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SCIENCE CHINA Life Sciences, Volume 62, Issue 4: 535-543(2019) https://doi.org/10.1007/s11427-018-9489-x

Testing the role of genetic variation of the MC4R gene in Chinese population in antipsychotic-induced metabolic disturbance

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  • ReceivedOct 5, 2018
  • AcceptedNov 15, 2018
  • PublishedMar 26, 2019

Abstract

Antipsychotic-induced metabolic disturbance (AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor (MC4R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4R in Chinese population by genotyping two SNPs (rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index (BMI), waist circumference (WC), glucose, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status (drug-naïve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-naïve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.


Funded by

the National Natural Science Foundation of China Key Project(91332205,81130024,81630030,to,T.L.)

National Key Technology R&D Program of the Ministry of Science and Technology of China(2016YFC0904300,to,T.L.)

National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme(8141101084,to,T.L.)

National Natural Science Foundation of China(8157051859,to,W.D.,et,al.)

Sichuan Science & Technology Department(2015JY0173,to,Q.W.)

and 1.3.5 Project for disciplines of excellence

West China Hospital of Sichuan University(ZY2016103,ZY2016203,to,T.L.)

commercial or not-for-profit sectors.


Acknowledgment

This work was supported by the National Natural Science Foundation of China Key Project (91332205, 81130024, 81630030 to T.L.), National Key Technology R&D Program of the Ministry of Science and Technology of China (2016YFC0904300 to T.L.), National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme (8141101084 to T.L.), National Natural Science Foundation of China (8157051859 to W.D. et al.), Sichuan Science & Technology Department (2015JY0173 to Q.W.), and 1.3.5 Project for disciplines of excellence, West China Hospital of Sichuan University (ZY2016103, ZY2016203 to T.L.). This research received no specific grant from any funding agency, commercial or not-for-profit sectors.


Interest statement

The author(s) declare that they have no conflict of interest. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.


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  • Figure 1

    Distribution of weight gain in drug-naïve subjects following 6-week antipsychotic treatment among genotype of rs489693.

  • Table 1   Clinical and demographic characteristics of patients

    All patients (n=1,991)

    Drug-naïve patients

    (n=567)

    Medicated patients (n=1,424)

    Statistics (P-value)

    Sex

    χ2=0.25 (0.62)

    male (%)

    999 (50.18)

    279 (49.21)

    720 (50.56)

     

    female (%)

    992 (49.82)

    288 (50.79)

    704 (49.44)

     

    Age

    31.95±7.93

    29.23±7.74

    33.03±7.74

    t=9.88 (<0.001)

    DOI (month)

    79.00±71.33

    31.12±43.29

    98.07±71.36

    F=579.16 (<0.001)

    PANSS score

    90.32±15.34

    89.39±15.62

    90.69±15.22

    F=2.93 (0.09)

    BMI

    22.20±3.57

    21.31±3.17

    22.55±3.65

    F=51.04 (<0.001)

    WC

    79.69±10.53

    77.18±9.63

    80.69±10.71

    F=48.67 (<0.001)

    Glucose

    4.88±0.79

    4.76±0.73

    4.93±0.81

    F=19.40 (<0.001)

    Triglyceride

    1.24±0.74

    1.17±0.69

    1.27±0.76

    F=8.48 (0.004)

    HDL

    1.32±0.36

    1.36±0.36

    1.30±0.36

    F=8.84 (0.003)

    LDL

    2.34±0.81

    2.23±0.74

    2.37±0.83

    F=11.65 (<0.001)

    Treatment

    χ2=3.59 (0.73)

    Ziprasidone

    330 (16.57)

    91 (16.05)

    239 (16.78)

     

    Aripiprazole

    313 (15.72)

    82 (14.46)

    231 (16.22)

     

    Olanzapine

    341 (17.13)

    108 (19.05)

    233 (16.36)

     

    Quetiapine

    332 (16.68)

    92 (16.23)

    240 (16.85)

     

    Risperidone

    344 (17.28)

    103 (18.17)

    241 (16.92)

     

    Haloperidol

    166 (8.34)

    48 (8.47)

    118 (8.29)

     

    Perphenazine

    165 (8.29)

    43 (7.58)

    122 (8.57)

     

    Except for age and sex, adjusted for age, sex, and research center for other variables.

  • Table 2   Association of BMI and SNPs in with additive model

    rs489693

    rs17782313

    Drug-naïvepatients (n=567)

    CC

    (n=364)

    CA

    (n=186)

    AA

    (n=17)

    P-value

    TT

    (n=354)

    TC

    (n=199)

    CC

    (n=14)

    P-value

    Baseline BMI

    21.24±3.08

    21.48±3.40

    21.12±2.43

    0.65

    21.29±3.12

    21.32±3.28

    21.86±2.99

    0.79

    BMI gain (%)

    3.31±6.28

    3.26±6.46

    5.31±5.13

    0.40

    3.33±6.24

    3.36±6.44

    4.07±6.39

    0.91

    BMI gain >7%

    60 (20.00)*

    30 (18.18)

    7 (43.75)

    AA (ref)

    58 (19.66)

    35 (20.23)

    4 (30.77)

    CC (ref)

    CA (0.01)

    TC (0.40)

    CC (0.03)

    TT (0.46)

    Medicatedpatients (n=1,424)

    CC

    (n=932)

    CA

    (n=426)

    AA

    (n=66)

    P-value

    TT

    (n=913)

    TC

    (n=444)

    CC

    (n=67)

    P-value

    Baseline BMI

    22.39±3.63

    22.95±3.75

    22.22±3.20

    0.02

    22.38±3.66

    22.84±3.63

    22.99±3.68

    0.04

    BMI gain (%)

    1.91±4.96

    2.06±5.19

    1.46±5.66

    0.63

    1.95±5.13

    1.88±4.82

    2.13±5.75

    0.92

    BMI gain >7%

    104 (13.11)

    47 (11.78)

    8 (13.11)

    AA (ref)

    104 (13.11)

    47 (11.24)

    8 (12.90)

    CC (ref)

    CA (0.95)

    TC (0.62)

    CC (0.98)

    TT (0.96)

    N (%) was displayed for BMI gain >7%, mean±SD was listed for other variables; adjusted for age, sex, research center, DOI, and treatment for baseline BMI; additionally adjusted for baseline BMI for other variables; ANCOVA was performed for baseline BMI, and BMI gain (% of baseline); logistic regression was performed for BMI gain >7%. *, the total number for this percentage is the number of patients who finished follow-up, which is smaller than 364. This is true for all percentages for the variable “BMI gain >7%” .

  • Table 3   Association of all metabolic measures and rs489693 with recessive model

    Genotype

    Overall (n=1,991)

    Drug-naïve patients (n=567)

    Medicated patients (n=1,424)

    BMI change (%)

    AA

    2.26±5.74

    5.31±5.13

    1.46±5.66

    CA/CC

    2.32±5.45

    3.30±6.33

    1.96±5.03

    Cohen’s F (P-value)

    0.00 (0.92)

    0.06 (0.19)

    0.02 (0.44)

    BMI gain >7%

    AA

    15 (19.48)

    7 (43.75)

    8 (13.11)

    CA/CC

    141 (14.05)

    90 (19.35)

    151 (12.08)

    OR (P-value)

    1.57 (0.16)

    3.80 (0.03)

    1.00 (0.99)

    WC change (%)

    AA

    2.42±5.49

    5.21±8.35

    1.69±4.25

    CA/CC

    1.86±4.87

    2.26±5.14

    1.71±4.76

    Cohen’s F (P-value)

    0.02 (0.30)

    0.11 (0.02)

    0.00 (0.97)

    Glucose change (%)

    AA

    –2.37±15.10

    –4.74±9.13

    –1.80±16.21

    CA/CC

    0.99±17.90

    2.85±18.13

    0.31±17.77

    Cohen’s F (P-value)

    0.04 (0.11)

    0.08 (0.11)

    0.03 (0.37)

    Triglyceride change (%)

    AA

    66.23±105.31

    113.02±143.00

    55.13±92.36

    CA/CC

    49.48±92.75

    56.51±90.27

    46.94±93.53

    Cohen’s F (P-value)

    0.04 (0.12)

    0.12 (0.02)

    0.02 (0.50)

    HDL change (%)

    AA

    –2.16±39.16

    –1.96±50.99

    –2.20±36.56

    CA/CC

    4.35±28.89

    4.02±27.66

    4.46±29.32

    Cohen’s F (P-value)

    0.05 (0.07)

    0.04 (0.45)

    0.05 (0.09)

    LDL change (%)

