Association between polymorphisms of LEP, LEPR, DRD2, HTR2A and HTR2C genes and risperidone- or clozapine-induced hyperglycemia

Figures & data

Table 1 Clinical characteristics of patients treated with risperidone or clozapine

	All (n=180)	Risperidone (n=130)	Clozapine (n=50)	p-value
Clinical parameter^a
Males, n (%)	86 (47.8)	61 (46.9)	25 (50)	0.741
Age, years	42.1 (18–77)	41.0 (18–77)	44.6 (26–68)	0.073
Diagnosis, n (%)				0.016
Schizophrenia	154 (85.5)	106 (81.5)	48 (96.0)
Other diagnosis	26 (14.5)	24 (18.5)	2 (4.0)
Dose equivalent to olanzapine^b	8.17 (0.82–25.00)	10.00 (1.25–25.00)	6.54 (0.82–13.07)	0.001
Duration of treatment, months	38.2 (1.2–227.0)	24.6 (1.2–160.7)	81.5 (3.7–227.0)	<0.001
Weight at antipsychotic initiation, kg	58.4 (32.0–118.0)	57.9 (32.0–118.0)	59.0 (37.4–95.0)	0.433
Weight at study visit, kg	62.0 (38.0–136.9)	63.0 (38.0–136.9)	60.3 (45.0–122.0)	0.670
Waist circumference, cm	87.0 (64–131)	88.5 (64–131)	87.0 (66–129)	0.767
Hip circumference, cm	96.0 (71–135)	97.0 (71–135)	94.5 (71–128)	0.094
Waist/hip ratio	0.90 (0.75–1.13)	0.89 (0.76–1.13)	0.92 (0.75–1.10)	0.028
Body mass index, kg/m^2	24.9 (17.2–48.0)	25.1 (17.2–45.4)	24.2 (18.0–48.0)	0.340
Current smoker, n (%)	47 (26.1)	32 (24.6)	15 (30.0)	0.570
Alcohol consumption, n (%)	7 (3.9)	4 (3.1)	3 (6.0)	0.399
Biomarker measures^c
Fasting glucose, mmol/L	5.67 (0.11)	5.50 (0.12)	6.12 (0.27)	0.014
Insulin, μIU/mL	7.237 (0.694)	6.993 (0.773)	7.870 (1.494)	0.573
HOMA-IR	2.078 (0.302)	1.977 (0.382)	2.340 (0.447)	0.592
hsCRP, mg/L	3.166 (0.431)	3.392 (0.569)	2.677 (0.588)	0.443
Leptin, ng/mL	12.86 (0.89)	13.29 (1.05)	11.73 (1.68)	0.433
Adiponectin, µg/mL	23.19 (1.33)	22.67 (1.44)	24.57 (3.00)	0.523
Prolactin, ng/mL	46.7 (3.4)	60.1 (4.1)	12.0 (1.5)	<0.001
Triglycerides, mmol/L	1.58 (0.10)	1.54 (0.11)	1.69 (0.21)	0.490
Total cholesterol, mmol/L	5.37 (0.09)	5.39 (0.10)	5.31 (0.19)	0.703
HDL-C, mmol/L	1.47 (0.03)	1.49 (0.04)	1.41 (0.06)	0.279
LDL-C, mmol/L	3.37 (0.08)	3.39 (0.09)	3.31 (0.15)	0.654
Small-dense LDL, mmol/L	0.33 (0.03)	0.34 (0.04)	0.33 (0.08)	0.920
Mean LDL particle size, nm	26.66 (0.46)	26.66 (0.52)	26.66 (0.94)	0.999

Notes: ^aData except for number (%) are the median (minimum-maximum). ^bThe doses equivalent to olanzapine are estimated according to the publication by Leucht et al³³ risperidone 0.4 mg/d or clozapine 30.6 mg/d is equal to olanzapine 1 mg/d. ^cData are given as mean (standard error of mean). All biochemical markers are expressed in Système international units; conversions to conventional units are as follows: fasting glucose (mg/dL), multiply by 18.02; triglycerides (mg/dL), multiply by 88.5; cholesterol (mg/dL), multiply by 38.6.

Abbreviations: HOMAIR, homeostasis Model Assessment of Insulin Resistance; hsCRP, high sensitivity C-reactive protein; HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoprotein–cholesterol; LDL, low density lipoprotein.

Figure 1 The prevalence of metabolic abnormality in patients receiving risperidone or clozapine. Metabolic syndrome and its major components are defined using the NCEP ATP III criteria modified for Asian population.²⁷ *p-value<0.05.

