This study aimed to evaluate the association of the paraoxonase (PON) gene variants and Alzheimer disease (AD) using meta-analysis.
Methods:
Relevant studies were identified by searching English and Chinese databases extensively. Allele and genotype frequencies for each included study were extracted. Newcastle-Ottawa Scale (NOS) was employed to assess the quality of included studies. The odds ratio (OR) with 95% confidence interval (95% CI) was calculated using a random-effects or fixed-effects model. A Q statistic was used to evaluate homogeneity, and Egger test and funnel plot were used to assess publication bias.
Results:
A total of 15 studies (involving 5 polymorphisms) were included and identified for the current meta-analysis. The NOS scores ranged from 7 to 8, meaning good quality of studies. It was found that the SS genotype of PON2 S311C polymorphism had an significant association with AD in the studied population (OR = 0.82, 95% CI: 0.68-0.99, P = .04), and the A allele of PON1 rs705379 polymorphism was positively related to AD in Caucasian population (OR = 1.21, 95% CI: 1.05-1.39, P = .009) as well as the GG genotype decreased AD risk significantly in Caucasians (OR = 0.7, 95% CI: 0.56-0.88, P = .002). However, there was no significant relationship between other 3 genetic variants of PON genes (L55 M, Q192 R, and −161C/T of PON1 gene) and AD.
Conclusion:
Existing evidence indicates that the S311C polymorphism (SS genotype) and the rs705379 (the A allele and GG genotype) are associated with risk of AD in studied population. Future studies with larger sample sizes will be necessary to confirm the present results.
WinbladBAmouyelPAndrieuS. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol. 2016;15(5):455–532.
2.
NiuHÁlvarez-ÁlvarezIGuillén-GrimaFAguinaga-OntosoI. Prevalence and incidence of Alzheimer’s disease in Europe: a meta-analysis[published online April 26, 2016]. Neurologia. 2016. pii: S0213-S4853(16)30003-2.
3.
SteenlandKGoldsteinFCLeveyAWhartonW. A meta-analysis of Alzheimer’s disease incidence and prevalence comparing African-Americans and Caucasians. J Alzheimers Dis. 2015;50(1):71–76.
4.
ChanKYWangWWuJJ. Epidemiology of Alzheimer’s disease and other forms of dementia in China, 1990–2010: a systematic review and analysis. Lancet. 2013;381(9882):2016–2023.
5.
YuanJZhangZWenH. Incidence of dementia and subtypes: a cohort study in four regions in China. Alzheimers Dement. 2016;12(3):262–271.
6.
BrookmeyerRJohnsonEZiegler-GrahamKArrighiHM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007;3(3):186–191.
7.
HurdMDMartorellPDelavandeA. Monetary costs of dementia in the United States. N Engl J Med. 2013;368(14):1326–1334.
ReitzC. Genetic loci associated with Alzheimer’s disease. Future Neurol. 2014;9(2):119–122.
10.
SunJHYuJTTanL. The role of cholesterol metabolism in Alzheimer’s disease. Mol Neurobiol. 2015;51(3):947–965.
11.
CagninALeonAVianelloD. LDL density and oxidation are modulated by PON1 promoter genotype in patients with Alzheimer’s disease. J Alzheimers Dis. 2013;34(2):377–385.
12.
AviramMRosenblatM. Paraoxonases analyses in vitro and in vivo in relation to cardiovascular diseases. Methods Mol Biol. 2008;477:259–276.
BacchettiTVigniniAGiuliettiA. Higher levels of oxidized low density lipoproteins in Alzheimer’s disease patients: roles for platelet activating factor acetyl hydrolase and paraoxonase-1. J Alzheimers Dis. 2015;46(1):179–186.
15.
ErlichPMLunettaKLCupplesLA. Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease. Neurobiol Aging. 2012;33(5):1015.e7-e23.
16.
