WO2002080755A2 - Kits and methods for assessing oxidative stress - Google Patents
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- WO2002080755A2 WO2002080755A2 PCT/US2002/010682 US0210682W WO02080755A2 WO 2002080755 A2 WO2002080755 A2 WO 2002080755A2 US 0210682 W US0210682 W US 0210682W WO 02080755 A2 WO02080755 A2 WO 02080755A2
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- Diatomic oxygen is ordinarily relatively harmless to body systems, as is fully reduced oxygen (i.e., water).
- transfer of one or more electrons to oxygen e.g., during reduction of oxygen to water during oxidative phosphorylation or by way of a side reaction of another biochemical process
- more reactive species of oxygen such as hydrogen peroxide, superoxide radicals, and hydroxyl radicals.
- These relatively reactive forms of oxygen can damage biochemical components of the body such as proteins, lipids, and DNA, destroying or inhibiting the normal function of the components.
- DNA is the genetic material that carries the 'instructions' for making the components of a normal human body.
- Oxidative damage to DNA can result in mutations (i.e., changes in the 'instructions') that lead the body to make abnormal components.
- the abnormal components can have inhibited (or no) ability to perform their normal function, and this can be manifested as a disease or disorder.
- oxidative damage to enzymes or lipid components of membranes can inhibit or ablate their normal function, and this too can be manifested as a disease or disorder.
- Oxidative stress The degree to which a cell or tissue of a human body is subjected to damage caused by reactive forms of oxygen is sometimes designated Oxidative stress.'
- Oxidative stress The diseases and disorders associated with oxidative damage to body components are thus manifestations of oxidative stress. Aging is another manifestation of oxidative stress. Over time, damage caused by interaction of reactive forms of oxygen with body components degrades the structure and function of those components, leading to detectable changes in body structure and function.
- the human body comprises enzymes which are able to catalyze transformation of reactive forms of oxygen to less toxic species and other enzymes which are able to repair damage done to body components by reactive forms of oxygen.
- Human immune reactions in response to pathogenic infection include activation of macrophages and polymorphonuclear neutrophilic granuloctyes. Activation of these and other immune cells enhances production of reactive oxygen species (e.g., superoxide radicals and hydrogen peroxide) by the cells. These reactive oxygen species exert an anti- infective effect by damaging the infecting cells, but can also harm host tissues, particularly if their production is not closely regulated. Some organisms, such as Bacillus anthracis, are able to induce overproduction of reactive oxygen species to the extent that systemic shock, or even death, is induced in the host.
- reactive oxygen species e.g., superoxide radicals and hydrogen peroxide
- the toxic effects of reactive oxygen species generated by immune cells in response to infection can be limited or prevented by production in the host of anti-oxidant compounds (e.g., glutathione) or enzymes that catalyze detoxification of reactive oxygen species or by administration of an anti-oxidant compound or precursor (e.g., N-acetyl-cysteine) to an infected (or potentially infected) host.
- anti-oxidant compounds e.g., glutathione
- enzymes that catalyze detoxification of reactive oxygen species e.g., glutathione
- an anti-oxidant compound or precursor e.g., N-acetyl-cysteine
- CGD chronic granulomatous disease
- Patients afflicted with CGD exhibit a marked reduction in the ability of their macrophages to produce microbicidally effective amounts of reactive oxygen species (or a complete absence of that ability), and are unusually susceptible to pathogenic infections.
- Most, if not all, human genes occur in a variety of forms which differ in at least minor ways. Heterogeneity in human genes is believed to have arisen, in part, from minor, non-fatal mutations that have occurred in the genome over time.
- differences between alternative forms of a gene are manifested as differences in the amino acid sequence of a protein encoded by the gene. Some amino acid sequence differences can alter the reactivity or substrate specificity of the protein. Differences between alternative forms of a gene can also affect the degree to which (if at all) the gene is expressed.
- heterogeneities include, for example, single nucleotide polymorphisms (i.e., alternative forms of a gene having a difference at a single nucleotide residue).
