Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis.
Agranulocytosis is a rare, but serious adverse reaction to sulphasalazine. The polymorphic enzyme N-acetyltransferase 2 (NAT2) plays an important role in the metabolism of sulphasalazine. This study was conducted to analyse whether the risk of sulphasalazine-induced agranulocytosis is increased in slow acetylators. Patients were treated for inflammatory disease, mostly joint disease, with a mean dose of 2 g sulphasalazine daily. Thirty-nine patients reacted with agranulocytosis, while 75 patients had been treated for a minimum of 3 months without haematological side-effects. A population-based control panel of 448 individuals was used for comparison. All subjects were genotyped for NAT2 by polymerase chain reaction followed by restriction enzyme digestion. The six most common allelic variants were analysed: NAT2*4, NAT2*5A, NAT2*5B, NAT2*5C, NAT2*6 and NAT2*7. The proportion of slow acetylators was significantly higher in patients with sulphasalazine-induced agranulocytosis (69%) and population-based controls (64%) compared to patients who tolerated sulphasalazine (45%); odds ratio 2.71 [95% confidence interval (CI) 1.20; 6.15], P = 0.015, and odds ratio 2.17 (95% CI 1.32; 3.56), P = 0.002, respectively. Patients who developed agranulocytosis did not differ from population-based control subjects in the frequency of slow acetylators; odds ratio 1.25 (95% CI 0.62; 2.53), P = 0.535. The risk of agranulocytosis did not appear to be increased in slow acetylators, provided that the difference compared with sulphasalazine-treated control subjects was not due to a predominance of fast acetylators among patients with inflammatory joint disease. Instead, selection bias was suspected since more slow acetylators may have discontinued sulphasalazine therapy because of drug-intolerance.
Wadelius
M
M
Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden. mia.wadelius@klinfarm.uu.se
Stjernberg
E
E
Wiholm
B E
BE
Rane
A
A
D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000380:Agranulocytosis / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000378:metabolism; D001168:Arthritis / Q000188:drug therapy; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006098:Granulocytes / Q000187:drug effects; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012460:Sulfasalazine / Q000009:adverse effects* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012460:Sulfasalazine; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human