PrécourtLPAmreDDenisMC. The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis. 2011;214(1):20–36.
17.
LittleJHigginsJPT, editors. The HuGENet™ HuGE Review Handbook, version 1.0. 2006.
18.
LiuHXiaPLiuM. PON gene polymorphisms and ischaemic stroke: a systematic review and meta analysis. Int J Stroke. 2013;8(2):111–123.
DerSimonianRLairdN. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188.
21.
BermanNGParkerRA. Meta-analysis: neither quick nor easy. BMC Med Res Methodol. 2002;2:10.
22.
EggerMDavey SmithGSchneiderMMinderC. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634.
23.
ZintzarasELauJ. Synthesis of genetic association studies for pertinent gene–disease associations requires appropriate methodological and statistical approaches. Clin Epidemiol. 2008;61(7):634–645.
24.
GinsbergGNeafseyPHattisDGuytonKZJohnsDOSonawaneB.Genetic polymorphism in paraoxonase 1 (PON1): population distribution of PON1 activity. Toxicol Environ Health B Crit Rev. 2009;12(5-6):473–507.
25.
ZulianiGBle’AZancaR. Genetic polymorphisms in older subjects with vascular or Alzheimer’s dementia. Acta Neurol Scand. 2001;103(5):304–308.
26.
DantoineTFDrouetMDebordJMerleLCogneMCharmesJP. Paraoxonase 1 192/55 gene polymorphisms in Alzheimer’s disease. Ann N Y Acad Sci. 2002;977(1):239–244.
27.
JankaZJuhászARimanóczyAABodaKMárki-ZayJKálmánJ. Codon 311 (Cys → Ser) polymorphism of paraoxonase-2 gene is associated with apolipoprotein E4 allele in both Alzheimer’s and vascular dementias. Mol Psychiatry. 2002;7(1):110–112.
28.
ScacchiRGambinaGMartiniMCBroggioEVilardoTCorboRM. Different pattern of association of paraoxonase Gln192 → Arg polymorphism with sporadic late-onset Alzheimer’s disease and coronary artery disease. Neurosci Lett. 2003;339(1):17–20.
29.
YamadaMSodeyamaNItohYOtomoEMatsushitaMMizusawaH. No association of paraoxonase genotype or atherosclerosis with cerebral amyloid angiopathy. Stroke. 2002;33(4):896–900.
30.
PolaRGaetaniEFlexA. Lack of association between Alzheimer’s disease and Gln-Arg 192 Q/R polymorphism of the PON-1 gene in an Italian population. Dement Geriatr Cogn Disord. 2003;15(2):88–91.
31.
ShiJZhangSTangM. Possible association between Cys311Ser polymorphism of paraoxonase 2 gene and late-onset Alzheimer’s disease in Chinese. Brain Res Mol Brain Res. 2004;120(2):201–204.
32.
CelliniETeddeABagnoliS. Association analysis of the paraoxonase-1 gene with Alzheimer’s disease. Neurosci Lett. 2006;408(3):199–202.
33.
HeXMZhangZXZhangJW. Gln192Arg polymorphism in paraoxonase 1 gene is associated with Alzheimer disease in a Chinese Han ethnic population. Chin Med J (Engl). 2006;119(14):1204–1209.
34.
ChapuisJBoscherM FCottelDCottelDAmouyelPLambertJC. Association study of the paraoxonase 1 gene with the risk of developing Alzheimer’s disease. Neurobiol Aging. 2009;30(1):152–156.
35.
QiangWShijunQ. The association of paraoxonase 2 polymorphisms with Alzheimer's disease[in Chinese]. Chin J Gerontol. 2007;27(11):1038–1041.
36.
YunfengBWenxiangQ. The association of polymorphism of PON gene in sporadic Alzbeimer’s disease[in Chinese]. Nerv Dis Mental Health. 2008;8(6):420–423.
37.