    AA

    12.80±51.89

    6.68±56.91

    14.15±51.14

    CA/CC

    8.99±36.45

    11.64±35.35

    8.07±36.80

    Cohen’s F (P-value)

    0.02 (0.38)

    0.03 (0.62)

    0.04 (0.21)

  • Table 4   Association of other metabolic measures and SNPs in with additive model

    Genotype

    Overall (n=1,991)

    Drug-naïve patients (n=567)

    Medicated patients (n=1,424)

    rs489693

    WC change (%)

    AA

    2.42±5.49

    5.21±8.35

    1.69±4.25

    CA

    1.48±3.85

    1.96±4.25

    1.28±3.66

    CC

    2.05±5.29

    2.43±5.57

    1.91±5.18

    Cohen’s F (P-value)

    0.06 (0.03)

    0.12 (0.04)

    0.06 (0.07)

    Glucose change (%)

    AA

    –2.37±15.1

    –4.74±9.13

    –1.80±16.21

    CA

    0.47±17.71

    3.25±15.13

    –0.62±18.53

    CC

    1.24±17.99

    2.64±19.57

    0.75±17.40

    Cohen’s F (P-value)

    0.06 (0.08)

    0.11 (0.12)

    0.06 (0.16)

    Triglyceride change (%)

    AA

    66.23±105.31

    113.02±143

    55.13±92.36

    CA

    45.69±84.02

    47.07±81.66

    45.14±85.03

    CC

    51.35±96.75

    61.63±94.36

    47.80±97.37

    Cohen’s F (P-value)

    0.05 (0.12)

    0.15 (0.01)

    0.03 (0.68)

    HDL change (%)

    AA

    –2.16±39.16

    –1.96±50.99

    –2.20±36.56

    CA

    5.56±29.64

    5.03±27.61

    5.77±30.41

    CC

    3.74±28.50

    3.46±27.73

    3.83±28.78

    Cohen’s F (P-value)

    0.06 (0.04)

    0.06 (0.54)

    0.07 (0.08)

    LDL change (%)

    AA

    12.80±51.89

    6.68±56.91

    14.15±51.14

    CA

    8.73±35.19

    12.38±37.35

    7.33±34.28

    CC

    9.13±37.08

    11.24±34.27

    8.42±37.97

    Cohen’s F (P-value)

    0.03 (0.59)

    0.04 (0.80)

    0.05 (0.32)

    rs17782313

    WC change (%)

    CC

    2.05±6.06

    4.95±9.39

    1.45±5.02

    TC

    1.52±3.86

    2.00±4.53

    1.32±3.54

    TT

    2.07±5.27

    2.46±5.45

    1.92±5.21

    Cohen’s F (P-value)

    0.06 (0.07)

    0.10 (0.10)

    0.06 (0.08)

    Glucose change (%)

    CC

    –3.26±13.16

    –0.77±12.79

    –3.72±13.28

    TC

    1.19±18.68

    4.3±17.37

    –0.05±19.05

    TT

    0.94±17.57

    1.77±18.44

    0.64±17.26

    Cohen’s F (P-value)

    0.06 (0.04)

    0.10 (0.14)

    0.07 (0.06)

    Triglyceride change (%)

    CC

    60.35±110.67

    96.06±175.36

    53.8±95.07

    TC

    47.67±83.65

    50.39±79.84

    46.59±85.19

    TT

    50.88±96.92

    61.43±94.96

    47.22±97.39

    Cohen’s F (P-value)

    0.03 (0.45)

    0.10 (0.14)

    0.02 (0.82)

    HDL change (%)

    CC

    0.10±36.78

    18.74±60.76

    –3.24±30.8

    TC

    4.73±29.65

    4.09±26.43

    4.98±30.83

    TT

    3.98±28.76

    3.04±27.96

    4.30±29.04

    Cohen’s F (P-value)

    0.04 (0.31)

    0.11 (0.11)

    0.07 (0.07)

    LDL change (%)

    CC

    14.05±52.83

    –6.67±38.01

    17.50±54.40

    TC

    8.28±35.56

    13.21±38.41

    6.39±34.26

    TT

    9.29±36.87

    11.21±34.63

    8.65±37.59

    Cohen’s F (P-value)

    0.04 (0.35)

    0.11 (0.13)

    0.08 (0.04)

    Adjusted for age, sex, research center, treatment, DOI, and baseline value.

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