- Other known polymorphic forms include those in which the sequence of larger (e.g., 2-1000 residues) portions of a gene exhibits numerous sequence differences and those which differ by the presence or absence of portion of a gene.
- Topically applied skin care products e.g., cremes such as facial and hand cremes, lotions such as sun tan lotions, antiseptic compositions, anti-itch compositions, shaving cremes and gels, shampoos and soaps, astringents, and the like
- antioxidant ingredients such as vitamin E.
- the invention relates to a method of assessing relative susceptibility of a human to oxidative damage.
- the method comprises assessing occurrence in the human's genome of disorder-associated polymorphisms (e.g., single nucleotide polymorphisms; SNPs) in at least two (and preferably three, four, six, ten, fifteen, or twenty or more) genes selected from the group consisting of a) genes which encode an enzyme that catalyzes conversion of a toxic oxygen species to a less toxic oxygen species; b) genes which encode a protein that provides protection against oxidative stress; c) genes which encode a protein that induces production of a toxic oxygen species; d) genes which encode a protein that indirectly affects oxidative stress; e) genes which encode a protein for which the level of expression of the protein is associated with oxidative stress; f) genes which encode a component of the human DNA repair system; and g) genes which encode a protein associated with production of a toxic oxygen species by a macrophage or polymorphonuclear neutrophilic granulocyte and which are not a gene of groups a),
- Occurrence of any of the polymorphisms is an indication that the human is more susceptible to oxidative damage than a human whose genome does not comprise the polymorphism.
- occurrence of any of the polymorphisms is an indication that it is more advisable for the human to use the product containing the antioxidant than when the polymorphism(s) do not occur, or that a skin care product containing a greater amount of the antioxidant ingredient should be used than when the polymorphism does not occur.
- occurrence of a plurality of the polymorphisms is an indication that the human is even more susceptible to oxidative damage than a human whose genome does not comprise the polymorphisms (or that it is even more advisable that a skin care product containing an antioxidant ingredient or that a skin care product containing a greater amount of the antioxidant ingredient should be used than when the plurality of polymorphisms does not occur).
- the genes are selected from the group consisting of a), b), c), and d), and more preferably they are selected from the group consisting of a), b), and c).
- the method comprises assessing occurrence in the human's genome of disorder-associated polymorphisms in at least four genes selected from the group consisting of genes which encode an enzyme that catalyzes conversion of a toxic oxygen species to a less toxic oxygen species (e.g., genes which encode mitochondrial manganese superoxide dismutase, cytoplasmic copper/zinc superoxide dismutase, catalase, and glutathione peroxidase).
- genes which encode an enzyme that catalyzes conversion of a toxic oxygen species to a less toxic oxygen species e.g., genes which encode mitochondrial manganese superoxide dismutase, cytoplasmic copper/zinc superoxide dismutase, catalase, and glutathione peroxidase.
- the genes include at least one gene associated with production of a toxic oxygen species by a macrophage or polymorphonuclear neutrophilic granulocyte.
- the assay can be used to assess the susceptibility of the human to the type of oxidative stress that is associated with reaction of the human's immune system to a microbial infection. For example, the susceptibility of the human to oxidative stress associated with an immune reaction prompted by a bacterial infection (e.g., infection by Bacillus anthracis, Staphylococcus aureus, or Escherichia coli).
- a bacterial infection e.g., infection by Bacillus anthracis, Staphylococcus aureus, or Escherichia coli.
- occurrence of a polymorphism in at least one gene from group e) is assessed.
- occurrence of a polymorphism can be assessed in a gene that encodes a matrix metalloproteinase (MMP), such as the gene that encodes MMP- 1, MMP-2, MMP-3, or MMP-7 (e.g., the 1G/2G polymorphism that occurs at base pair 1607 of the gene that encodes MMP-1).
- MMP matrix metalloproteinase
- occurrence of a polymorphism in at least one gene from group d) is assessed.
- occurrence of a polymorphism can be assessed in a gene that encodes a glutathione S-transferase, such as the gene that encodes glutathione S- transferase PI, glutathione S-transferase theta 1, or glutathione S-transferase Ml (e.g., the polymorphism that occurs at one of amino acid residues 21, 141, and 169 of glutathione S- transferase theta 1).