Klimkowicz-MrowiecAMaronaMWolkowP. Paraoxonase gene polymorphism and the risk for Alzheimer’s disease in the polish population. Dement Geriatr Cogn Disord. 2011;31(31):417–423.
38.
Bednarska-MakarukM EKrzywkowskiTGrabanA. Paraoxonase 1 (PON1) gene-108C>T and p.Q192 R polymorphisms and arylesterase activity of the enzyme in patients with dementia. Folia Neuropathol. 2013;51(2):111–119.
39.
AlamRTripathiMMansooriN. Synergistic epistasis of paraoxonase 1 (rs662 and rs85460) and apolipoprotein E4 genes in pathogenesis of Alzheimer’s disease and vascular dementia. Am J Alzheimers Dis Other Demen. 2014;29(8):769–776.
40.
AnsteyKJLipnickiDMLowLF. Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry. 2008;16(5):343–354.
41.
KivipeltoMHelkalaELLaaksoMP. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ. 2001;322(7300):1447–1451.
42.
TianYCrumpCJLiYM. Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production. J Biol Chem. 2010;285(42):32549–32556.
43.
MacknessBDurringtonPNMacknessMI. Human serum paraoxonase. Gen Pharmacol. 1998;31(3):329–336.
44.
LeducVTherouxLDeaDRobitailleYPoirierJ. Involvement of paraoxonase 1 genetic variants in Alzheimer’s disease neuropathology. Eur J Neurosci. 2009;30(9):1823–1830.
45.
ErlichPMLunettaKLCupplesLA. Polymorphisms in the PON gene cluster are associated with Alzheimer disease. Hum Mol Genet. 2006;15(1):77–85.
46.
HegeleRAHarrisSBConnellyPW. Genetic variation in paraoxonase-2 is associated with variation in plasma lipoproteins in Canadian Oji-Cree. Clin Genet. 1998;54(5):394–399.
47.
BorightAPConnellyPWBruntJHSchererSWTsuiLCHegeleRA. Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with variation in plasma lipoproteins in Alberta Hutterites. Atherosclerosis. 1998;139(1):131–136.
48.
BrophyVHJampsaRLClendenningJBMcKinstryLAJarvikGPFurlongCE. Effects of 5′ regulatory-region polymorphism on paraoxonase gene (PON1) expression. Am J Hum Genet. 2001;68(6):1428–1436.
49.
WangXFanZHuangJ. Extensive association analysis between polymorphisms of PON gene cluster with coronary heart disease in Chinese Han population. Arterioscler Thromb Vasc Biol. 2003;23(2):328–334.
50.
PiYZhangLChangK. Lack of an association between Paraoxonase 1 gene polymorphisms (Q192 R, L55 M) and Alzheimer’s disease: a meta-analysis. Neurosci Lett. 2012;523(2):174–179.
51.
ZhaoCTanLZhangY. Correlation between Gln192Arg polymorphism of the paraoxonase 1 and Alzheimer’s disease: a meta-analysis[in Chinese]. J Commun Med. 2012;10(4):7–11.
52.
HigginsJPTGreenS. Cochrane Handbook for Systematic Reviews of Interventions (Wiley Cochrane Series). England, UK: The Cochrane Collaboration and John Wiley & Sons Ltd; 2008.
53.
MunafòMRFlintJ. Meta-analysis of genetic association studies. Trends Genet. 2004;20(9):439–444.
54.
WingoTSRosenACutlerDJLahJJLeveyAI. Paraoxonase-1 polymorphisms in Alzheimer’s disease, Parkinson’s disease, and AD-PD spectrum diseases. Neurobiol Aging. 2012;33(1):204. e13-e15.
55.
SeowDCGaoQYapP. Profile of the Paraoxonase 1 (PON1) gene 192Q/R polymorphism and clinical associations among Older Singaporean Chinese with Alzheimer’s and mixed dementia. Dement Geriatr Cogn Dis Extra. 2016;6(1):43–54.
