MDR1 gene polymorphisms and risk of gingival hyperplasia induced by calcium antagonists.
BACKGROUND
Gingival overgrowth is a common side effect of calcium antagonists. Although the pathogenesis is unknown, several lines of evidence point to a modulation of inflammatory processes. Because the calcium antagonists, albeit to a variable degree, act as inhibitors of P-glycoprotein (P-gp), the gene product of multidrug resistance 1 (MDR1), and inflammation may modify P-gp expression, we analyzed the MDR1 polymorphisms as risk factors for gingival overgrowth induced by calcium antagonists.


METHODS
Clinical, laboratory, and anamnestic data including periodontal parameters and use of calcium antagonists were assessed in a cross-sectional epidemiologic investigation (N = 1484). MDR1 polymorphisms in exon 21 G2677T/A and exon 26 C3435T were determined. P-gp expression was detected in gingival tissues. In a matched-pair analysis, 93 subjects using calcium antagonists and 186 not using them were compared.


RESULTS
P-gp is expressed in the endothelial layers of blood vessels obtained from healthy or inflamed gingiva. Subjects treated with calcium antagonists had significantly deeper gingival pockets than their drug-free counterparts (P <.0001). This drug-related side effect was associated with the MDR1 2677G/G or G/TA genotype (P <.001) but not with the variant genotype T/TA. This drug effect was proved by multiple regression analysis with adjustment for the risk factors of periodontitis (age, sex, smoking, and education) (P <.0001) and was associated with elevated C-reactive protein levels. The association of probing depth with the MDR1 polymorphism was confirmed in the matched-pair analysis (P <.0001).


CONCLUSIONS
Treatment with calcium antagonists leads to gingival hyperplasia, which is associated with the MDR1 G2677T/A polymorphism. The MDR1 genotype may modify the inflammatory response to the drugs.
Meisel
Peter
P
Department of Pharmacology, Unit of Periodontology, Ernst Moritz Arndt University Greifswald, Germany. meiselp@uni-greifswald.de
Giebel
Jürgen
J
Kunert-Keil
Christiane
C
Dazert
Peter
P
Kroemer
Heyo K
HK
Kocher
Thomas
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000375:Aging / Q000502:physiology; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D005881:Gingiva / Q000473:pathology; D005885:Gingival Hyperplasia / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers