Association of CETP Gene Variants with Atherogenic Dyslipidemia Among Thai Patients Treated with Statin

Figures & data

Table 1 Clinical Parameters and Biomarker Levels^†

	All (n = 299)	Men (n = 95)	Women (n = 204)	p-value
Clinical parameter, mean (range)
Age, years	63.0 (37–92)	62.7 (38–92)	63.3 (37–89)	0.707
Systolic BP (mm Hg)	132.3 (91–210)	131.7 (92–180)	132.6 (91–210)	0.860
Diastolic BP (mm Hg)	76.0 (44–120)	76.2 (44–100)	76.0 (50–120)	0.852
Body mass index, kg/m^2	25.9 (15.7–49.5)	25.9 (15.7–49.5)	26.0 (17.4–42.3)	0.842
Statin dosage
Low intensity	176 (58.9)	50 (52.6)	126 (61.8)	0.306
Moderate intensity	116 (38.8)	42 (44.2)	74 (36.3)
High intensity	7 (2.3)	3 (3.2)	4 (2.0)
CETP Polymorphisms
rs3764261 (C>A) genotype
CC	126 (42.1)	40 (42.1)	86 (42.2)	0.822
CA	140 (46.8)	43 (45.3)	97 (47.5)
AA	33 (11.0)	12 (12.6)	21 (10.3)
rs708272 (G>A) genotype
GG	101 (33.8)	34 (35.8)	67 (32.8)	0.760
GA	153 (51.2)	49 (51.6)	104 (51.0)
AA	45 (15.0)	12 (12.6)	33 (16.2)
rs12149545 (G>A) genotype
GG	193 (64.5)	61 (64.2)	132 (64.7)	0.993
GA	97 (32.5)	31 (32.6)	66 (32.4)
AA	9 (3.0)	3 (3.2)	6 (2.9)
Biomarkers
Fasting glucose, mmol/L	5.78 (5.17–7.15)	6.44 (5.33–8.14)	5.67 (5.12–6.82)	0.001
Insulin, μIU/mL	7.0 (4.8–10.7)	7.3 (4.8–10.8)	7.0 (4.7–10.7)	0.965
HOMA-IR	1.98 (1.19–3.17)	2.05 (1.37–3.72)	1.90 (1.14–3.04)	0.157
HbA1c (mmol/mol)	47.7 (41.2–58.7)	51.1 (41.6–62.1)	46.7 (40.1–56.5)	0.039

Notes: ^†Continuous data are given as median (interquartile range). Categorical variables are presented as numbers (%). All biochemical measures are given in Système International units; conversions to conventional units are as follows: fasting glucose (mg/dL), multiply by 18.02; HbA1c (%), use the formula: [0.0915 HbA1c (mmol/mol) + 2.15].

Abbreviations: BP, blood pressure; HOMAIR, homeostasis model assessment of insulin resistance.

Figure 1 Linkage disequilibrium pattern between CETP polymorphisms of rs3764261, rs708272 and rs12149545. The numbers in each box correspond to measured linkage disequilibrium coefficients among all SNV (n = 299).

Table 2 Plasma Lipid, Lipoprotein and Apolipoprotein Biomarkers Among CETP Variants in Patients Treated with Statin

