Impact of Genetic Polymorphisms on 6-Thioguanine Nucleotide Levels and Toxicity in Pediatric Patients with IBD Treated with Azathioprine.
BACKGROUND
Thiopurine-related toxicity results in discontinuation of therapy in up to 30% of patients with inflammatory bowel disease. Although thiopurine S-methyltransferase (TPMT) is implicated in toxicity, not all toxicity can be attributed to TPMT polymorphisms. We investigated the effects of polymorphisms of genes involved in thiopurine and folate metabolism pathways on 6-thioguanine nucleotide levels and toxicity.


METHODS
Retrospective clinical data and blood samples were collected from 132 pediatric patients with inflammatory bowel disease treated with azathioprine. Eighty-seven genetic polymorphisms of 30 genes were screened using the MassARRAY system, and 70 polymorphisms of 28 genes were selected for further analysis.


RESULTS
TPMT genotype (P < 0.001), concurrent use of mesalazine (P = 0.006), ABCC5 (rs2293001) (P < 0.001), ITPA (rs2236206 and rs8362) (P = 0.010 and P = 0.003), and ABCB1 (rs2032582) (P = 0.028) were all associated with the ratio of 6-thioguanine nucleotides to azathioprine dose. ADK (rs10824095) (P = 0.004, odds ratio [OR] = 6.220), SLC29A1 (rs747199) (P = 0.016, OR = 5.681), and TYMS (rs34743033) (P = 0.045, OR = 3.846) were associated with neutropenia. ABCC1 (rs2074087) (P = 0.022, OR = 3.406), IMPDH1 (rs2278294) (P = 0.027, OR = 0.276), and IMPDH2 (rs11706052) (P = 0.034, OR = 3.639) had a significant impact on lymphopenia.


CONCLUSIONS
This study describes genetic polymorphisms in genes whose products may affect pharmacokinetics and which may predict the relative likelihood of benefit or risk from thiopurine treatment. These findings may serve as a basis for personalized thiopurine therapy in pediatric patients with inflammatory bowel disease, although our data need to be validated in further studies.
Departments of *Laboratory Medicine and Genetics and †Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; ‡Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea; and §Biostatistics Team, Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Mi-Na
MN
Lee
Ben
B
Kang
So Yoon
SY
Choi
Mi Jin
MJ
Kim
Sook Young
SY
Woo
Jong-Won
JW
Kim
Yon Ho
YH
Choe
Soo-Youn
SY
Lee
D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001379:Azathioprine / Q000009:adverse effects* / Q000493:pharmacokinetics; D003093:Colitis, Ulcerative / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D019804:Mesalamine / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics; D011110:Polymorphism, Genetic / Q000187:drug effects*; D012189:Retrospective Studies; D013873:Thionucleotides / Q000097:blood*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D019804:Mesalamine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine