The association of the fat mass and obesity-associated gene (FTO) rs9939609 polymorphism and the severe obesity in a Brazilian population

Figures & data

Table 1 Candidate genes and genetic variants included in this study

Gene	Chromosome location	Biological relevance	dbSNP#	SNP location	MAF*	Previous studies
Agouti related protein (AGRP)	16q22	Endogenous antagonist of melanocortin receptors (MC4R and MC3R) that regulates appetite and energy expenditure.	rs5030980	Exon 3	0.015	Associated with BMI in European Americans (n=1,982) and body weight in Quebec families (n=874).^Citation53,Citation54 No association with BMI in Dutch adults (n=582) and Latvian population (n=789).^Citation12,Citation57
Melanocortin 4 receptor (MC4R)	18q21.3/18q22	Stimulation of MC4R leads to a reduction in energy intake and an increased basal energy expenditure.	rs17782313	188 kb downstream of MC4R	0.240	No association with biochemical or anthropometric variables in individuals with Northern Han Chinese ancestry (n=3,859).^Citation64 No relation with anthropometric and dietary parameters in a Brazilian childhood cohort followed-up since birth (n=745).^Citation14 Associated with obesity susceptibility in a Japonese (n=1,129), Caucasian (n=1,361) and North Indians cohorts (n=696).^Citation35,Citation59,Citation65
Brain-derived neurotrophic factor (BDNF)	11p13	Protein involved in neuronal survival, maturation and differentiation during central nervous system development.	rs4074134	~31 kb of 3’-flanking of BDNF	0.252	Associated with BMI, WC, fasting and postprandial glucose, fasting serum insulin and HOMA-IR in subjects with Northern Han Chinese ancestry (n=3,859).^Citation64 Linked to BMI and body weight in large mixed cohort (n=31,392).^Citation66 Risk factor for obesity in a Japanese cohort (n=1,129).^Citation35
Ghrelin (GHRL)	3p26	Orexigenic peptide that modulates appetite, gastrointestinal motility, gastric acid release and pancreatic secretions.	rs696217	Exon 4	0.083	Carriers of the mutant allele (T) showed a significant reduction in BMI after 52 weeks of bariatric surgery (n=100)^Citation67 Positively associated with BMI and obesity susceptibility in a Japanese cohort (n=5,112).^Citation10 No association with obesity, eating behavior and glucose metabolisms in French families (n=2,334).^Citation51
Neuropeptide Y (NPY)	7q15.1	This peptide regulates energy homeostasis thought binds to its receptor on PVN .	rs535870237	17-bp deletion at 5’UTR	0.00039	Observed in one Mexican American family (n=934).^Citation58
Fat Mass Obesity-Associated gene (FTO)	16q12.2	Demethylation enzyme involved in controlling of energy homeostasis, DNA methylation and abiogenesis	rs9939609	Intron 1	0.340	No association with obesity phenotype in Egyptian adolescents and children; however, the presence of the risk allele was linked to higher LDL cholesterol (n=200).^Citation42 Associated with morbid obesity risk in the Brazilian adults (n=239) and Mexican population (n=1,156).^Citation13,Citation44 Associated with satiety sensations (n=70), food intake control (n=97), food choice (n=97) and cardiorespiratory fitness (n=420).^Citation25,Citation49,Citation68

Abbreviations: BMI, Body mass index; dbSNP, Single nucleotide polymorphism database; HOMA-IR, Homeostatic model assessment - Insulin resistance; LDL, Low density lipoprotein; MAF, Minor allele frequency; MC3R, Melanocortin 3 receptor; PVN, Paraventricular nucleus; SNP, Single nucleotide polymorphism; UTR, Untranslated region; WC, Waist circumference.

Table 2 Association of AGRP, BDNF, FTO, GHRL and MC4R polymorphisms with obesity susceptibility