	Lipid Biomarkers^†
	Total cholesterol (mmol/L)	LDL-C (mmol/L)	HDL-C (mmol/L)	Triglycerides (mmol/L)	Apolipoprotein-AI (mg/dL)	Apolipoprotein-B (mg/dL)
CETP rs3764261 (C>A)
CC (n = 126)	4.87 (4.37–5.34)	2.71 (0.74)	1.26 (1.06–1.55)	1.98 (1.22–2.44)	157.6 (24.2)	90.1 (79.3–106.0)
CA (n = 140)	4.90 (4.45–5.31)	2.74 (0.87)	1.40 (1.19–1.70)	1.52 (1.11–2.03)	164.3 (27.2)	86.7 (76.5–102.0)
AA (n = 33)	5.10 (4.75–5.53)	3.02 (0.61)	1.53 (1.39–1.88)	1.40 (1.13–1.78)	171.7 (25.6)	86.0 (77.6–99.5)
p-value	0.180	0.118	<0.001	0.004	0.010	0.597
CETP rs708272 (G>A)
GG (n = 101)	4.84 (4.39–5.31)	2.72 (0.78)	1.32 (1.11–1.57)	1.79 (1.18–2.27)	158.6 (25.7)	86.4 (78.2–99.8)
GA (n = 153)	4.95 (4.43–5.54)	2.77 (0.83)	1.35 (1.10–1.66)	1.73 (1.16–2.44)	161.6 (26.6)	88.6 (78.0–108.5)
AA (n = 45)	4.92 (4.51–5.21)	2.79 (0.72)	1.50 (1.30–1.77)	1.32 (1.05–1.53)	173.0 (23.2)	87.7 (76.5–94.6)
p-value	0.617	0.852	0.006	0.001	0.008	0.398
CETP rs12149545 (G>A)
GG (n = 193)	4.95 (4.43–5.37)	2.77 (0.77)	1.35 (1.14–1.61)	1.66 (1.16–2.28)	161.7 (25.6)	88.9 (78.8–101.0)
GA (n = 97)	4.84 (4.42–5.34)	2.74 (0.86)	1.37 (1.17–1.72)	1.58 (1.13–2.27)	162.3 (27.0)	87.1 (75.9–107.0)
AA (n = 9)	4.95 (4.60–5.44)	2.69 (0.65)	1.71 (1.27–1.98)	1.37 (1.09–1.85)	175.3 (27.2)	84.2 (75.1–98.9)
p-value	0.756	0.937	0.119	0.516	0.312	0.666

Notes: ^†The parametric variables are given as mean (standard deviation) and the nonparametric variables are given as median (interquartile range). All biochemical measures are given in Système International units; conversions to conventional units are as follows: cholesterol (mg/dL), multiply by 38.6; triglycerides (mg/dL), multiply by 88.5.

Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

Table 3 LDL Subclass Among CETP Variants in Patients Treated with Statin

	LDL Subclass (mmol/L)^†
	VLDL-C	IDL-C	LDL1-C	LDL2-C	LDL3-C to LDL7-C	Mean LDL particle size (nm)
CETP rs3764261 (C>A)
CC (n = 126)	0.84 (0.65–1.09)	1.15 (0.96–1.37)	0.70 (0.54–0.93)	0.57 (0.41–0.73)	0.23 (0.08–0.52)	26.52 (26.05–26.99)
CA (n = 140)	0.70 (0.65–0.85)	1.22 (1.04–1.40)	0.80 (0.62–1.01)	0.57 (0.41–0.75)	0.13 (0.08–0.39)	26.82 (26.35–27.00)
AA (n = 33)	0.70 (0.60–0.82)	1.22 (1.01–1.50)	0.93 (0.79–1.05)	0.60 (0.44–0.74)	0.10 (0.08–0.19)	26.87 (26.66–27.04)
p-value	0.002	0.008	<0.001	0.910	0.112	0.017
CETP rs708272 (G>A)
GG (n = 101)	0.80 (0.67–1.01)	1.19 (0.96–1.37)	0.72 (0.54–0.91)	0.54 (0.41–0.73)	0.18 (0.06–0.47)	26.65 (26.15–27.05)
GA (n = 153)	0.78 (0.65–1.02)	1.19 (1.01–1.37)	0.78 (0.60–1.00)	0.60 (0.41–0.75)	0.18 (0.08–0.47)	26.67 (26.12–26.97)
AA (n = 45)	0.67 (0.57–0.71)	1.22 (1.05–1.44)	0.96 (0.79–1.10)	0.60 (0.44–0.74)	0.13 (0.05–0.21)	26.90 (26.66–27.04)
p-value	<0.001	0.576	<0.001	0.708	0.039	0.016
CETP rs12149545 (G>A)
GG (n = 193)	0.78 (0.65–1.01)	1.19 (1.01–1.40)	0.78 (0.57–1.01)	0.57 (0.41–0.75)	0.16 (0.08–0.45)	26.68 (26.17–27.00)
GA (n = 97)	0.73 (0.62–0.91)	1.17 (0.98–1.37)	0.80 (0.60–1.00)	0.60 (0.41–0.76)	0.16 (0.08–0.44)	26.72 (26.34–27.00)
AA (n = 9)	0.67 (0.54–0.89)	1.30 (1.06–1.52)	0.96 (0.84–1.02)	0.47 (0.40–0.75)	0.08 (0.05–0.23)	26.96 (26.51–27.16)
p-value	0.097	0.534	0.206	0.799	0.441	0.245

Note: ^†Data are given as median (interquartile range).

