Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-06-01
2001-06-05
Jones, W. Gary (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S022100, C536S024300
Reexamination Certificate
active
06242186
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for detecting or predicting the risk of, or predisposition to, cancer and coronary heart disease in a subject. The present invention also relates to a kit for carrying out the said method.
BACKGROUND OF THE INVENTION
Oxidative stress and free radicals have been implicated in the etiology of a number of diseases, including cancers, coronary heart diseases and type II diabetes. The human body has a number of endogenous free radicals scavenging systems which have genetic variability. The serum paraoxonase (PON) is an enzyme carried in the HDL that contributes to the detoxification of organophosphorus compounds but also of carcinogenic products of lipid peroxidation. Paraoxonase has been suggested to account for an important part of the antioxidative properties of HDL
1-3
. PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme.
4-7
Two polymorphisms are currently known in human PON1. The Q191R polymorphism was the first mutation of PONI reported.
4,6
The second one is the missense mutation of A to T in codon 54, producing a substitution of methionine (M) to leucine (L) (Met45Leu
4a
; known also as Met55Leu
4
). Both these polymorphisms have been shown to affect serum PON activity,
6,8,9
and in particular, the L54 allele has been associated with an increased PON activity. There are a few previous studies concerned with the association of Met54Leu polymorphism and coronary heart disease (CHD), the findings are, however, inconclusive
8
. To our knowledge, only two studies concerning the association of the Met54Leu polymorphism with CHD have been published.
8,10
In a cross-sectional study, the prevalence of LL homozygosity was twofold among diabetics who already had clinical CHD compared with diabetics who had no clinical CHD, even though LL homozygotes had 1.7-fold PON activity, compared with MM homozygotes.
8
In a Japanese retrospective case-control study, Met54Leu PON polymorphism had no association with CHD.
10
SUMMARY OF THE INVENTION
The present invention was based on the hypothesis that homozygosity of the L54 allele in the PON1 gene might protect against certain diseases associated with oxidative stress, in particular cancer and coronary heart disease. For this purpose, the said hypothesis was tested in a prospective population-based cohort study. The results of this study show that our hypothesis is true and that there is a clear association between homozygosity of the L54 allele, and a reduced risk for cancer and coronary heart disease.
The present invention is thus directed to a method for detecting a risk of cancer and coronary heart disease, in a subject, comprising isolating genomic DNA from said subject, determining the allelic pattern for the codon 54 of the paraoxonase encoding PON1 gene in the genomic DNA, and identification of M54L mutation indicating said risk being reduced.
The present invention is also directed to a kit for detecting a risk of cancer and coronary heart disease in a subject, comprising means for determining the allelic pattern for the codon 54 of the paraoxonase encoding PON1 gene in a genomic DNA sample, and means for carrying out a comparison of the allelic pattern so determined to a control sample.
REFERENCES:
patent: 5652106 (1997-07-01), Plikaytis et al.
Schmidt et al. Paraoxonase PON1 polymorphism Leu-Met54 is associated with carotid atherosclerosis results of the austrian stroke prevention study, Stroke, vol. 29 (10), p. 2043-2048, 1998.*
M. Navab et al., Arterioscler Thromb Vasc Biol, 16:831-42 (1996).
M.I. Mackness et al., Atherosclerosis, 104:129-135 (1993).
A.D. Watson et al., J. Clin Invest, 96:2882-91 (1995).
B.N. La Du et al., Chem Biol Interact, 87(1-3):25-34 (Jun. 1993).
R. Humbert et al., Nature Genet, 3:73-6 (1993).
M.I. Mackness et al., Curr Opin Lipidol, 7:69-76 (1996).
M.I. Mackness et al., Lancet, 349:851-2 (1997).
B. Mackness et al., Lancet, 353:468-9 (1999).
M.C. Garin et al., J. Clin Invest, 99:62-6 (1997).
B. Mackness et al., Br J Pharmacol, 122:265-8 (1997).
T. Zama et al., Arterioscler Thromb Vasc Biol, 17:3565-9 (1997).
Birch & Stewart Kolasch & Birch, LLP
Jones W. Gary
Oy Jurilab Ltd.
Tung Joyce
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