089 (41.8)	143(48.6)	1.34(1.05-1.72) *	0.0182	1.33(1.04-1.70) *	0.0219
Women	TT	720 (56.3)	44(51.8)	1.00 (reference)		1.00 (reference)
	TC/ CC	558 (43.7)	41(48.2)	1.25(0.80-1.96)	0.3337	1.10(0.70-1.75)	0.6878
All Healthy	TT	1357 (58.6)	82(50.9)	1.00 (reference)		1.00 (reference)
(n = 2,477)	TC /CC	959 (41.4)	79(49.1)	1.46(1.05-2.02) *	0.0234	1.40(1.01-1.95) *	0.0424
Men	TT	887 (59.9)	67(54.9)	1.00 (reference)		1.00 (reference)
	TC/ CC	594 (40.1)	55(45.1)	1.27(0.88-1.85)	0.2082	1.24(0.85-1.81)	0.2580
Women	TT	470 (56.3)	15(38.5)	1.00 (reference)		1.00 (reference)
	TC/ CC	365 (43.7)	24(61.5)	2.13(1.09-4.19) *	0.0277	1.99(1.01-3.93) *	0.0490

Model 1: Adjusted for age and sex. Model 2: Adjusted for age, sex, and body mass index

^aCI, confidence interval. ^b Diabetes was defined as fasting serum glucose ≥126 mg/dL or medication. * significant of p < 0.05.

The relationship of the MC4R gene SNP rs17782313 to cardiovascular disease was also examined (Table 4). Men with the TC/CC genotype had a 1.21-fold (range, 1.04–1.41-fold) higher risk of cardiovascular disease than did those with the TT genotype when for adjusting age, sex, BMI (OR, 1.21; 95% CI, 1.04-1.41). In contrast, the relationship of MC4R with cardiovascular disease was not found in women.

Table 4. Odds ratios (OR) of the polymorphic rs17782313 MC4R genotypes for cardiovascular diseasein the population (n = 4,259)

Subjects		Normal	Cardiovascular Disease
				Model 1		Model 2
	Genotype	N (%)	N (%)	OR (95% CI^a)	P-value	OR (95% CI)	P-value
All	TT	1439 (58.1)	989 (55.5)	1.00 (reference)		1.00 (reference)
	TC /CC	1038 (41.9)	793 (44.5)	1.13 (1.00-1.28)	0.0599	1.11 (0.98-1.26)	0.1174
Men	TT	954 (59.5)	710 (54.9)	1.00 (reference)		1.00 (reference)
	TC/ CC	649 (40.5)	583 (45.1)	1.22 (1.05-1.42)*	0.0096	1.21 (1.04-1.41)*	0.0144
Women	TT	485 (55.5)	279 (57.1)	1.00 (reference)		1.00 (reference)
	TC/ CC	389 (44.5)	210 (42.9)	0.94 (0.75-1.19)	0.5990	0.89 (0.71-1.13)	0.3474

Model 1: Adjusted for age and sex

Model 2: Adjusted for age, sex, and body mass index

^aCI, confidence interval. * significant of p < 0.05.

Table 5 shows the analysis by BMI for men. The relationship between MC4R and cardiovascular disease was stronger in men with BMI < 24.75 (OR, 1.40; 95% CI, 1.12–1.74, p = 0.0028) than in subjects with BMI >= 24.75 (p = 0.6461). However, the interaction between BMI and MC4R (rs17782313) genotype for cardiovascular disease was not significant (p for interaction = 0.0753).

Table 5. Odds ratios (OR) of polymorphic rs17782313 MC4R genotypes for cardiovascular diseasein Korean men (n = 2,896)

		Normal	Cardiovascular Disease
Subjects	Genotype	N (%)	N (%)	OR^a (95% CI^b)	P-value
BMI<24.75	TT	516(61.4)	325(53.4)	1.00 (reference)
	TC/ CC	325(38.6)	284(46.6)	1.40(1.12-1.74)*	0.0028
BMI>=24.75	TT	438(57.5)	385(56.3)	1.00 (reference)
	TC/ CC	324(42.5)	299(43.7)	1.05(0.85-1.30)	0.6461

^aAdjusted for age and BMI ^bCI, confidence interval

* significant of p < 0.05.

** p for the interaction between obesity (BMI >= 24.75) and MC4R (rs17782313) =0.0753.

In a cohort of 4,259 people, the rs17782313 SNP in the MC4R gene was related to serum glucose level, as in previous studies. A meta-analysis of 123,373 individuals reported that the rs17782313 polymorphism in MC4R gene has the BMI independent significant association with risk of type 2 diabetes [7]. A recent study reported a strong association with MC4R loci for type 2 diabetes (OR = 1.70) [2]. Another study reported that the rs17782313 SNP was significantly associated with increased risk of diabetes [3]. A recent study reported that a Mediterranean dietary pattern could influence the relationship between MC4R gene rs17782313 polymorphisms and the risk of type 2 diabetes [8]. In our study for healthy subjects, the association of MC4R gene rs17782313 with diabetes was stronger in women than in men. A study also reported that the allele C of MC4R (rs17782313) was associated with a higher risk of type 2 diabetes mellitus in women [15].