- occurrence of a polymorphism can be assessed in the gene that encodes tumor necrosis factor alpha (e.g., the polymorphism that occurs at one of nucleotide residues -238 and -308 of the TNFA gene) or in the gene that encodes methylenetetrahydrofolate reductase.
- the method by which occurrence of an individual disorder-associated polymorphism is assessed is not critical.
- occurrence of the polymorphisms can be assessed using a method that includes contacting a nucleic acid derived from the human's genome with a first oligonucleotide.
- the first oligonucleotide can be one that anneals with higher stringency with the disorder-associated polymorphism than with a corresponding non-disorder-associated polymorphism. Annealing of the first oligonucleotide and the nucleic acid can be assessed, and such annealing is an indication that the human's genome comprises the disorder-associated polymorphism.
- Use of an oligonucleotide has the advantage that the oligonucleotide can be attached to a support using routine methods, and that a plurality of oligonucleotides can be attached to the same support, to allow simultaneous detection of multiple polymorphisms.
- allelic content of the human's genome can be determined. Detection of polymorphic sequences can be simplified by using labeled oligonucleotides, such as molecular beacon oligonucleotides.
- assessment of susceptibility to oxidative damage can further comprise calculating a susceptibility score for the human.
- a susceptibility score can be calculated by summing, for each of the selected genes in which a disorder-associated polymorphism occurs in the human's genome, the product of a constant and a correlation factor.
- the correlation factor ' can, alternatively, be a factor that represents the fraction of humans heterozygous for the disorder-associated polymorphism who exhibit the corresponding disorder or a factor that represents the fraction of humans homozygous for the disorder-associated polymorphism who exhibit the corresponding disorder.
- the constant can be selected based on the known or surmised relevance of the gene with respect to oxidative damage.
- the susceptibility score represents the relative susceptibility of the human to oxidative damage. Likewise, a greater susceptibility score corresponds to a greater advisability that the human should employ a skin care product comprising an antioxidant ingredient than does a lower score, and. a greater score can also indicate that the human should use a skin care product the contains a greater amount of such an ingredient.
- the invention relates to a method of selecting a dose of an antioxidant composition (i.e., a composition comprising a compound that exhibits anti-oxidant properties, such as vitamin E or vitamin C, or a compound that can otherwise supplement the body's normal anti-oxidant mechanisms, such as alpha-lipoic acid and coenzyme Q) for administration to a human.
- This method comprises assessing occurrence in the human's genome of disorder-associated polymorphisms in at least one of the genes selected from the group consisting of a), b), c), d), e), and f), as indicated above.
- a dose of the composition is selected. Occurrence of any of the polymorphisms is an indication that a greater dose of the composition should be administered to the human.
- the invention also relates to a kit for assessing relative susceptibility of a human to oxidative damage.
- the kit comprises reagents for assessing occurrence in the human's genome of disorder-associated polymorphisms in at least one gene selected from the group consisting of a), b), c), d), e), and f), as indicated above.
- suitable reagents include oligonucleotides (e.g., molecular beacon oligonucleotides) that anneal with higher stringency with the disorder-associated polymorphisms than with corresponding non- disorder-associated polymorphisms and oligonucleotide primers that are complementary to the region adjacent a characteristic residue of the disorder-associated polymorphism.
- the invention relates to a method of selecting a dose of an anti- oxidant composition in a skin care product (i.e., a skin care product comprising a compound that exhibits anti-oxidant properties, such as vitamin E or vitamin C, or a compound that can otherwise supplement the body's normal anti-oxidant mechanisms, such as alpha-lipoic acid and coenzyme Q) for administration to a human.
