Associations of polymorphisms of cytochrome P450 enzymes (CYP2D6 and CYP2C9) with early-onset severe pre-eclampsia and labetalol therapy

Abstract

Objective To explore the associations of the genetic polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with early-onset severe pre-eclampsia and the efficacy of labetalol therapy. Methods Totally 105 gravidas diagnosed with early-onset severe pre-eclampsia (experimental group) and 103 healthy gravidas (control group) were recruited from Beijing Obstetrics and Gynecology Hospital between August 2013 and July 2016. Labetalol was given to control blood pressures in gravidas with early-onset severe pre-eclampsia. If labetalol administration alone did not exceed the mean dose (100 mg, one dose per eight hours) and effectively controlled the blood pressures, it would be considered to be valid (n=75), otherwise it would be viewed as an invalid treatment. Genotype and allele frequencies of CYP2C9 gene (rs1057910 and rs4918758) and CYP2D6 gene (rs1065852, rs28371725, rs35742686 and rs3892097) in the gravidas were analyzed by TaqMan probe polymerase chain reaction. Differences in the genotype and allele frequencies were compared between the experimental and control groups, and the valid and invalid labetalol treatment groups. Chi-square test, analysis of variance and LSD test were used as statistical methods. Results The gravidas in both experimental and control groups were AA genotype in CYP2C9 gene rs1057910, TT genotype in CYP2D6 gene rs35742686 and CC genotype in CYP2D6 gene rs3892097. Frequencies of CC and CT genotypes in CYP2D6 gene rs28371725 in the experimental group were higher than those in the control group [18.1% (19/105) vs 14.6% (15/103); 56.2% (59/105) vs 42.7% (44/103); χ2=6.707], and higher C allele frequency in CYP2D6 gene rs28371725 was also observed in the experimental group [46.2% (97/210) vs 35.9% (74/206), χ2=4.529] (all P 0.05). Compared with the gravidas with CT or TT genotype of CYP2D6 gene rs28371725, those with CC genotype had longer gestational age [(32.5±2.1) vs (29.5±1.8) and (29.8±2.2) weeks] and higher plasma albumin [(27.2±9.3) vs (20.3±10.4) and (22.5±7.4) g/L], but lower systolic pressure and 24 hours urine protein (LSD test, all P<0.05). The G allele frequency in CYP2D6 gene rs1065852 in invalid labetalol treatment group was higher than that in valid labetalol treatment group [93.3% (56/60) vs 76.0% (114/150), χ2=8.351, P=0.004]. Conclusions The polymorphism of CYP2D6 gene rs28371725 may be associated with early-onset severe pre-eclampsia, and the allele of G in CYP2D6 gene rs1065852 may be associated with the efficacy of labetalol in treatment of early-onset severe pre-eclampsia. Key words: Pre-eclampsia; Labetalol; CYP2D6; CYP2C9; Polymorphism, single nucleotide