The impact of genetic variation in the region of the GPIIIa gene, on Pl expression bias and GPIIb/IIIa receptor density in platelets.
Some studies have suggested that genetic variability in the glycoprotein (GP) IIIa gene modulates expression of platelet GPIIb/IIIa (alpha(2b)beta(3)). We sought to determine as to whether combinations of genetic variants within the GPIIIa gene (haplotypes) influenced the expression of GPIIIa RNA and protein levels in human platelets. Three promoter polymorphisms, Pl(A1/A2) genotype and platelet receptor densities were determined in 207 acute coronary syndrome (ACS) patients. Allele-specific quantitative reverse transcription-polymerase chain reaction of platelet RNA from Pl(A1/A2) heterozygotes identified a greater expression of Pl(A2) bearing transcripts among heterozygotes. Among the patients studied, the ratio of Pl(A1)/Pl(A2) RNA expression was significantly influenced by promoter haplotype (P < 0.01). However, this effect reflected carriership of rare not common haplotypes (P = 0.2). There was a threefold variation between subjects in the number of GPIIb/IIIa receptors expressed per platelet, although no association between receptor density and the Pl(A2) (P = 0.93) or promoter polymorphisms was demonstrated (-468A, P = 0.52; -425C, P = 0.59; -400A, P = 0.52). Among common haplotypes, Pl(A1)/Pl(A2) RNA expression was negatively correlated with adjusted GPIIb/IIIa receptor density (P = 0.04). The overall trend towards higher expression of Pl(A2) bearing message in Pl(A1/A2) heterozygotes, and the existence of rare haplotypes with more pronounced changes indicate the existence of cis-acting genetic factors that remain to be identified.
O'Halloran
Aisling M
AM
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Curtin
Ronan
R
O'Connor
Fiona
F
Dooley
Michelle
M
Fitzgerald
Anthony
A
O'Brien
John K
JK
Fitzgerald
Desmond J
DJ
Shields
Denis C
DC
D000704:Analysis of Variance; D001792:Blood Platelets / Q000378:metabolism*; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics; D039661:Integrin beta3 / Q000235:genetics*; D010974:Platelet Aggregation; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000032:analysis* / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis; D010980:Platelet Membrane Glycoproteins / Q000032:analysis; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C032193:glycoprotein receptor GPIb-IX; D012313:RNA