Gene (polymorphism)	Control	Case	Model 1		Model 2
	n=192 (%)	n=298 (%)	OR (95% CI)	P	OR (95% CI)	P
AGRP (rs5030980)^a
Genotype
CC	179 (93.2)	278 (93.3)	1.00 (Ref.)	-	1.00 (Ref.)	-
CT	13 (6.8)	20 (6.7)	1.08 (0.50–2.33)	0.841	1.11 (0.47–2.59)	0.811
Allele
C	371 (96.6)	576 (96.6)	1.00 (Ref.)	-	1.00 (Ref.)	-
T	13 (3.4)	20 (3.4)	1.08 (0.50–2.33)	0.841	1.11 (0.47–2.59)	0.811
BDNF (rs4074134)
Genotype
CC	122 (63.6)	204 (68.5)	1.00 (Ref.)	-	1.00 (Ref.)	-
CT	64 (33.3)	82 (27.5)	0.79 (0.51–1.22)	0.293	0.87 (0.54–1.40)	0.571
TT	6 (3.1)	12 (4.0)	1.42 (0.47–4.23)	0.536	2.12 (0.60–7.50)	0.242
Dominant Model
CC	122 (63.5)	204 (68.5)	1.00 (Ref.)	-	1.00 (Ref.)	-
CT+TT	70 (36.5)	94 (31.5)	0.84 (0.55–1.28)	0.419	0.95 (0.60–1.50)	0.819
Recessive Model
CC+CT	186 (96.9)	286 (96.0)	1.00 (Ref.)	-	1.00 (Ref.)	-
TT	6 (3.1)	12 (4.0)	1.53 (0.51–4.58)	0.451	2.22 (0.63–7.77)	0.212
Allele
C	308 (80.2)	490 (82.2)	1.00 (Ref.)	-	1.00 (Ref.)	-
T	76 (19.8)	106 (17.8)	0.92 (0.65–1.32)	0.663	0.92 (0.63–1.34)	0.667
FTO (rs9939609)
Genotype
TT	71 (37.0)	73 (24.5)	1.00 (Ref.)	-	1.00 (Ref.)	-
TA	85 (44.3)	146 (49.0)	1.66 (1.05–2.63)	0.031	1.80 (1.09–2.98)	0.021
AA	36 (18.7)	79 (26.5)	2.24 (1.28–3.92)	0.005	2.24 (1.22–4.12)	0.010
Dominant Model
TT	71 (37.0)	73 (24.5)	1.00 (Ref.)	-	1.00 (Ref.)	-
TA+AA	121 (63.0)	225 (75.5)	1.82 (1.19–2.80)	0.006	1.94 (1.21–3.09)	0.006
Recessive Model
TT+TA	156 (81.2)	219 (73.5)	1.00 (Ref.)	-	1.00 (Ref.)	-
AA	36 (18.7)	79 (26.5)	1.65 (1.01–2.69)	0.044	1.58 (0.93–2.70)	0.092
Allele
T	227 (59.1)	292 (49.0)	1.00 (Ref.)	-	1.00 (Ref.)	-
A	157 (40.9)	304 (51.0)	1.53 (1.14–2.00)	0.004	1.53 (1.13–2.07)	0.006
GHRL (rs696217)
Genotype
GG	177 (92.2)	277 (93.0)	1.00 (Ref.)	-	1.00 (Ref.)	-
GT+TT	15 (7.8)	21 (7.0)	0.76 (0.35–1.63)	0.475	0.91 (0.38–2.18)	0.838
Allele
G	369 (96.1)	575 (96.5)	1.00 (Ref.)	-	1.00 (Ref.)	-
T	15 (3.9)	21 (3.5)	0.76 (0.35–1.63)	0.475	0.91 (0.38–2.18)	0.838
MC4R (rs17782313)
Genotype
TT	126 (65.6)	172 (57.7)	1.00 (Ref.)	-	1.00 (Ref.)	-
TC	58 (30.2)	113 (37.9)	1.28 (0.84–1.96)	0.254	1.39 (0.87–2.23)	0.170
CC	8 (4.1)	13 (4.4)	1.20 (0.46–3.16)	0.706	1.09 (0.38–3.10)	0.872
Dominant Model
TT	126 (65.6)	172 (57.7)	1.00 (Ref.)	-	1.00 (Ref.)	-
TC+CC	66 (34.4)	126 (42.3)	1.27 (0.84–1.19)	0.249	1.35 (0.96–2.11)	0.193
Recessive Model
TT+TC	184 (95.8)	285 (95.6)	1.00 (Ref.)	-	1.00 (Ref.)	-
CC	8 (4.2)	13 (4.4)	1.10 (0.42–2.87)	0.841	0.97 (0.35–2.74)	0.962
Allele
T	310 (80.7)	457 (76.7)	1.00 (Ref.)	-	1.00 (Ref.)	-
C	74 (19.3)	139 (23.3)	1.20 (0.85–1.69)	0.299	1.23 (0.84–1.80)	0.284

Notes:P-value and OR were calculated using logistic regression and adjusted for gender and age (Model 1). P¥-value and OR were calculated using logistic regression and adjusted for age, gender, race/skin color, marital status and exercises habits (Model 2). ^aNo homozygous mutant was identified.

Abbreviations: AGRP, protein related to aguti; BDNF, brain-derived neurotrophic factor; CI, confidence interval; FTO, fat mass and obesity-associated gene; GHRL, ghrelin; MC4R, melanocortin 4 receptor; OR, Odds ratio; Ref, Reference.

Table S1 Phenotypic characteristics of study population

Parameters	n	All	n	Control	n	Case	P*
Age (years)	490	36.0 (27.0; 45.0)	192	29.0 (24.0; 27.0)	298	40.0 (31.0; 48.0)	<0.001
Gender (female/male)
Female	490	358 (76.1)	192	117 (60.9)	298	241 (80.9)	<0.001
Male		132 (26.9)		75 (39.1)		57 (19.1)
Race/skin color
White	489	231 (47.2)	191	128 (67.0)	298	103 (34.6)	<0.001
Brown		169 (34.6)		49 (25.7)		120 (40.3)
Black		89 (18.2)		14 (7.3)		75 (25.1)
Marital status
Single	488	220 (45.1)	192	117 (61.0)	296	103 (34.8)	<0.001
Married/cohabiting		213 (43.6)		64 (33.3)		149 (50.3)
Separated/divorced		34 (7.0)		4 (2.1)		30 (10.2)
Widower		21 (4.3)		7 (3.6)		14 (4.7)
Smoking status
Already smoked	483	56 (9.4)	191	18 (13.0)	292	38 (11.6)	0.228
Never smoked		427 (90.6)		173 (87.0)		254 (88.4)
Physical activity practice
Yes	487	155 (31.8)	192	99 (51.6)	295	56 (19.0)	<0.001
No		332 (68.2)		93 (48.4)		239 (81.0)
Type 2 Diabetes
Yes	484	59 (12.2)	192	0 (0.0)	292	59 (20.2)	<0.001
No		425 (87.8)		192 (100)		233 (79.8)
Hypertension
Yes	490	217 (44.3)	192	9 (4.7)	298	208 (69.8)	<0.001
No		273 (55.7)		183 (95.3)		90 (30.2)
Weight (kg)	490	105.1 (67; 132.3)	192	63.0 (57.0; 70.0)	298	126.3 (109.5; 144.2)	<0.001
Height (m)	490	1.65 (1.59; 1.72)	192	1.68 (1.61; 1.74)	298	1.63 (1.58; 1.69)	<0.001
BMI (kg/m^2)	490	40.0 (23.4; 48.8)	192	22.8 (21.1; 23.9)	298	46.8 (41.8; 52.8)	<0.001
Waist circumference (cm)	488	120.5 (80.0; 139.9)	192	81.0 (75.0; 85.5)	296	136.0 (125.0; 147.0)	<0.001
Hip circumference (cm)	488	128.0 (99.5; 145.4)	192	98.0 (93.0; 101.4)	296	141.2 (131.1; 152.7)	<0.001
WHR	488	0.91 (0.84; 0.98)	192	0.83 (0.78; 0.89)	296	0.96 (0.90; 1.00)	<0.001
BAI	488	41.8 (28.1; 51.6)	192	26.9 (24.1; 29.6)	296	49.5 (44.0; 56.0)	<0.001
Inverted BMI	490	24.9 (20.4; 42.7)	192	43.8 (41.8; 47.4)	298	21.35 (18.9; 23.9)	<0.001
Waist to height ratio	488	0.70 (0.50; 0.90)	192	0.5 (0.4; 0.5)	296	0.80 (0.80; 0.90)	<0.001
Waist to weight ratio	488	1.10 (1.00; 1.30)	192	1.30 (1.20; 1.40)	296	1.10 (1.00; 1.10)	<0.001
Glucose (mg/dL)	385	93.0 (87.0; 102.0)	176	89.0 (84.0; 95.0)	209	97.0 (90.0; 110.0)	<0.001
Total cholesterol (mg/dL)	423	186.0 (160.0; 216.0)	184	178.5 (156.0; 200.0)	239	193.0 (166.0; 224.0)	<0.001
HDL cholesterol (mg/dL)	423	51.0 (43.0; 61.0)	184	59.0 (48.0; 69.0)	239	47.0 (41.0; 53.0)	<0.001
LDL cholesterol (mg/dL)	416	110.0 (91.0; 135.0)	179	102.0 (86.0; 123.0)	233	117.0 (95.0; 143.0)	<0.001
Triglycerides (mg/dL)	423	102.0 (74.0; 139.0)	184	77.0 (61.0; 101.7)	239	125.0 (96.0; 168.0)	<0.001
Hemoglobin (%)	340	5.3 (4.9; 5.9)	165	5.1 (4.8; 5.4)	175	5.8 (5.1; 6.3)	<0.001
CRP (mg/dL)	336	0.42 (0.12; 1.09)	164	0.13 (0.08; 0.28)	172	1.00 (0.55; 1.59)	<0.001
SBP (mm Hg)	345	121.0 (111.0; 133.0)	178	118.0 (109.7; 125.2)	167	130.0 (117.0; 76.0)	<0.001
DBP (mm Hg)	345	80.0 (70.5; 89.0)	178	76.0 (68.0; 82.0)	167	85.0 (76.0; 92.0)	<0.001

Notes: Data are presented as median values (interquartile range 25–75%) for quantitative traits and n (%) for qualitative traits. Data were analyzed by Mann–Whitney Test (for non-normally distributed continuous variables) or χ2 test (for categorical variables). P*-value for differences between severely obese and normal-weight subjects.

Abbreviations: BMI, Body Mass Index; WHR, Waist–hip ratio; BAI, Body Adipose Index; SBP, Systolic blood pressure; DBP, Diastolic blood pressure; HDL cholesterol, High-density lipoprotein-cholesterol; LDL cholesterol, Low-density lipoprotein-cholesterol; CRP, C-reactive protein.

Table S2 Association of polymorphisms studied and anthropometric, biochemical and blood pressure variables

Parameters	AgRP (rs5030980)		BDNF (rs4074134)		FTO (rs9939609)		GHRL (rs696217)		MC4R (rs17782313)
	Genotypes (n)	Values	Genotypes (n)	Values	Genotypes (n)	Values	Genotypes (n)	Values	Genotypes (n)	Values
Weight (kg)	CC (457)	104.9 (67.0; 132.1)	CC (326)	106.1 (66.7; 134.5)	TT (144)	85.3 (63.0; 126.42)	GG (454)	105.4 (66.8; 132.3)	TT (298)	100.3 (65.1; 132.1)
	CT (33)	111.0 (64.1; 140.8)	CT (146)	98.5 (64.6; 127.8)	TA (231)	105.4 (67.5; 131.5)	GT+TT (36)	96.9 (67.5; 133.0)	TC (171)	112.0 (71.2; 134.7)
			TT (18)	111.9 (73.5; 136.5)	AA (115)	114.0 (72.0; 140.5)			CC (21)	113.5 (59.4; 128.9)
β		0.005 ± 0.028		−0.003 ± 0.013		0.030 ± 0.010		−0.002±0.027		0.015±0.012
P		0.856		0.808		0.002		0.927		0.229
BMI (kg/m^2)	CC (457)	40.1 (23.3; 48.9)	CC (326)	40.4 (23.6; 49.4)	TT (144)	35.7 (22.5; 46.8)	GG (454)	40.1 (23.3; 48.8)	TT (298)	38.5 (23.1; 48.2)
	CT (33)	39.7 (23.2; 46.9)	CT (146)	37.8 (22.8; 46.9)	TA (231)	40.1 (23.6; 47.5)	GT+TT (36)	37.2 (24.1; 49.6)	TC (171)	42.7 (24.0; 49.3)
			TT (18)	44.3 (24.3; 47.6)	AA (115)	43.6 (24.5; 52.6)			CC (21)	41.9 (22.2; 47.9)
β		0.001±0.027		−0.004 ± 0.013		0.032±0.009		−0.009±0.026		0.015±0.012
P		0.975		0.757		0.001		0.736		0.198
BAI	CC	41.9 (28.1; 51.6)	CC (325)	42.1 (28.3; 51.7)	TT (143)	34.2 (26.6; 48.4)	GG (452)	42.1 (28.0; 51.6)	TT (297)	40.9 (27.4; 50.2)
	CT (33)	33.7 (26.3; 48.7)	CT (145)	37.5 (27.3; 50.4)	TA (230)	42.1 (29.0; 51.2)	GT+TT (36)	38.7 (28.4; 48.1)	TC (170)	43.6 (29.5; 53.1)
			TT (18)	44.4 (26.8; 55.3)	AA (115)	46.6 (31.4; 54.7)			CC (21)	44.5 (27.7; 52.0)
β		−0.016±0.010		0.002±0.005		0.007±0.003		0.005±0.010		0.005±0.004
P		0.101		0.641		0.054		0.631		0.243
Waist to weight ratio	CC (455)	1.10 (1.00; 1.30)	CC (325)	1.10 (1.00; 1.30)	TT (143)	1.20 (1.00; 1.30)	GG (452)	1.10 (1.00; 1.30)	TT (297)	1.10 (1.00; 1.30)
	CT (33)	1.1 (1.00; 1.25)	CT (145)	1.20 (1.05; 1.30)	TA (230)	1.10 (1.00; 1.30)	GT+TT (36)	1.10 (1.00; 1.30)	TC (170)	1.10 (1.00; 1.30)
			TT (18)	1.10 (1.00; 1.20)	AA (115)	1.10 (1.00; 1.20)			CC (21)	1.20 (1.10; 1.35)
β		−0.002±0.011		0.002±0.005		−0.012±0.004		−0.007±0.011		0.001±0.005
P		0.831		0.727		0.003		0.489		0.883
Waist to height ratio	CC (455)	0.70 (0.50; 0.90)	CC (325)	0.70 (0.50; 0.90)	TT (143)	0.60 (0.50; 0.80)	GG (452)	0.70 (0.50; 0.90)	TT (297)	0.70 (0.50; 0.80)
	CT (33)	0.70 (0.50; 0.80)	CT (145)	0.70 (0.50; 0.80)	TA (230)	0.70 (0.50; 0.80)	GT+TT (36)	0.70 (0.50; 0.80)	TC (170)	0.80 (0.50; 0.90)
			TT (18)	0.80 (0.50; 0.82)	AA (115)	0.80 (0.50; 0.90)			CC (21)	0.70 (0.50; 0.90)
β		0.001±0.008		0.003±0.004		0.001±0.003		−0.011±0.008		0.004±0.003
P		0.937		0.372		0.676		0.153		0.248
Inverted BMI	CC (457)	24.9 (20.4; 42.6)	CC (326)	24.7 (20.2; 42.4)	TT (144)	27.9 (21.3; 44.3)	GG (454)	24.9 (20.5; 42.9)	TT (298)	25.8 (20.6; 43.4)
	CT (33)	25.2 (21.3; 43.0)	CT (146)	26.2 (21.3; 43.7)	TA (231)	24.9 (21.1; 42.4)	GT+TT (36)	26.9 (20.1; 41.5)	TC (171)	23.4 (20.3; 41.7)
			TT (18)	22.5 (21.0; 41.1)	AA (115)	22.9 (19.0; 40.8)			CC (21)	23.9 (20.9; 45.0)
β		0.001±0.028		0.001 ± 0.013		−0.029±0.010		0.010±0.027		−0.013±0.012
P		0.976		0.983		0.003		0.712		0.275
Waist circumference (cm)	CC (455)	120.0 (84.0; 140.0)	CC (325)	121.0 (84.0; 141.7)	TT (143)	101.0 (81.5; 137.0)	GG (452)	121.0 (84.0; 139.9)	TT (297)	116.0 (82.0; 139.0)
	CT (33)	125.5 (81.5; 139.7)	CT (145)	117.0 (92.0; 138.0)	TA (230)	120.5 (84.7; 139.5)	GT+TT (36)	111.5 (82.2; 142.0)	TC (170)	126.2 (86.7; 141.5)
			TT (18)	125.5 (84.4; 137.6)	AA (115)	128.0 (86.0; 146.0)			CC (21)	125.0 (81.7; 143.7)
β		0.003±0.007		0.001 ± 0.013		−0.001±0.002		−0.002±0.007		0.004±0.003
P		0.682		0.778		0.589		0.759		0.156
Hip circumference (cm)	CC (455)	128.0 (100.0; 145.0)	CC (325)	129.5 (100.0; 146.0)	TT (143)	108.0 (98.0; 141.0)	GG (452)	128.0 (99.0; 145.9)	TT (297)	125.0 (99.0; 144.0)
	CT (33)	124.0 (97.5; 145.7)	CT (145)	123.0 (98.5; 142.2)	TA (230)	127.2 (84.7; 139.5)	GT+TT (36)	125.5 (101.2; 144.2)	TC (170)	132.0 (101.9; 147.1)
			TT (18)	136.7 (100.0; 148.6)	AA (115)	135.5 (101.0; 150.0)			CC (21)	131.0 (98.7; 147.5)
β		−0.008±0.005		0.004 ± 0.002		0.002±0.002		0.006±0.005		0.002±0.002
P		0.141		0.128		0.267		0.712		0.378
WHR	CC (455)	0.91 (0.84; 0.98)	CC (325)	0.92 (0.84; 0.98)	TT (143)	0.91 (0.82; 0.98)	GG (452)	0.91 (0.84; 0.98)	TT (297)	0.90 (0.83; 0.97)
	CT (33)	0.93 (0.84; 0.98)	CT (145)	0.90 (0.82; 0.97)	TA (230)	0.91 (0.83; 0.97)	GT+TT (36)	0.90 (0.82; 0.99)	TC (170)	0.93 (0.85; 0.98)
			TT (18)	0.88 (0.84; 0.95)	AA (115)	0.92 (0.85; 0.98)			CC (21)	0.90 (0.84; 0.98)
β		0.011±0.007		−0.003±0.003		−0.004±0.002		−0.007±0.006		0.002±0.003
P		0.108		0.321		0.138		0.260		0.451
Glucose (mg/dL)	CC (354)	92.5 (87.0; 102.0)	CC (260)	94.0 (87.0; 103.0)	TT (110)	91.5 (84.7; 98.2)	GG (357)	92.0 (87.0; 101.5)	TT (239)	92.0 (86.0; 102.0)
	CT (31)	94.0 (86.0; 105.0)	CT (112)	92.0 (86.0; 100.7)	TA (193)	93.0 (87.0; 102.0)	GT+TT (28)	96.0 (90.0; 111.0)	TC (132)	94.0 (87.2; 102.7)
			TT (13)	93.0 (89.5; 102.5)	AA (92)	96.0 (89.0; 108.0)			CC (14)	94.0 (87.0; 104.2)
β		−0.001±0.015		8,139E-5±0.007		0.006±0.006		0.023±0.015		−0.003±0.007
P		0.966		0.991		0.283		0.130		0.643
Total cholesterol (mg/dL)	CC (392)	186.0 (160.0; 216.7)	CC (280)	186.0 (159.2; 218.0)	TT (119)	182.0 (160.0; 212.0)	GG (391)	185.0 (160.0; 215.0)	TT (261)	185.0 (161.0; 220.0)
	CT (31)	182.0 (161.0; 211.0)	CT (129)	189.0 (162.0; 215.5)	TA (210)	187.0 (160.0; 216.2)	GT+TT (32)	192.0 (170.2; 231.5)	TC (146)	186.0 (159.0; 209.5)
			TT (14)	175.0 (153.5; 188.2)	AA (94)	192.0 (161.0; 228.2)			CC (16)	190.0 (160.2; 233.5)
β		−0.005±0.016		−0.003±0.008		0.008±0.006		0.016±0.016		−0.001±0.007
P		0.774		0.694		0.164		0.318		0.920
HDL cholesterol (mg/dL)	CC (392)	51.0 (43.0; 61.0)	CC (280)	49.5 (43.0; 60.0)	TT (119)	52.0 (45.0; 60.0)	GG (391)	51.0 (43.0; 61.0)	TT (261)	51.0 (43.0; 61.5)
	CT (31)	50.0 (45.0; 57.0)	CT (129)	53.0 (45.0; 65.0)	TA (210)	49.0 (43.0; 60.0)	GT+TT (32)	49.5 (42.0; 61.2)	TC (146)	50.0 (42.0; 59.0)
