A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events.
OBJECTIVE
Extracellular adenosine triphosphate (ATP) regulates inflammatory cells by activation of the P2X(7) receptor. We hypothesized that polymorphisms in P2RX7 influence the risk of ischemic heart disease (IHD), ischemic stroke (IS) and cardiovascular risk factors and tested this hypothesis using genetic association studies.


METHODS
Two loss-of-function SNPs in P2RX7 were genotyped in 1244 IHD cases and 2488 controls as well as 5969 individuals with cardiovascular risk factors. Eleven SNPs in a 250 kb region on chromosome 12 spanning P2RX7 as well as neighboring genes OASL, P2RX4 and CAMKK2 were genotyped in 4138 individuals with IS and 2528 controls. Association was examined using linear and logistic regression models with an additive genetic model.


RESULTS
The common loss-of-function variant rs3751143 was significantly associated with a decreased risk of IHD in smokers (P = 0.03) as well as decreased risk of IS (OR 0.89; 95% CI = 0.81-0.97; P = 0.012). In addition, an intronic SNP in CAMKK2, rs2686342, were associated with a decreased risk of IS (OR 0.89; 95% CI = 0.82-0.97; P = 0.011). In subgroup analyses, both SNPs were associated with decreased risk of IS in individuals with hypertension (P = 0.045 and 0.015, respectively).


CONCLUSIONS
A common loss-of-function missense variant in the gene encoding the P2X(7) receptor is associated with reduced risk of IS and with IHD in smokers. These findings might implicate a role of purinergic signaling in atherogenesis or atherothrombosis.
Department of Clinical Sciences, Lund University, Lund, Sweden. olof.gidlof@med.lu.se
Olof
O
Gidlöf
J Gustav
JG
Smith
Olle
O
Melander
Håkan
H
Lövkvist
Bo
B
Hedblad
Gunnar
G
Engström
Peter
P
Nilsson
Joyce
J
Carlson
Göran
G
Berglund
Sandra
S
Olsson
Katarina
K
Jood
Christina
C
Jern
Bo
B
Norrving
Arne
A
Lindgren
David
D
Erlinge
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D058486:Receptors, Purinergic P2X7 / Q000235:genetics* / Q000378:metabolism; D012306:Risk
D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate