Associations of ABCB1 and IL-10 genetic polymorphisms with sirolimus-induced dyslipidemia in renal transplant recipients.
BACKGROUND
Hyperlipidemia is a common adverse effect of sirolimus (SRL). We previously showed significant associations of ABCB1 3435C>T and IL-10 -1082G>A with log-transformed SRL dose-adjusted weighted-normalized trough. We further examined to see whether these polymorphisms were also associated with SRL-induced dyslipidemia.


METHODS
Genotyping was performed for ABCB1 1236C>T, 2677 G>T/A, and 3435C>T; CYP3A4 -392A>G; CYP3A5 6986A>G and 14690G>A; IL-10 -1082G>A; TNF -308G>A; and ApoE ε2, ε3, and ε4 alleles. The longitudinal changes of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels after SRL treatment before statin therapy were analyzed by a linear mixed-effects model, with adjustments for selected covariates for each lipid.


RESULTS
Under the dominant genetic model, ABCB1 3435C>T was associated with TC (P=0.0001) and LDL-C (P<0.0001) values after SRL administration. Mean TC and LDL-C levels were 26.9 and 24.9 mg/dL higher, respectively, in ABCB1 3435T carriers than 3435CC homozygotes at an average SRL trough concentration of 4 ng/mL without concomitant medication. ABCB1 1236C>T under the recessive model and IL-10 -1082G>A under the dominant model were associated with log-transformed TG values (P=0.0051 and 0.0436, respectively). Mean TG value was 25.1% higher in ABCB1 1236TT homozygotes compared with ABCB1 1236C carriers and was 12.4% higher in IL-10 -1082AA homozygotes than -1082G carriers.


CONCLUSIONS
ABCB1 polymorphisms were found to be associated with lipid responses to SRL treatment, confirming the role of ABCB1 gene in SRL pharmacokinetics and pharmacodynamics. Further studies are necessary to define the role of ABCB1 and IL-10 polymorphisms on SRL-induced dyslipidemia in renal transplantation.
Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD 20892, USA.
Wai-Johnn
WJ
Sam
Christine E
CE
Chamberlain
Su-Jun
SJ
Lee
Joyce A
JA
Goldstein
Douglas A
DA
Hale
Roslyn B
RB
Mannon
Allan D
AD
Kirk
Yuen Yi
YY
Hon
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016753:Interleukin-10 / Q000235:genetics*; D016030:Kidney Transplantation / Q000276:immunology*; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008078:Cholesterol, LDL; D007166:Immunosuppressive Agents; D014280:Triglycerides; D016753:Interleukin-10; D020123:Sirolimus