MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine.
BACKGROUND
Mefloquine, a drug used for treatment and prophylaxis of malaria, is known for its neuropsychiatric adverse effects. We hypothesized that neuropsychiatric adverse effects of mefloquine are associated with polymorphisms in the MDR1/ABCB1 gene that encodes for the efflux pump P-glycoprotein.


METHODS
The association between MDR1 C1236T, G2677T, and C3435T single-nucleotide polymorphisms and the occurrence of neuropsychiatric adverse effects was examined in a prospective cohort study of 89 healthy white travelers taking mefloquine.


RESULTS
Of the subjects, 27 (28%) reported neuropsychiatric adverse effects, women significantly more frequently than men. Allele frequencies of the C1236T, G2677T, and C3435T polymorphisms were similar to those found in other white populations, and there was no significant association between any of the individual polymorphisms and neuropsychiatric adverse effects. However, women with the 1236TT, 2677TT, and 3435TT genotypes had a higher risk of neuropsychiatric adverse effects than the reference groups of women with heterozygous and homozygous CC or GG genotypes, with odds ratios of 6.3 (95% confidence interval [CI], 1.1-36.9), 10.5 (95% CI, 1.1-100.6), and 5.4 (95% CI, 1.1-30.0), respectively. The association for women homozygous for the 1236-2677-3435 TTT haplotype was even stronger (P = .004) than the effect of any of the individual polymorphisms. No associations with mefloquine blood levels were observed.


CONCLUSIONS
In this study the MDR1 1236TT, 2677TT, and 3435TT genotypes, along with the 1236-2677-3435 TTT haplotype, were associated with neuropsychiatric adverse effects of mefloquine in women. MDR1 polymorphisms may play an important role in predicting the occurrence of neuropsychiatric adverse effects of mefloquine, particularly in female travelers.
Aarnoudse
Albert L H J
AL
Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
van Schaik
Ron H N
RH
Dieleman
Jeanne
J
Molokhia
Mariam
M
van Riemsdijk
Melanie M
MM
Ligthelm
Robert J
RJ
Overbosch
David
D
van der Heiden
Ilse P
IP
Stricker
Bruno H Ch
BH
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000009:adverse effects*; D016001:Confidence Intervals; D003545:Cysteine; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR; D005998:Glycine; D006239:Haplotypes; D006801:Humans; D008297:Male; D015767:Mefloquine / Q000009:adverse effects*; D001523:Mental Disorders / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D008875:Middle Aged; D009422:Nervous System Diseases / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D016017:Odds Ratio; D027361:Organic Anion Transporters / Q000235:genetics; D011110:Polymorphism, Genetic; D012016:Reference Values; D013912:Threonine; D014195:Travel; D044465:White People / Q000235:genetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D027361:Organic Anion Transporters; D013912:Threonine; D003545:Cysteine; D005998:Glycine; D015767:Mefloquine