Polymorphisms of SLCO1B1 rs4149056 and SLC22A1 rs2282143 are associated with responsiveness to acitretin in psoriasis patients

Abstract

Acitretin is widely used to treat psoriasis, but the efficacy varies significantly among individuals. To explore the association between polymorphisms and acitretin efficacy, we enrolled 46 and 105 Chinese Han psoriasis vulgaris patients for discovery and validation phases, respectively. The patients were treated with acitretin (30 mg/day) and calcipotriol ointment for at least 8 weeks, and their genotypes were detected. The wild-type genes and variants were transfected into HEK293 cells, which were then incubated with acitretin. The cellular acitretin concentration was measured by liquid chromatography-mass spectrometry. We found that the polymorphisms rs4149056 in the SLCO1B1 gene and rs2282143 in the SLC22A1 gene were associated with efficacy, both in the discovery (P = 0.013 and P = 0.002) and validation phases (P = 0.028 and P = 0.014), based on a 50% reduction from before to after treatment of the psoriasis area severity index (PASI50). When the PASI75 was used as an efficacy cutoff, a similar conclusion was drawn. The uptake of acitretin was lower with the rs4149056C (P = 0.002) and rs2282143T alleles (P = 0.038) than the wild-type alleles. Our results imply that the rs4149056C and rs2282143T variants decrease the acitretin uptake, and significantly associated with clinical effective responsiveness.

Figure 1

Expression of SLCO1B1 and SLC22A1 in HEK293 cells with or without transfection. Legend: (A,B) mRNA and protein of SLCO1B1 expressed in HEK293 cells transfected with different alleles of SLCO1B1 rs4149056T/C; (B,C,D) mRNA and protein of SLC22A1 expressed in HEK293 cells transfected with different alleles of SLC22A1 rs2282143C/T. GAPDH was used as the internal control.

Figure 2

Cellular levels of acitretin with different SLCO1B1 rs4149056 alleles. Legend: (A) Uptake of acitretin was significantly higher in HEK293-SLCO1B1 cells than in HEK293-MOCK cells. (B) Uptake mediated by SLCO1B1 521 C allele was less than that in the wild-type 521 T cells. (C,D) Uptake of acitretin mediated by SLCO1B1 was inhibited by rifampicin. SLCO1B1 521 T is the wild-type allele, and 521 C is the variant.

Figure 3

Uptake of [¹⁴C]-metformin in HEK293-SLC22A1 cells expressing different alleles. Legend: Uptake of [³²S]-metformin by the SLC22A1 1022 C/T alleles. With 5 or 10 μM [¹⁴C]-metformin incubation, there was no significant difference in uptake between the two alleles. As the concentration increased, the uptake by SLC22A1 1022 T was less than that by the wild-type 1022 C allele. SLC22A1 1022 C is the wild-type allele, and 1022 T is the variant for this polymorphism.

Figure 4

Cellular levels of acitretin with different SLC22A1 rs2282143 alleles. Legend: (A) Uptake of acitretin was significantly higher in HEK293-SLC22A1 cells than in HEK293-MOCK cells. (B) Uptake of acitretin mediated by SLC22A1 1022 T was less than that by wild-type 1022 C.