Abbreviations: VLDL-C, very low-density lipoprotein cholesterol; IDL-C, intermediate density lipoprotein cholesterol; LDL1-C and LDL2-C, large-buoyant low-density lipoprotein cholesterol; LDL3-C to LDL7-C, small-dense low-density lipoprotein cholesterol.

Table 4 Genotype Frequency of CETP Variants Among Patients without and with Dyslipidemia^†

	All, n (%)		Men, n (%)		Women, n (%)
HDL-cholesterol	M ≥1.04 mmol/L W ≥1.30 mmol/L (n = 206)	M <1.04 mmol/L W <1.30 mmol/L (n = 93)	≥1.04 mmol/L (n = 71)	<1.04 mmol/L (n = 24)	≥1.30 mmol/L (n = 135)	<1.30 mmol/L (n = 69)
CETP rs3764261 (C>A)
CC, n = 40 (M); 86 (W)	73 (57.9)	53 (42.1)	25 (62.5)	15 (37.5)	48 (55.8)	38 (44.2)
CA, n = 43 (M); 97 (W)	103 (73.6)	37 (26.4)	35 (81.4)	8 (18.6)	68 (70.1)	29 (29.9)
AA, n = 12 (M); 21 (W)	30 (90.9)	3 (9.1)	11 (91.7)	1 (8.3)	19 (90.5)	2 (9.5)
OR (95% CI) ^‡	2.414 (1.464–3.980)		3.067 (1.175–8.003)		2.222 (1.230–4.012)
p-value	0.001		0.022		0.008
CETP rs708272 (G>A)
GG, n = 34 (M); 67 (W)	65 (64.4)	36 (35.6)	25 (73.5)	9 (26.5)	40 (59.7)	27 (40.3)
GA, n = 49 (M); 104 (W)	100 (65.4)	53 (34.6)	34 (69.4)	15 (30.6)	66 (63.5)	38 (36.5)
AA, n = 12 (M); 33 (W)	41 (91.1)	4 (8.9)	12 (100)	0 (0.0)	29 (87.9)	4 (12.1)
OR (95% CI) ^§	5.529 (1.918–15.935)		-^¶		4.446 (1.495–13.223)
p-value	0.002		-^¶		0.007
CETP rs12149545 (G>A)
GG, n = 61 (M); 132 (W)	129 (66.8)	64 (33.2)	42 (68.9)	19 (31.1)	87 (65.9)	45 (34.1)
GA, n = 31 (M); 66 (W)	69 (71.1)	28 (28.9)	26 (83.9)	5 (16.1)	43 (65.2)	23 (43.8)
AA, n = 3 (M); 6 (W)	8 (88.9)	1 (11.1)	3 (100.0)	0 (0.0)	5 (83.3)	1 (16.7)
OR (95% CI) ^‡	1.317 (0.782–2.219)		2.624 (0.880–7.826)		1.034 (0.563–1.900)
p-value	0.301		0.084		0.913
Triglycerides	<1.70 mmol/L (n = 161)	≥1.70 mmol/L (n = 138)	<1.70 mmol/L (n = 43)	≥1.70 mmol/L (n = 52)	<1.70 mmol/L (n = 118)	≥1.70 mmol/L (n = 86)
CETP rs3764261 (C>A)
CC, n = 40 (M); 86 (W)	53 (42.1)	73 (57.9)	13 (32.5)	27 (67.5)	40 (46.5)	46 (53.5)
CA, n = 43 (M); 97 (W)	87 (62.1)	53 (37.9)	24 (55.8)	19 (44.2)	63 (64.9)	34 (35.1)
AA, n = 12 (M); 21 (W)	21 (63.6)	12 (36.4)	6 (50.0)	6 (50.0)	15 (71.4)	6 (28.6)
OR (95% CI) ^‡	2.289 (1.432–3.657)		2.492 (1.067–5.829)		2.243 (1.268–3.065)
p-value	0.001		0.035		0.005
CETP rs708272 (G>A)
GG, n = 34 (M); 67 (W)	49 (48.5)	52 (51.5)	15 (44.1)	19 (55.9)	34 (50.7)	33 (49.3)
GA, n = 49 (M); 104 (W)	74 (48.4)	79 (51.6)	19 (38.8)	30 (61.2)	55 (52.9)	49 (47.1)
AA, n = 12 (M); 33 (W)	38 (84.4)	7 (15.6)	9 (75.0)	3 (25.0)	29 (87.9)	4 (12.1)
OR (95% CI) ^§	5.782 (2.489–13.431)		4.324 (1.090–17.150)		6.680 (2.251–19.820)
p-value	<0.001		0.037		0.001
CETP rs12149545 (G>A)
GG, n = 61 (M); 132 (W)	101 (52.3)	92 (47.7)	25 (41.0)	36 (59.0)	76 (57.6)	56 (42.4)
GA, n = 31 (M); 66 (W)	53 (54.6)	44 (45.4)	16 (51.6)	15 (48.4)	37 (56.1)	29 (43.9)