			TT (14)	50.0 (41.7; 59.5)	AA (94)	52.5 (43.7; 65.0)			CC (16)	50.5 (46.0; 67.0)
β		0.006±0.017		0.013 ± 0.008		0.010±0.006		−0.006±0.017		0.003±0.008
P		0.739		0.121		0.112		0.717		0.735
LDL cholesterol (mg/dL)	CC (386)	110.0 (91.0; 135.0)	CC (275)	109.0 (92.0; 135.0)	TT (119)	108.0 (90.0; 132.0)	GG (386)	109.0 (90.0; 132.2)	TT (256)	110.0 (92.0; 137.0)
	CT (30)	105.0 (90.5; 127.7)	CT (129)	112.5 (90.2; 136.5)	TA (207)	111.0 (91.0; 133.0)	GT+TT (30)	119.0 (99.7; 145.0)	TC (144)	108.5 (88.0; 126.7)
			TT (13)	98.0 (77.0; 120.0)	AA (90)	109.0 (93.0; 139.5)			CC (16)	121.0 (95.7; 158.5)
β		−0.020±0.023		−0.003±0.011		0.004±0.009		0.021±0.023		−0.007±0.011
P		0.384		0.791		0.661		0.359		0.522
Triglycerides (mg/dL)	CC (392)	102.5 (74.0; 139.0)	CC (280)	107.0 (74.2; 142.0)	TT (119)	96.0 (70.0; 135.0)	GG (391)	102.0 (74.0; 139.0)	TT (261)	100.0 (72.5; 137.5)
	CT (31)	100.0 (70.0; 140.0)	CT (129)	95.0 (70.5; 131.5)	TA (210)	104.5 (74.0; 137.2)	GT+TT (32)	105.0 (78.0; 141.5)	TC (146)	113.5 (78.0; 158.0)
			TT (14)	93.5 (75.5; 133.7)	AA (94)	109.5 (76.5; 173.2)			CC (16)	95.0 (69.2; 109.2)
β		0.001±0.037		0.015 ± 0.018		0.007±0.014		0.031±0.036		0.008±0.017
P		0.994		0.382		0.612		0.389		0.636
Hemoglobin	CC (318)	5.3 (4.9; 5.9)	CC (223)	5.3 (4.9; 5.8)	TT (99)	5.2 (4.9; 5.7)	GG (314)	5.3 (4.9; 5.9)	TT (211)	5.3 (4.9; 5.8)
	CT (22)	5.2 (5.0; 6.0)	CT (104)	5.4 (4.9; 6.0)	TA (160)	5.4 (4.9; 6.0)	GT+TT (26)	5.4 (5.0; 6.1)	TC (115)	5.4 (4.9; 6.0)
			TT (13)	5.5 (4.0; 5.9)	AA (81)	5.4 (4.9; 6.0)			CC (14)	5.2 (4.7; 6.3)
β		0.006±0.020		0.008 ± 0.009		0.003±0.007		−0.002±0.018		−0.007±0.009
P		0.748		0.342		0.627		0.928		0.446
CRP	CC (316)	0.43 (0.13; 1.11)	CC (218)	0.46 (0.13; 1.16)	TT (98)	0.28 (0.09; 0.90)	GG (310)	0.40 (0.11; 1.05)	TT (209)	0.46 (0.11; 1.14)
	CT (20)	0.16 (0.07; 0.79)	CT (105)	0.32 (0.10; 1.00)	TA (158)	0.45 (0.15; 1.14)	GT+TT (26)	0.72 (0.17; 1.30)	TC (113)	0.39 (0.12; 1.00)
			TT (13)	0.44 (0.09; 0.81)	AA (80)	0.57 (0.17; 1.14)			CC (14)	0.37 (0.06; 6.3)
β		−0.161±0.105		0.007±0.045		−0.019±0.035		0.104±0.094		−0.098±0.043
P		0.126		0.868		0.578		0.268		0.025
SBP	CC (319)	122.0 (110.0; 134.0)	CC (224)	123.0 (111.0; 133.7)	TT (105)	121.0 (110.0; 131.0)	GG (322)	121.0 (110.0; 133.2)	TT (215)	120.0 (110.0; 131.0)
	CT (26)	120.0 (113.5; 125.7)	CT (105)	119.0 (110.0; 130.5)	TA (159)	120.0 (112.0; 134.0)	GT+TT (23)	122.0 (112.0; 130.0)	TC (118)	126.0 (115.0; 139.2)
			TT (16)	130.0 (117.0; 156.7)	AA (81)	124.0 (111.0; 136.5)			CC (12)	118.0 (110.0; 129.2)
β		−0.016±0.016		−0.001±0.007		−0.004±0.006		0.006±0.017		0.005±0.008
P		0.320		0.854		0.456		0.710		0.551
DBP	CC (319)	80.0 (70.0; 90.0)	CC (224)	80.0 (70.0; 90.0)	TT (105)	80.0 (72.5; 90.0)	GG (322)	80.0 (70.7; 89.0)	TT (215)	80.0 (71.0; 89.0)
	CT (26)	77.5 (70.7; 87.5)	CT (105)	80.0 (71.0; 87.0)	TA (159)	80.0 (70.0; 87.0)	GT+TT (23)	78.0 (70.0; 90.0)	TC (118)	80.0 (70.7; 90.0)
			TT (16)	78.5 (69.7; 95.2)	AA (81)	81.0 (71.5; 90.0)			CC (12)	78.0 (62.0; 91.5)
β		−0.005±0.022		0.012±0.010		−0.001±0.008		0.004±0.023		−0.001±0.010
P		0.834		0.239		0.889		0.866		0.926