The MC4R gene was associated with BMI and is involved in the regulation of insulin secretion [5, 16]. Loos et al. [5] in a meta-analysis from European subjects reported a significant association between rs17782313 in the MC4R gene and BMI in adults and children. A study also demonstrated that genetic variants in MC4R affect the obesity phenotype in Koreans [6]. In another meta-analysis, the association of the MC4R gene with insulin resistance and type 2 diabetes was reported even after adjustment for BMI [7]. The MC4R gene (rs17782313 and rs17700633) were related to obesity risk and insulin resistance in two genome-wide association studies [5, 17]. In this study, we found that the MC4R SNP rs17782313 was associated with BMI and weight.

In this study, the rs17782313 SNP in the MC4R gene was related to cardiovascular disease in men. The association was stronger in lean men than in overweight men. A recent study reported that MC4R gene may contribute the co-occurrence of coronary artery disease and obesity [10]. They reported that the MC4R gene SNPs were associated with coronary artery disease (p < 5x10^-8). They also explained that the mechanisms whereby MC4R SNPs contribute to obesity can increase the liability to coronary artery disease. Another study reported that the MC4R showed higher expression in mesenteric fat among obese and diabetic rats then compared with lean rats [18]. In the present study, the mean age in men with BMI < 24.75 (52.6 years old) was higher than in men with BMI >= 24.75 (51.3 years old) (p = 0.0012). The CVD patients in men with BMI < 24.75 (42.0 %) was smaller than in men with BMI >= 24.75 (47.3 %) (p = 0.0046) (Data not shown).

MC4R is localized to chromosome 18q21.3 [19], is highly expressed in the hypothalamus, and is related to appetite and energy control [20]. In mice research, the MC4R gene is associated with hyperinsulinemia before the onset of extreme obesity [21]. Lipocalin-2 crosses the blood brain barrier and binds to MC4R in the paraventricular and ventromedial neurons of the hypothalamus. A recent loss- and gain-of-junction experiment in mice reported that osteoblast-derived lipocalin-2 maintains glucose homeostasis [22]. Another recent study reported that the MC4R gene SNPs influence the body fat content and distribution, as well as relative increase in postprandial carbohydrate utilization [23].

This study has some limitations that need to be discussed. There were the differences in the baseline characteristics including smoking rate, cardiovascular disease, and diabetes prevalence by gender. When we assessed the distribution of the MC4R alleles by gender, the genotype frequency of MC4R gene was similar between men and women (Data not shown). Another limitation is that this study subjects included many CVD patients because the CVD cases were obtained from the KCPS2 dataset (n=156,701) for the case control study design [13]. Therefore, we analyzed the association between diabetes and MC4R gene in the healthy subjects who did not have the cardiovascular disease.

Asian people may have genetic backgrounds different from those of Western individuals [24]. However, this Korean cohort showed that the rs17782313 SNP in the MC4R gene is related to diabetes and obesity. The SNP was also associated with cardiovascular disease in lean men.

CI: Confidence intervals; CVD: Cardiovascular disease; FBS: Fasting blood sugar; MC4R: Melanocortin-4 receptor; BMI: Body mass index; ICD: International classification of Disease; OR: Odds ratios; SD: Standard deviation; SNP: Single nucleotide polymorphism.

Acknowledgements

Not applicable.

Funding

This study was funded by the Basic Science Research Program of the National Research Foundation of Korea through the Ministry of Education, Science, and Technology (2018R1D1A1B07050834). The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Authors’ contributions

Study design: JWS, SHJ. Subjects recruitment and acquisition of data: SHJ. Analysis and interpretation of data: JWS, GK, SHJ. Revision of manuscript content: all authors. Approving final version of manuscript: all authors.

Ethics approval and consent to participate

The Severance Medical Ethics Committee approved the study, and all participants provided written, informed consent prior to participation.

Consent for publication

Not applicable.

Competing interests

The authors declare they have no competing interests.

