Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease.
Previous studies have shown association of single nucleotide polymorphisms (SNPs) in 3 contiguous genes (PON1, PON2, and PON3) encoding paraoxonase with risk of Alzheimer disease (AD). We evaluated the association of serum paraoxonase activity measured by phenyl acetate (PA) and thiobutyl butyrolactone (TBBL) with risk of AD and with 26 SNPs spanning the PON gene cluster in 266 AD cases and 306 sibling controls from the MIRAGE study. The odds of AD (adjusted for age, gender, and ethnicity) increased 20% for each standard deviation decrease in PA or TBBL activity. There were association signals with activity in all 3 genes. Haplotypes including SNPs spanning the PON genes were generally more significant than haplotypes comprising SNPs from 1 gene. Significant interactions were observed between SNP pairs located across the PON cluster with either serum activity measure as the outcome, and between several PON SNPs and PA activity with AD status as the outcome. Our results suggest that low serum paraoxonase activity is a risk factor for AD. Furthermore, multiple variants in PON influence serum paraoxonase activity and their effects may be synergistic.
Erlich
Porat M
PM
Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA 02118, USA. farrer@bu.edu
Lunetta
Kathryn L
KL
Cupples
L Adrienne
LA
Abraham
Carmela R
CR
Green
Robert C
RC
Baldwin
Clinton T
CT
Farrer
Lindsay A
LA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000097:blood* / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D004357:Drug Synergism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D005810:Multigene Family / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C468411:PON2 protein, human; C113656:PON3 protein, human