The fat mass and obesity-associated (FTO) gene variant rs9939609 predicts long-term incidence of cardiovascular disease and related death independent of the traditional risk factors

Figures & data

Table I. Allele frequencies, genotype counts, and Hardy–Weinberg equilibrium P value of FTO rs9939609 variant.

Variant	Allele	Frequency	Genotype	Count	HWE p value
rs9939609	A	0.407	AA	183	0.147
			AT	478
	T	0.593	TT	376

HWE = Hardy–Weinberg equilibrium; a non-significant p value (p > 0.05) indicates that the variant does not deviate significantly from HWE.

Table II. Measurements of the risk factors for atherosclerosis and obesity-related peptide hormones at baseline in relation to FTO rs9939609 genotypes.

	AA n = 183	AT n = 478	TT n = 376	P value
Males/females (n)	97/86	234/244	181/195	0.541^a
Hypertensive/control (n)	93/90	241/237	184/192	0.882^a
Age (years)	51 (6)	51 (6)	52 (6)	0.237^b
BMI (kg/m^2)	28.3 (5.1)	27.6 (4.5)	27.5 (4.5)	0.200^b
Waist circumference (cm)	92.0 (13.5)	90.3 (13.2)	90.3 (13.2)	0.349^b
SBP (mmHg)	149 (22)	148 (22)	148 (23)	0.919^b
Plasma triglycerides (mmol/L)	1.7 (1.3)	1.5 (0.9)	1.6 (1.0)	0.393^b
Total cholesterol (mmol/L)	5.8 (1.2)	5.7 (1.0)	5.7 (1.1)	0.567^b
LDL-C (mmol/L)	3.5 (1.0)	3.5 (0.9)	3.6 (1.0)	0.958^b
HDL-C (mmol/L)	1.3 (0.4)	1.3 (0.4)	1.4 (0.4)	0.943^b
Smoking (pack-year)	12.7 (14.6)	11.7 (13.5)	12.1 (14.4)	0.187^b
Fasting glucose (mmol/L)^c	5.0 (1.8)	4.6 (1.1)	4.8 (1.7)	0.029^b
Fasting glucose (mmol/L)^d	4.4 (0.5)	4.4 (0.5)	4.4 (0.5)	0.882^b
Fasting insulin (mU/L)^c	13.5 (10.1)	14.0 (12.8)	13.2 (9.0)	0.302^b
Fasting insulin (mU/L)^d	12.5 (9.8)	13.2 (11.7)	12.3 (7.4)	0.178^b
OGTT-2h glucose (mmol/L)^c	6.6 (3.7)	5.9 (2.6)	5.9 (3.0)	0.035^b
OGTT-2h glucose (mmol/L)^d	5.5 (1.6)	5.4 (1.5)	5.3 (1.4)	0.456^b
CRP (mg/L)	4.1 (6.9)	4.0 (7.7)	3.6 (7.5)	0.598^b
Leptin (ng/mL)	10.9 (8.7)	10.7 (8.0)	10.4 (8.2)	0.378^b
Adiponectin (mg/L)	15.2 (7.0)	15.9 (6.8)	16.2 (6.9)	0.544^b
Ghrelin (pg/mL)	645 (258)	675 (246)	671 (233)	0.459^b
MI at baseline, n (%)	5 (2.7)	8 (1.7)	7 (1.9)	0.671^a
Stroke at baseline, n (%)	3 (1.6)	8 (1.7)	11 (2.9)	0.399^a
Diabetes at baseline, n (%)	30 (16.4)	33 (6.9)	29 (7.7)	0.000^a

Values are means and SD.

^a,bP values are obtained with Pearson’s chi-square^a or ANCOVA^b adjusted for sex, age, and BMI when appropriate. Significant p-values are bolded.

^cAll subjects.

^dDiabetic subjects excluded.

BMI = body mass index; CRP = C-reactive protein; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; OGTT = oral glucose tolerance test; SBP = systolic blood pressure.

Table III. The all-cause mortality and major outcomes in relation to FTO rs9939609.

	AA n = 183	AT n = 478	TT n = 376	p value
All deaths	35 (19.1%)	64 (13.4%)	67 (17.8%)	0.096
CVD event or death	53 (29.0%)	88 (18.4%)	71 (18.9%)	0.007
CVD deaths	21 (11.5%)	23 (4.8%)	25 (6.6%)	0.009
CHD event or death	40 (21.9%)	61 (12.8%)	51 (13.6%)	0.009
CHD deaths	16 (8.7%)	18 (3.8%)	24 (6.4%)	0.032
Cancer event or death	17 (9.3%)	60 (12.6%)	53 (14.1%)	0.273
Cancer death	7 (3.8%)	15 (3.1%)	22 (5.9%)	0.142

Values are numbers of the subjects with event or death (% within the genotype). p values are achieved from Pearson’s chi-square test. Significant p-values are bolded.

CHD = major coronary heart disease; CVD = cardiovascular disease.

Table IV. The logistic regression analysis of the total mortality and cardiovascular outcomes in relation to FTO rs9939609.

	Model 1			Model 2
	OR	95% CI	p value	OR	95% CI	p value
Total mortality	1.323	0.863–2.026	0.199	1.273	0.815–1.987	0.289
CVD event or death	1.849	1.265–2.702	0.001	1.844	1.246–2.729	0.002
CHD event or death	1.905	1.250–2.903	0.003	1.895	1.222–2.938	0.004

The analysis is performed as comparing AA genotype to AT and TT genotypes. Model 1 adjusted for sex, age, and study group; model 2 adjusted for sex, age, study group, SBP, BMI, LDL, and smoking. Significant p-values are bolded.

Figure 1. The Kaplan–Meier curves of total, CVD, CHD, and cancer mortality. The graph includes both sexes together. The survival differs statistically significantly with respect to both CVD and CHD mortality.

Table V. The Cox regression analysis of the total mortality and major causes of death in relation to FTO rs9939609.

	AA (n = 183)	AT + TT (n = 854)	HR	95% CI	p value
All deaths	35 (19.1%)	131 (15.3%)	1.268	0.873–1.843	0.213
Cause of death
CVD	21 (11.5%)	48 (5.6%)	2.067	1.235–3.459	0.006
CHD	16 (8.7%)	42 (4.9%)	1.801	1.010–3.212	0.046
Cancer	7 (3.8%)	37 (4.3%)	0.895	0.398–2.011	0.788

The model is adjusted for sex, age, and study group. CVD deaths include CHD deaths. Significant p-values are bolded.

Table VI. The Cox regression modeling of factors predicting CVD mortality.

	Crude	Model 1	Model 2	Model 3	Model 4	Model 5
rs9939609	2.031 (1.216–3.392)**	2.004 (1.199–3.350)**	1.954 (1.167–3.270)*	2.039 (1.217–3.416)**	2.066 (1.232–3.465)**	1.715 (1.006–2.922)*
Sex	3.250 (1.848–5.714)**	3.483 (1.975–6.141)**	3.494 (1.979–6.169)**	3.053 (1.722–5.412)**	1.990 (1.103–3.589)*	2.073 (1.133–3.792)*
Age	1.054 (1.012–1.098)*	1.062 (1.020–1.110)**	1.063 (1.019–1.109)**	1.050 (1.006–1.097)*	1.036 (0.991–1.083)	1.023 (0.978–1.071)
Study group	1.618 (0.998–2.624)
BMI	1.070 (1.025–1.118)**		1.067 (1.018–1.118)**	1.035 (0.984–1.089)
SBP	1.025 (1.015–1.036)**			1.019 (1.007–1.030)**	1.022 (1.012–1.032)**	1.018 (1.008–1.029)**
Smoking	1.058 (1.041–1.076)**				1.047 (1.030–1.065)**	1.051 (1.033–1.069)**
LDL-C	1.250 (0.976–1.601)
Diabetes	4.120 (2.403–7.063)**					3.229 (1.809–5.764)**

Values are HR (95% CI). Study group (hypertensive/control), BMI (body mass index), SBP (systolic blood pressure, mmHg), smoking (pack-year), LDL-C (low-density lipoprotein cholesterol, mmol/L), diabetes diagnosed at baseline.

*P < 0.05, **P < 0.01.

Table VII. Discrimination of the risk models in prediction of cardiovascular event.

	Cardiovascular event
	C-index	Binary R^2
Final model	0.715	0.151
Removed variable:
Sex = male	0.676	0.103
Age ≥ 54 years	0.701	0.124
Systolic blood pressure (≥141 mmHg)	0.705	0.136
Current smoker = yes	0.705	0.139
Baseline diabetes status = yes	0.709	0.138
FTO rs9939609 variant	0.709	0.139

Table VIII. Reclassification of cases and non-cases according to cardiovascular event or death with and without FTO rs9939609 variant in the model where variables of best regression model (sex, age, systolic blood pressure, smoking, and baseline diabetes status) were included.

	Predicted risk with FTO variant
Predicted risk without FTO variant	0 – <6%	6 – <20%	≥20%
Cases (CVD event or death, n = 195)
0 – <6%	1	0	0
6 – <20%	0	70	13
≥20%	0	4	107
Non-cases (n = 839)
0 – <6%	92	9	0
6 – <20%	0	446	44
≥20%	0	27	221

Integrated discrimination index = 0.010 (p = 0.011); net reclassification index = 0.015 (p = 0.52).