Codon 311 (Cys → Ser) polymorphism of paraoxonase-2 gene is associated with apolipoprotein E4 allele in both Alzheimer's and vascular dementias

The gene of an esterase enzyme, called paraoxonase (PON, EC.3.1.8.1.) is a member of a multigene family that comprises three related genes PON1, PON2, and PON3 with structural homology clustering on the chromosome 7.1,2 The PON1 activity and the polymorphism of the PON1 and PON2 genes have been found to be associated with risk of cardiovascular diseases such as hypercholesterolaemia, non-insulin-dependent diabetes, coronary heart disease (CHD) and myocardial infaction.3–8 The importance of cardiovascular risk factors in the pathomechanism of Alzheimer's disease (AD) and vascular dementia (VD)9–13 prompted us to examine the genetic effect of PON2 gene codon 311 (Cys→Ser; PON2*S) polymorphism and the relationship between the PON2*S allele and the other dementia risk factor, the apoE polymorphism in these dementias. The PON2*C and PON2*S allele frequencies were similar in both AD (25% and 75%) and VD groups (23% and 77%), respectively, compared with the controls (27% and 73%). The ratio of the PON2*S carriers was significantly higher among the apoE4 allele carrier AD (27%) and VD (25%) groups than in the control (12%). Our results indicate that the PON2*S and apoE4 alleles have interactive effect on the development of the two most common forms of dementias AD and VD, and further support the hypothesis that cardiovascular factors contribute to the development of AD.

[1]  C. Walker,et al.  Distribution of paraoxon hydrolytic activity in the serum of patients after myocardial infarction. , 1986, Clinical chemistry.

[2]  R R Sokal,et al.  Classification of the European language families by genetic distance. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[4]  E. Boerwinkle,et al.  The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. , 1991, American journal of human genetics.

[5]  P. Winocour,et al.  Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. , 1991, Atherosclerosis.

[6]  The genetic mapping and gene structure of mouse paraoxonase/arylesterase. , 1995, Genomics.

[7]  J. Berliner,et al.  Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. , 1995, The Journal of clinical investigation.

[8]  A. Boulton,et al.  Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[9]  G. Charpentier,et al.  Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes , 1995, The Lancet.

[10]  M. Jauhiainen,et al.  The Gln-Arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns. , 1996, The Journal of clinical investigation.

[11]  B. Winblad,et al.  Low blood pressure and dementia in elderly people: the Kungsholmen project , 1996, BMJ.

[12]  B. La Du,et al.  The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. , 1996, Genomics.

[13]  D. Sparks,et al.  Intraneuronal β-amyloid immunoreactivity in the CNS , 1996, Neurobiology of Aging.

[14]  Z. Janka,et al.  Apolipoprotein E allele frequencies in patients with late‐onset sporadic Alzheimer's dementia in Hungary , 1997, Acta neurologica Scandinavica.

[15]  Z. Janka,et al.  Association of the apolipoprotein A-IV codon 360 mutation in patients with Alzheimer's disease , 1997, Neuroscience Letters.

[16]  N. Ossei-Gerning,et al.  The paraoxonase Gln‐Arg 192 polymorphism in subjects with ischaemic heart disease , 1997, Coronary artery disease.

[17]  I. Ferrer,et al.  Identification of necrotic cell death by the TUNEL assay in the hypoxic-ischemic neonatal rat brain , 1997, Neuroscience Letters.

[18]  P. Froguel,et al.  Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. , 1997, The Journal of clinical investigation.

[19]  B. La Du,et al.  Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. , 1998, The Journal of clinical investigation.

[20]  D. Sanghera,et al.  DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. , 1998, American journal of human genetics.

[21]  A. Montali,et al.  The gln-Arg192 polymorphism of human paraoxonase gene is not associated with coronary artery disease in italian patients. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[22]  J. Miller,et al.  Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. , 1998, Atherosclerosis.

[23]  Z. Janka,et al.  Increased apolipoprotein E4 allele frequency is associated with vascular dementia in the Hungarian population , 1998, Acta neurologica Scandinavica.

[24]  M. Yamada,et al.  No association of paraoxonase gene polymorphism with atherosclerosis or Alzheimer’s disease , 1999, Neurology.

[25]  Z. Janka,et al.  Evaluation of Serum-Lipid-Related Cardiovascular Risk Factors in Alzheimer’s Disease , 1999, Dementia and Geriatric Cognitive Disorders.

[26]  J. C. Torre,et al.  Critical threshold cerebral hypoperfusion causes Alzheimer’s disease? , 1999, Acta Neuropathologica.