Marks DL , Boucher N , Lanouette C , et al. Ala67Thr polymorphism in the Agouti‐related peptide gene is associated with inherited leanness in humans. Am J Med Genet A . 2004;126(3):267–271. doi:10.1002/ajmg.a.20600

 Web of Science ®Google Scholar

Li P , Tiwari HK , Lin W-Y , et al. Genetic association analysis of 30 genes related to obesity in a European American population. Int J Obes . 2014;38(5):724. doi:10.1038/ijo.2013.140

 Web of Science ®Google Scholar

Kalnina I , Kapa I , Pirags V , Ignatovica V , Schiöth HB , Klovins J . Association between a rare SNP in the second intron of human Agouti related protein gene and increased BMI. BMC Med Genet . 2009;10(1):63. doi:10.1186/1471-2350-10-63 19602223

 PubMed Web of Science ®Google Scholar

Van Rossum CTM , Pijl H , Adan RAH , Hoebee B , Seidell JC . Polymorphisms in the NPY and AGRP genes and body fatness in Dutch adults. Int J Obes . 2006;30(10):1522. doi:10.1038/sj.ijo.0803314

 Web of Science ®Google Scholar

Han X , Luo Y , Zhang X , et al. Rs4074134 near BDNF gene is associated with type 2 diabetes mellitus in Chinese Han population independently of body mass index. PLoS One . 2013;8(2):e56898. doi:10.1371/journal.pone.0056898 23431394

 PubMed Web of Science ®Google Scholar

Zandona MR , Sangalli CN , Campagnolo PDB , Vitolo MR , Almeida S , Mattevi VS . Validation of obesity susceptibility loci identified by genome‐wide association studies in early childhood in South Brazilian children. Pediatr Obes . 2017;12(1):85–92. doi:10.1111/ijpo.12113 27005443

 PubMed Web of Science ®Google Scholar

Hotta K , Nakamura M , Nakamura T , et al. Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population. J Hum Genet . 2009;54(12):727–731. doi:10.1038/jhg.2009.106 19851340

 PubMed Web of Science ®Google Scholar

Srivastava A , Mittal B , Prakash J , Srivastava P , Srivastava N . Analysis of MC4R rs17782313, POMC rs1042571, APOE-Hha1 and AGRP rs3412352 genetic variants with susceptibility to obesity risk in North Indians. Ann Hum Biol . 2016;43(3):285–288. doi:10.3109/03014460.2015.1061597 26226973

 PubMed Web of Science ®Google Scholar

Beckers S , Zegers D , de Freitas F , Mertens IL , Van Gaal LF , Van Hul W . Association study of MC4R with complex obesity and replication of the rs17782313 association signal. Mol Genet Metab . 2011;103(1):71–75. doi:10.1016/j.ymgme.2011.01.007 21303735

 PubMed Web of Science ®Google Scholar

Thorleifsson G , Walters GB , Gudbjartsson DF , et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet . 2009;41(1):18. doi:10.1038/ng.274 19079260

 PubMed Web of Science ®Google Scholar

Vitolo E , Santini E , Seghieri M , et al. Heterozygosity for the rs696217 SNP in the preproghrelin gene predicts weight loss after bariatric surgery in severely obese individuals. Obes Surg . 2017;27(4):961–967. doi:10.1007/s11695-016-2387-6 27681093

 PubMed Web of Science ®Google Scholar

Imaizumi T , Ando M , Nakatochi M , et al. Effect of dietary energy and polymorphisms in BRAP and GHRL on obesity and metabolic traits. Obes Res Clin Pract . 2016. 12:39–48.

 Web of Science ®Google Scholar

Gueorguiev M , Lecoeur C , Meyre D , et al. Association studies on ghrelin and ghrelin receptor gene polymorphisms with obesity. Obesity . 2009;17(4):745–754. doi:10.1038/oby.2008.589 19165163

 PubMed Web of Science ®Google Scholar

Bray MS , Boerwinkle E , Hanis CL . Sequence variation within the neuropeptide Y gene and obesity in Mexican Americans. Obes Res . 2000;8(3):219–226. doi:10.1038/oby.2000.25 10832764

 PubMedGoogle Scholar

Abdelmajed SS , Youssef M , Zaki ME , Hassan NA-M , Ismail S . Association analysis of FTO gene polymorphisms and obesity risk among Egyptian children and adolescents. Genes Dis . 2017;4(3):170–175. doi:10.1016/j.gendis.2017.06.002 30258920

 PubMed Web of Science ®Google Scholar

León-Mimila P , Villamil-Ramírez H , Villalobos-Comparán M , et al. Contribution of common genetic variants to obesity and obesity-related traits in mexican children and adults. PLoS One . 2013;8(8):e70640. doi:10.1371/journal.pone.0070640 23950976

 PubMed Web of Science ®Google Scholar

Ramos AV , Bastos-Rodrigues L , Resende BA , et al. The contribution of FTO and UCP-1SNPs to extreme obesity, diabetes and cardiovascular risk in Brazilian individuals. BMC Med Genet . 2012;13(1):101. doi:10.1186/1471-2350-13-101 23134754

 PubMed Web of Science ®Google Scholar

Magno FCCM , Guaraná HC , Fonseca ACP , et al. Influence of FTO rs9939609 polymorphism on appetite, ghrelin, leptin, IL6, TNFα levels, and food intake of women with morbid obesity. Diabetes Metab Syndr Obes . 2018;11:199–207. doi:10.2147/DMSO.S154978 29785132

 PubMed Web of Science ®Google Scholar

Cecil JE , Tavendale R , Watt P , Hetherington MM , Palmer CNA . An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med . 2008;359(24):2558–2566. doi:10.1056/NEJMoa0803839 19073975

 PubMed Web of Science ®Google Scholar

Reuter CP , Rosane De Moura Valim A , Gaya AR , et al. FTO polymorphism, cardiorespiratory fitness, and obesity in Brazilian youth. Am J Hum Biol . 2016;28(3):381–386. doi:10.1002/ajhb.22798 26458076

 PubMed Web of Science ®Google Scholar