- a skin care product i.e., a skin care product comprising a compound that exhibits anti-oxidant properties, such as vitamin E or vitamin C, or a compound that can otherwise supplement the body's normal anti-oxidant mechanisms, such as alpha-lipoic acid and coenzyme Q
- This method comprises assessing occurrence in the human's genome of disorder-associated polymorphisms in at least one of the genes selected from the group consisting of a), b), c), d), e), and f), as indicated above. After assessing occurrence of the polymorphisms, a dose of the composition is selected. Occurrence of any of the polymorphisms is an indication that a greater dose of the composition should be administered to the human in the skin care product.
- the invention relates to kits and methods for assessing the relative susceptibility of a human to oxidative damage by assessing occurrence in the human's genome of genetic polymorphisms that are associated with disorders.
- the methods involves determining whether one or more polymorphisms that have been associated (by the inventors or by others) with a disorder (e.g., a disease or pathological state) in humans occur in the genome of the human being tested.
- a disorder e.g., a disease or pathological state
- the number of polymorphisms that occur in the human's genome are summed to yield a value; the higher the value is, the greater the susceptibility of the human to oxidative damage is assessed to be.
- a weighting factor is assigned to each polymorphism tested, and the weighting factors of polymorphisms that occur in the human's genome are summed to yield a value that represents relative susceptibility to oxidative damage.
- the weighting factor can represent the product of a constant assigned to the gene in which the corresponding polymorphism occurs and a correlation factor that describes how informative occurrence of the polymorphism is for occurrence of the disorder with which it is associated.
- the invention includes a variety of alternative methods and kits for performing the methods, as described in greater detail herein. [0024] Definitions
- a "polymorphism" in a gene is one of the alternative forms of a portion of the gene that are known to occur in the human population. For example, many genes are known to exhibit single nucleotide polymorphic forms, whereby the identity of a single nucleotide residue of the gene differs among the forms. Each of the polymorphic forms represents a single polymorphism, as the term is used herein. Other known polymorphic forms include alternative forms in which multiple consecutive or closely-spaced, non-consecutive nucleotide residues vary in sequence, forms which differ by the presence or absence of a single nucleotide residue or a small number of nucleotide residues, and forms which exhibit different mRNA splicing patterns.
- a "single nucleotide polymorphism” (“SNP") is one of the alternative forms of a portion of a gene that vary only in the identity of a single nucleotide residue in that portion.
- a "disorder-associated” polymorphism is an alternative form of a portion of a gene, wherein occurrence of the alternative form in the genome of a human has been correlated with exhibition by the human of a disease or a pathological state.
- a “non-disorder-associated” polymorphism is an alternative form of a portion of a gene for which no significant correlation has been made between occurrence of the alternative form in the genome and a disease or a pathological state.
- Non-disorder- associated polymorphisms are sometimes designated "neutral" polymorphisms in the art.
- a disorder-associated polymorphism and a non-disorder-associated polymorphism "correspond" with one another if the two polymorphisms are two alternative forms of the same portion of the gene.
- the identity of residue 100 of a gene is adenine in a disorder-associated polymorphism of the gene and cytosine in a non- disorder-associated polymorphism of the gene, then the two polymorphisms correspond with one another. It is understood that there may be three or more corresponding polymorphisms when there are more than two alternative forms of the same portion of the gene.
- a "characteristic residue" of a polymorphism is a nucleotide residue, the identity of which is known to vary among the alternative forms corresponding to the polymorphism.
- “Toxic oxygen species” include, in approximate order of reactivity, hydroxyl radicals, superoxide radicals, nitric oxide, peroxy nitrite (ONOO"; the product of a reaction between nitric oxide and superoxide radical), and hydrogen peroxide. Ordinary diatomic oxygen is not a toxic oxygen species, as the term is used herein.
- Oxidative damage refers to chemical reaction of a normal cellular component (e.g., DNA, a protein, or a lipid) with a toxic oxygen species, whereby at least one normal function of the component is inhibited or eliminated.
- a normal cellular component e.g., DNA, a protein, or a lipid
- oxidative damage and oxidative stress are used interchangeably herein.
- a "molecular beacon oligonucleotide” is a single-stranded oligonucleotides having a fluorescent label (e.g., rhodamine, FAM, TET, VIC, JOE, or HEX) attached to the 5'-end thereof and a fluorescence quencher (e.g., TAMRA or DABCYL) attached to the 3'- end thereof (or vice versa), as described (Kostrikis et al., 1998, Science 279:1228-1229).