Ogata E, Asahi K, Yamaguchi S, et al. Low fasting plasma glucose level as a predictor of new-onset diabetes mellitus on a large cohort from a Japanese general population. Sci Rep. 2018;8(1):13927. doi:10.1038/s41598-018-31744-4
Osman W, Tay GK, Alsafar H. Multiple genetic variations confer risks for obesity and type 2 diabetes mellitus in arab descendants from UAE. Int J Obes (Lond). 2018 Jul;42(7):1345-1353.
Qi L, Kraft P, Hunter DJ, Hu FB. The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum Mol Genet. 2008 Nov 15;17(22):3502-8.
Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003 Mar 20;348(12):1085-95.
Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI; Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM; KORA, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O'Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L; Nurses' Health Study, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK; Diabetes Genetics Initiative, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M; SardiNIA Study, Vogel CI, Wallace C, Waterworth DM, Weedon MN; Wellcome Trust Case Control Consortium, Willer CJ; FUSION, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, Mohlke KL. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008 Jun;40(6):768-75.
Sull JW, Lee M, Jee SH. Replication of genetic effects of MC4R polymorphisms on body mass index in a Korean population. Endocrine. 2013 Dec;44(3):675-9.
Xi B, Takeuchi F, Chandak GR, Kato N, Pan HW; AGEN-T2D Consortium, Zhou DH, Pan HY, Mi J. Common polymorphism near the MC4R gene is associated with type 2 diabetes: data from a meta-analysis of 123,373 individuals. Diabetologia. 2012 Oct;55(10):2660-2666.
Koochakpoor G, Hosseini-Esfahani F, Daneshpour MS, Hosseini SA, Mirmiran P. Effect of interactions of polymorphisms in the Melanocortin-4 receptor gene with dietary factors on the risk of obesity and Type 2 diabetes: a systematic review. Diabet Med. 2016 Aug;33(8):1026-34.
Jee SH, Sull JW, Park J, et al. Body-mass index and mortality in Korean men and women. N Engl J Med. 2006;355(8):779–787.
Nikpay M, Turner AW, McPherson R. Partitioning the Pleiotropy Between Coronary Artery Disease and Body Mass Index Reveals the Importance of Low Frequency Variants and Central Nervous System-Specific Functional Elements. Circ Genom Precis Med. 2018 Feb;11(2):e002050. doi: 10.1161/CIRCGEN.117.002050.
Song Z, Qiu L, Hu Z, Liu J, Liu D, Hou D. Evaluation of the Obesity Genes FTO and MC4R for Contribution to the Risk of Large Artery Atherosclerotic Stroke in a Chinese Population. Obes Facts. 2016;9(5):353-362.
Cho ER, Jee YH, Kim SW, Sull JW. Effect of obesity on the association between MYL2 (rs3782889) and high-density lipoprotein cholesterol among Korean men. J Hum Genet. 2016 May;61(5):405-9.
Jee YH, Emberson J, Jung KJ, Lee SJ, Lee S, Back JH, Hong S, Kimm H, Sherliker P, Jee SH, Lewington S. Cohort Profile: The Korean Cancer Prevention Study-II (KCPS-II) Biobank. Int J Epidemiol. 2018 Apr 1;47(2):385-386f. doi:10.1093/ije/dyx226.
Hui, L., DelMonte, T. & Ranade, K. Genotyping using the TaqMan assay. Curr Protoc Hum. Genet. doi:10.1002/0471142905.hg0210s56 (2008).
Marcadenti A, Fuchs FD, Matte U, Sperb F, Moreira LB, Fuchs SC. Effects of FTO RS9939906 and MC4R RS17782313 on obesity, type 2 diabetes mellitus and blood pressure in patients with hypertension. Cardiovasc Diabetol. 2013 Jul 12;12:103. doi: 10.1186/1475-2840-12-103.
Mansour M, White D, Wernette C, Dennis J, Tao YX, Collins R, Parker L, Morrison E. Pancreatic neuronal melanocortin-4 receptor modulates serum insulin levels independent of leptin receptor. Endocrine. 2010 Feb;37(1):220-30.
Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, Froguel P, Balding D, Scott J, Kooner JS. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet. 2008 Jun;40(6):716-8.
Schmid PM, Heid I, Buechler C, et al. Expression of fourteen novel obesity-related genes in Zucker diabetic fatty rats. Cardiovasc Diabetol. 2012;11:48. doi:10.1186/1475-2840-11-48
Turki A, Mahjoub T, Mtiraoui N, Abdelhedi M, Frih A, Almawi WY. Association of POL1, MALT1, MC4R, PHLPP and DSEL single nucleotide polymorphisms in chromosome 18q region with type 2 diabetes in Tunisians. Gene. 2013;527(1):243–247.
Walley AJ, Asher JE, Froguel P. The genetic contribution to non-syndromic human obesity. Nat Rev Genet. 2009 Jul;10(7):431-42.
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997 Jan 10;88(1):131-41.
Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He Z, Huang Y, Zong H, Friedman RA, Barasch J, Lanzano P, Deng L, Leibel RL, Rubin M, Nickolas T, Chung W, Zeltser LM, Williams KW, Pessin JE, Kousteni S. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. 2017 Mar 16;543(7645):385-390.
Adamska-Patruno E, Goscik J, Czajkowski P, Maliszewska K, Ciborowski M, Golonko A, Wawrusiewicz-Kurylonek N, Citko A, Waszczeniuk M, Kretowski A, Gorska M. The MC4R genetic variants are associated with lower visceral fat accumulation and higher postprandial relative increase in carbohydrate utilization in humans. Eur J Nutr. 2019 Oct;58(7):2929-2941.
Sung HJ, Jung MK, Eom Y, Lee J, Sull JW, Jee SH. Effects of MTNR1B variants on fasting glucose levels in a Korean population. Genes Genomics. 2012;34:103–6.

Association of MC4R (rs17782313) with diabetes and cardiovascular disease in Korean men and women

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Abstract

Background

Methods

Results

Discussion

Conclusion

Abbreviations

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References

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