Incidence of genetic polymorphisms involved in lipid metabolism among Chinese patients with osteonecrosis of the femoral head.
BACKGROUND AND PURPOSE Corticosteroid treatment is associated with osteonecrosis of the femoral head (ON) in certain patients. The degree of drug sensitivity in general is governed by genetic variation between individuals. We investigated the relationship between ON and the presence of different alleles of the cytochrome P450 gene (CYP3A4), the product of which metabolizes corticosteroids, and of the P-glycoprotein (P-gp) gene (ABCBI), the product of which modulates cellular uptake of corticosteroids, to determine whether patients with certain alleles may be at higher risk of ON after corticosteroid treatment.


METHODS
We studied 31 patients from Guangdong, China who were both treated with corticosteroid therapy and developed ON, and 17 corticosteroid-therapy patients without ON. Patient DNA was screened for known polymorphisms in the CYP3A4 gene (CYP3A4*4, CYP3A4*5, CYP3A4*6) and the P-gp gene ABCB1 (mutations C3435T, G2677T/A).


RESULTS
The majority (20/31) of the corticosteroid-treated patients who developed ON were heterozygous for ABCB1, whereas only 3/17 without ON were heterozygous. Statistical significance was observed between the ON and the control groups for the ABCB1 G2677T/A polymorphism. Analysis of haplotypic frequencies indicated significant linkage disequilibrium between the two ABCB1 polymorphisms, C3435T and G2677T/A (D' = 0.034). No CYP3A4 polymorphisms were detected in any of the patients.


CONCLUSIONS
Patients carrying an ABCB1 polymorphism had a higher risk of having corticosteroid-associated ON than those with wild-type genotypes. This statistically significant association conflicts with previous studies, possibly due to different sampling methods. Knowing which genetic backgrounds are most strongly associated with corticosteroid-associated ON provides a method of screening for patients who are most at risk of developing ON.
He
Wei
W
Department of Orthopaedics, First Affiliated Hospital of Guangzhou, University of Traditional Chinese Medicine, BaiYun District, Guangzhou, China.
Li
Keda
K
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000009:adverse effects; D000328:Adult; D002648:Child; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005271:Femur Head Necrosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000305:Adrenal Cortex Hormones; D051544:Cytochrome P-450 CYP3A