First genome-wide association study on rocuronium dose requirements shows association with SLCO1A2

Abstract

Background: Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10e25%) and bile (>70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation. Methods: One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50e100 mg kg À1 min À1 ) and remifentanil (0.05e0.25 mg kg À1 min À1 ). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0e10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further. Results: The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P<0.001) with the rocuronium dose in a linear regression model. The GWAS highlighted one genome-wide significant locus in chromosome 12. The single-nucleotide polymorphisms (SNPs) with the most significant evidence of association were located in or near SLCO1A2. The two top SNPs, rs7967354 (P¼5.3e À11 ) and rs11045995 (P¼1.4e À10 ), and the clinical variables accounted for 41% of the variability in rocuronium dosage. Conclusions: Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.

Risk factors for administration of additional reversal following neuromuscular blockade with rocuronium in children: A retrospective case–control study

“…20,21 Single-nucleotide polymorphisms in the organic anion transporting polypeptide (OATP) family have also been identified as a potential source of variability in rocuronium dose requirements, as rocuronium is a known substrate of OATP1A2 and allelic frequency appears to vary by race. [22][23][24] Interestingly, TOF monitoring was also found to be associated with the need for additional reversal. We felt, however, this is likely related to a selection bias because clinicians who are concerned that, either they may have given too much relaxant or have not had adequate time for the relaxant to wear off, may be more likely to apply a qualitative TOF monitor to attempt to assess depth of neuromuscular blockade and further reassure themselves that the patient is in a good position to be reversed with neostigmine.…”

Polymorphisms contribute to differences in the effect of rocuronium in Chinese patients

“…Importantly, variants of SLCO1B1 were well demonstrated associated with reduced transport activity of OATP1B1, and variants of SLCO1A2 decreased transport activity towards the OATP1A2 substrate 28,29 . Moreover, rocuronium is a substrate for organic anion transporters (OATPs) 2,29 . Recently, a genome‐wide association study comprising 918 women undergoing surgery for breast cancer suggested that SLCO1A2 variation may alter uptake of rocuronium by OATP1A2 and was estimated to account for 4% of the variability in rocuronium dose 2 .…”

“…2,29 Recently, a genome-wide association study comprising 918 women undergoing surgery for breast cancer suggested that SLCO1A2 variation may alter uptake of rocuronium by OATP1A2 and was estimated to account for 4% of the variability in rocuronium dose. 2 Additionally, our results and those of Mei 8 indicate that OATP1B1 variants affect the clinical action of rocuronium. However, Costa and colleagues suggested that patients genotyped as -A or AA for SLCO1A2-189_-188InsA showed a reduction of total clearance of rocuronium compared to patients genotyped as -/-(151.6 vs. 207.1 ml/min).…”

“…Rocuronium is widely utilized in general clinical anaesthesia for rapid sequence induction by providing skeletal muscle relaxation 1 . However, numerous clinical studies have demonstrated that age, sex and liver and kidney function may affect its pharmacological actions and result in individual variance in the effect and clearance of rocuronium 2–5 . Inappropriate muscle relaxation will affect surgical vision and may result in prolonged extubation and recovery times.…”

“…1 However, numerous clinical studies have demonstrated that age, sex and liver and kidney function may affect its pharmacological actions and result in individual variance in the effect and clearance of rocuronium. [2][3][4][5] Inappropriate muscle relaxation will affect surgical vision and may result in prolonged extubation and recovery times. Therefore, individualized muscle relaxation management is particularly important.…”