- Two molecular beacon oligonucleotides are "spectrally distinct” if they can be differentially detected using spectrophotometric or spectrofluorimetric methods. Examples of characteristics that can be used to differentiate spectrally distinct oligonucleotides include absorption or excitation wavelength, emission wavelength, and fluorescent lifetime.
- An "instructional material” is a publication, a recording, a diagram, or any other medium of expression which can be used to communicate how to use a kit described herein, numerical values for weighting the significance of various polymorphisms that are detectable using the kit, or both.
- the instructional material of the kit of the invention can, for example, be affixed to a container which contains a kit of the invention or be shipped together with a container which contains the kit. Alternatively, the instructional material can be shipped separately from the container with the intention that the instructional material and the kit be used cooperatively by the recipient.
- the "stringency" with which two polynucleotides anneal means the relative likelihood that the polynucleotides will anneal in a solution as the conditions of the solution become less favorable for annealing. Examples of stringent conditions are known in the art and can be found in available references (e.g., Current Protocols in Molecular Biology, John Wiley & Sons, N.Y., 1989, 6.3.1-6.3.6). Aqueous and non-aqueous annealing methods are described in that reference and either can be used.
- a first pair of polynucleotides anneal with higher stringency than a second pair if the first pair is more likely to anneal (or remain annealed) as one or more of the salt concentration, temperature, and detergent concentration are increased.
- a "correlation factor" for a disorder-associated polymorphism is the fractions of humans who are heterozygous or homozygous for the polymorphism who exhibit the disorder.
- the correlation factor can, alternatively, be based solely on those who are heterozygous, solely on those who are homozygous, or on those who are either heterozygous or homozygous.
- a "non-extendable" nucleotide residue is a nucleotide residue that is capable of being added to a polynucleotide by a polymerase (i.e., by extension of the polynucleotide in association with a complement thereof, catalyzed by the polymerase) and that, upon addition to the polynucleotide, renders the polynucleotide incapable of being further extended by the polymerase.
- the invention relates to kits and methods for assessing the relative susceptibility of a human to oxidative damage by assessing occurrence in the human's genome of genetic polymorphisms that are associated with disorders.
- genes which are assessed are genes that are associated with oxidative stress, including both genes which provide protection against oxidative damage and genes which exacerbate oxidative damage.
- genes which protect the body against oxidative stress are genes which encode an enzyme that catalyzes conversion of a toxic oxygen species to a less toxic oxygen species, genes that encode a protein that directly provides protection against oxidative damage, genes which encode a protein that indirectly provides protection against oxidative damage, genes which encode a component of the human DNA repair system, and genes (not necessarily included within the preceding groups) which are associated with inducible production of reactive oxygen species in immune cells upon microbial infection.
- Numerous genes encode components of the human DNA repair system, and disorder-associated polymorphisms in substantially any of these genes can be informative of the susceptibility of the individual to oxidative stress.
- genes include those which encode apurinic and apyrimidinic endonucleases, enzymes that catalyze excision of nucleotide residues damaged by ultraviolet radiation, and enzymes that catalyze site specific-recombination. Many such genes are known, and include those listed in Wood et al., 2001, Science 291(5507):1284-1289.
- Genes that induce production of reactive oxygen species in immune cells upon microbial infection include genes (e.g., genes which encode components of the human phagocyte-specific NADPH-oxidase complex) associated with respiratory burst (sometimes designated oxidative burst) phenomena of macrophages and polymorphonuclear nucleophilic granulocytes, whereby toxic oxygen species are produced in response to invasion of a tissue by a microbe (e.g., a protozoan, or a bacterium such as a Pseudomonas, Salmonella, or Serratia bacterium or a known pathogen such as Bacillus anthracis, Escherichia coli, or Staphylococcus aureus).