AA, n = 3 (M); 6 (W)	7 (77.8)	2 (22.2)	2 (66.7)	1 (33.3)	5 (83.3)	1 (16.7)
OR (95% CI) ^‡	1.188 (0.738–1.914)		1.620 (0.696–3.771)		1.032 (0.576–1.846)
p-value	0.479		0.263		0.917
VLDL-cholesterol	≤0.75 mmol/L (n = 149)	>0.75 mmol/L (n = 150)	≤0.75 mmol/L (n = 37)	>0.75 mmol/L (n = 58)	≤0.75 mmol/L (n = 112)	>0.75 mmol/L (n = 92)
CETP rs3764261 (C>A)
CC, n = 40 (M); 86 (W)	42 (33.3)	84 (66.7)	9 (22.5)	31 (77.5)	33 (38.4)	53 (61.6)
CA, n = 43 (M); 97 (W)	85 (60.7)	55 (39.3)	23 (53.5)	20 (46.5)	62 (63.9)	35 (36.1)
AA, n = 12 (M); 21 (W)	22 (66.7)	11 (33.3)	5 (41.7)	7 (58.3)	17 (81.0)	4 (19.0)
OR (95% CI) ^‡	3.242 (2.004–5.245)		3.572 (1.436–8.884)		3.253 (1.822–5.809)
p-value	<0.001		0.006		<0.001
CETP rs708272 (G>A)
GG, n = 34 (M); 67 (W)	38 (37.6)	63 (62.4)	10 (29.4)	24 (70.6)	28 (41.8)	39 (58.2)
GA, n = 49 (M); 104 (W)	71 (46.4)	82 (53.6)	18 (36.7)	31 (63.3)	53 (51.0)	51 (49.0)
AA, n = 12 (M); 33 (W)	40 (88.9)	5 (11.1)	9 (75.0)	3 (25.0)	31 (93.9)	2 (6.1)
OR (95% CI) ^§	10.642 (4.065–27.859)		5.893 (1.477–23.508)		17.222 (3.995–74.238)
p-value	<0.001		0.012		<0.001
CETP rs12149545 (G>A)
GG, n = 61 (M); 132 (W)	87 (45.1)	106 (54.9)	19 (31.1)	42 (68.9)	68 (51.5)	64 (48.5)
GA, n = 31 (M); 66 (W)	56 (57.7)	41 (42.3)	17 (54.8)	14 (45.2)	39 (59.1)	27 (40.9)
AA, n = 3 (M); 6 (W)	6 (66.7)	3 (33.3)	1 (33.3)	2 (66.7)	5 (83.3)	1 (16.7)
OR (95% CI) ^‡	1.717 (1.063–2.772)		2.487 (1.048–5.903)		1.479 (0.825–2.652)
p-value	0.026		0.039		0.189
LDL subclass	Pattern A (n = 188)	Pattern B (n = 111)	Pattern A (n = 47)	Pattern B (n = 48)	Pattern A (n = 141)	Pattern B (n = 63)
CETP rs3764261 (C>A)
CC, n = 40 (M); 86 (W)	64 (50.8)	62 (49.2)	15 (37.5)	25 (62.5)	49 (57.0)	37 (43.0)
CA, n = 43 (M); 97 (W)	96 (68.6)	44 (31.4)	24 (55.8)	19 (44.2)	72 (74.2)	25 (25.8)
AA, n = 12 (M); 21 (W)	28 (84.8)	5 (15.2)	8 (66.7)	4 (33.3)	20 (95.2)	1 (4.8)
OR (95% CI) ^‡	2.452 (1.515–3.966)		2.319 (1.006–5.343)		2.672 (1.452–4.916)
p-value	<0.001		0.048		0.002
CETP rs708272 (G>A)
GG, n = 34 (M); 67 (W)	55 (54.5)	46 (45.5)	17 (50.0)	17 (50.0)	38 (56.7)	29 (43.3)
GA, n = 49 (M); 104 (W)	94 (61.4)	59 (38.6)	20 (40.8)	29 (59.2)	74 (71.2)	30 (28.8)
AA, n = 12 (M); 33 (W)	39 (86.7)	6 (13.3)	10 (83.3)	2 (16.7)	29 (87.9)	4 (12.1)
OR (95% CI) ^§	4.581 (1.872–11.211)		6.216 (1.282–30.139)		3.819 (1.282–11.381)
p-value	<0.001		0.023		0.016
CETP rs12149545 (G>A)
GG, n = 61 (M); 132 (W)	115 (59.6)	78 (40.4)	27 (44.3)	34 (55.7)	88 (66.7)	44 (33.3)
GA, n = 31 (M); 66 (W)	66 (68.0)	31 (32.0)	18 (58.1)	13 (41.9)	48 (72.7)	18 (27.3)
AA, n = 3 (M); 6 (W)	7 (77.8)	2 (22.2)	2 (66.7)	1 (33.0)	5 (83.3)	1 (16.7)
OR (95% CI) ^‡	1.500 (0.909–2.478)		1.799 (0.769–4.207)		1.395 (0.738–2.637)
p-value	0.113		0.176		0.306