Table 2 Genotype frequency of LEP, LEPR, DRD2, HTR2A, and HTR2C polymorphisms among patients with and without impaired fasting glucose

	Risperidone				Clozapine
	NFG^a (n=90)	IFG^b (n=40)	p-value^c	OR (95% CI)^d	NFG^a (n=18)	IFG^b (n=32)	p-value^c	OR (95% CI)^d
LEP rs7799039 (G>A)
GG	9 (100.0)	0 (0.0)	0.008	3.28 (1.44–7.50)	2 (40.0)	3 (60.0)	0.913	0.78 (0.24–2.48)
AG	38 (79.2)	10 (20.8)			7 (31.8)	15 (68.2)
AA	43 (58.9)	30 (41.1)			9 (39.1)	14 (60.9)
LEPR rs1137101 (A>G)
AA	4 (100.0)	0 (0.0)	0.427	1.92 (0.84–4.36)	0 (0.0)	1 (100.0)	>0.999	0.73 (0.19–2.82)
AG	25 (71.4)	10 (28.6)			4 (33.3)	8 (66.7)
GG	61 (67.0)	30 (33.0)			14 (37.8)	23 (62.2)
DRD2 rs4436578 (T>C)
TT	45 (72.6)	17 (27.4)	0.116	1.35 (0.64–2.87)	8 (44.4)	10 (55.6)	0.220	1.76 (0.53–5.80)
CT	37 (72.5)	14 (27.5)			7 (25.9)	20 (74.1)
CC	8 (47.1)	9 (52.9)			3 (60.0)	2 (40.0)
HTR2A rs6313 (T>C)
TT	36 (67.9)	17 (32.1)	0.964	0.90 (0.42–1.92)	9 (37.5)	15 (62.5)	>0.999	1.13 (0.36–3.60)
CT	43 (69.4)	19 (30.6)			7 (33.3)	14 (66.7)
CC	11 (73.3)	4 (26.7)			2 (40.0)	3 (60.0)
HTR2C rs518147 (G>C)
GG	70 (70.0)	30 (30.0)	0.269	1.17 (0.49–2.79)	13 (39.4)	20 (60.6)	0.565	1.56 (0.45–5.47)
CG	14 (77.8)	4 (22.2)			4 (40.0)	6 (60.0)
CC	6 (50.0)	6 (50.0)			1 (14.3)	6 (85.7)
HTR2C rs12836771 (A>G)
AA	73 (70.9)	30 (29.1)	0.332	1.43 (0.59–3.48)	14 (37.8)	23 (62.2)	0.889	1.37 (0.35–5.30)
AG	11 (73.3)	4 (26.7)			3 (37.5)	5 (62.5)
GG	6 (50.0)	6 (50.0)			1 (20.0)	4 (80.0)

Notes: ^aNFG: normal fasting plasma glucose. ^bIFG: increased fasting plasma glucose. ^cχ² test (Pearson chi-square or Fisher’s exact) for the genotype frequencies between NFG and IFG groups ^dOdds ratio (95% confidence interval): Recessive genetic model; LEP rs7799039: AA vs AG + GG; LEPR rs1137101: GG vs AG + GG. Dominant genetic model; DRD2 rs4436578: CC + CT vs TT; HTR2A rs6313: CC + CT vs TT; HTR2C rs518147: CC + CG vs.GG; HTR2C rs12836771: GG + AG vs AA.

Table 3 Logistic regression analysis between the pharmacodynamic genetic and clinical risk factors with impaired fasting glucose

Dependent Variables	Independent Variables	Logistic Regression^a
		Risperidone		Clozapine
		Odds Ratio (95% CI)	p-value	Odds Ratio (95% CI)	p-value
Model 1^b	LEP rs7799039	4.168 (1.584–10.966)	0.004	4.832 (0.638–36.615)	0.127
	LEPR rs1137101	1.083 (0.409–2.869)	0.872	0.833 (0.065–10.732)	0.888
	DRD2 rs4436578	1.618 (0.834–3.139)	0.155	28.618 (1.530–535.40)	0.025
	HTR2A rs6313	0.621 (0.286–1.347)	0.228	0.120 (0.015–0.963)	0.046
	HTR2C rs518147	0.523 (0.118–2.326)	0.395	12.012 (0.891–162.0)	0.061
	HTR2C rs12836771	1.736 (0.388–7.757)	0.470	0.123 (0.008–1.966)	0.138
	Sex	2.781 (0.939–8.237)	0.065	3.263 (0.260–40.953)	0.360
	Age	1.032 (0.989–1.077)	0.144	1.149 (0.996–1.327)	0.057
	BMI	0.951 (0.867–1.042)	0.281	2.169 (1.190–3.953)	0.012
	Smoking	0.412 (0.125–1.361)	0.146	0.016 (0.000–0.877)	0.043
	Duration of treatment	1.012 (0.994–1.029)	0.187	0.982 (0.954–1.011)	0.217
	Constant	-	0.038	-	0.021
Model 2^c	LEP: rs7799039	3.188 (1.399–7.262)	0.006	-	-
	BMI	-	-	1.623 (1.170–2.252)	0.004
	Smoking	-	-	0.052 (0.004–0.656)	0.002
	Constant	-	0.001	-	0.082

Notes: ^aLogistic Regression parameters; Odds ratio (95% CI): odds ratio (95% confidential interval). ^bData are from logistic regression analyses: enter method; adjusted for sex, age, BMI, smoking status and duration of treatment. ^cData are from logistic regression analyses: backward likelihood ratio method; adjusted for sex, age, BMI, smoking status and duration of treatment.

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