Notes: ^†Classified as HDL-cholesterol ≥ 1.04 mmol/L and <1.04 mmol/L for men and ≥1.30 mmol/L and <1.30 mmol/L for women;³⁸ triglycerides <1.70 mmol/L and ≥1.70 mmol/L;³⁸ VLDL-cholesterol <0.75 mmol/L and ≥0.75 mmol/L (median concentration); LDL subclass Pattern A: mean LDL particle size >26.50 nm; Pattern B: mean LDL particle size ≤26.50 nm.³⁶ ‡Odds ratio (95% confidence interval): Recessive genetic model for CETP rs3764261: CC vs AA+CA and CETP rs12149545: GG vs AA+GA. ^§Odds ratio (95% confidence interval): Dominant genetic model for CETP rs708272: GG+GA vs AA. ^¶The odds ratio and the p-value are not calculated because the number of hypo HDL-cholesterolemia in AA genotype group is zero.

Table 5 Logistic Regression Analysis Between CETP Genetic Variants, Potential Confounders and Atherogenic Dyslipidemia Complex^†

Dependent Variable	Independent Variables	Logistic Regression^‡
		All		Men		Women
		OR (95% CI)	p-value	OR (95% CI)	p-value	OR (95% CI)	p-value
Model 1^§	rs3764261	2.11 (1.27–3.50)	0.004	2.23 (0.97–5.14)	0.061	2.54 (1.26–5.11)	0.009
	rs708272	2.12 (1.29–3.49)	0.003	1.64 (0.68–3.92)	0.271	2.37 (1.24–4.53)	0.009
	HOMA-IR	1.47 (1.27–1.71)	<0.001	1.32 (1.06–1.64)	0.013	1.57 (1.27–1.92)	<0.001
	Constant	0.003	<0.001	0.019	0.001	0.000	<0.001
Model 2^¶	rs3764261 and rs708272	2.99 (1.78–5.02)	<0.001	2.90 (1.16–7.25)	0.023	3.40 (1.72–6.71)	<0.001
	HOMA-IR	1.45 (1.25–1.67)	<0.001	1.31 (1.06–1.62)	0.014	1.55 (1.26–1.90)	<0.001
	Constant	0.008	<0.001	0.010	<0.001	0.001	0.001

Notes: ^†Atherogenic dyslipidemia complex; all features of reduced HDL-C, elevated triglycerides and LDL subclass pattern B. ^‡Data are from logistic regression with backward Wald method, adjusted age, BMI, systolic and diastolic blood pressure, HOMA-IR and statin dosage; OR (95% CI): odds ratio (95% confidential interval). ^§Variables entered in method: rs3764261, rs708272, and rs12149545. ^¶Variables entered in method: combination of variants at rs3764261 and rs708272. The detail of the combination groups is shown in supplementary Table 1.

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