- a microbe e.g., a protozoan, or a bacterium such as a Pseudomonas, Salmonella, or Serratia bacterium or a known pathogen such as Bacillus anthracis, Escherichia coli
- genes which are known to be aberrant in patients afflicted with disorders that inhibit or abolish antimicrobial activities of macrophages e.g., chronic granulomatous disease.
- macrophages e.g., chronic granulomatous disease.
- GST glutathione S-transferase family of enzymes, such as GST theta 1 (GSTT1), GSTM1, and GSTP1, participate in the biotransformation of allergens. These enzymes also catalyze interconversions among more and less reactive forms of oxygen. Occurrence of one or more polymorphism in one of these GST genes can therefore be used to assess the susceptibility of a human to oxidative stress.
- Lutz et al. indicate the presence of GSTT1 and GSTM1 enzymes in skin and state that carriers of defective one or both of the GSTT1 and GSTM1 genes is associated with increased vulnerability to allergenic effects of allergens (Lutz et al., 2001, Med. Pr. 52:45- 51).
- TNFA tumor necrosis factor alpha
- Allen et al. 2000, Immunogenetics 51 :201-205 described a polymorphism that occurs at base pair -308 (i.e., in the promoter region) of the gene that encodes TNFA. This polymorphism affects an individual's response to a skin irritant. Assessing which of the two forms of this disorder-associated polymorphism occurs in alleles of a human's TNFA gene allows assessment of the human's susceptibility to oxidative stress (e.g., that resulting from the immune response induced by skin irritant exposure).
- MnSOD mitochondrial manganese superoxide dismutase
- CZSOD cytoplasmic copper/zinc superoxide dismutase
- CAT catalase
- GP glutathione peroxidase
- kits described herein preferably include reagents for detecting di disorder-associated polymorphisms in at least one (and preferably two, three, or all) of these four genes.
- significance of occurrence of disorder-associated polymorphisms in these genes can be applied by assigning a greater weighting factor to disorder-associated polymorphisms of these genes than to disorder-associated polymorphisms in other genes associated with oxidative stress.
- genes encode proteins which provide direct or indirect protection against oxidative damage, for example by converting toxic species of oxygen to less toxic species, by eliminating precursors of toxic forms of oxygen, or by repairing oxidative damage.
- these genes include those which encode glutathione S-transferase PI, glutathione S-transferase theta 1, glutathione S-transferase Ml, glutathione reductase, thioredoxin reductase, paraoxonase, NAD(P)H:quinone oxidoreductases 1 and 2, 8-oxo-7,8- dihydrodeoxyguanosine triphosphatase, and epoxide hydrolase. Detection in a human genome of disorder-associated polymorphisms in one or more of these genes indicates that the human exhibits enhanced susceptibility to oxidative damage. The methods and kits described herein can use this indication to assess the susceptibility of a human to oxidative stress.
- genes which exacerbate oxidative damage are genes which encode a protein that induces production of a toxic oxygen species, either directly (e.g., by catalyzing a reaction in which a toxic species of oxygen is a direct or side product) or indirectly (e.g., by enhancing flux through a metabolic pathway that leads to production of a toxic species of oxygen).
- proteins that directly or indirectly induce production of toxic oxygen species include myeloperoxidase, tumor necrosis factor alpha, NADH/NADPH oxidase p22 phox protein, nitric oxide synthase xanthine oxidase, and cytochrome P450. Detection in a human genome of disorder-associated polymorphisms in one or more genes encoding one of these proteins indicates that the human exhibits enhanced susceptibility to oxidative damage.
- apolipoprotein E is a multi-functional molecule that is able to affect oxidative stress.
- the ApoE4 phenotype for example, is known to be associated with enhanced hydroxyl radical levels in patients afflicted with Alzheimer's disease, and ApoE expression is known to exacerbate oxidative stress.
- enhancement of oxidative stress is known to be associated with each of elevated homocysteine level, depressed serum bilirubin level, depressed acid phosphatase activity, depressed protein phosphotyrosine phosphatase activity, and depressed epinephrine oxidase activity.
- occurrence in the genome of polymorphisms in genes which encode proteins that affect these levels and activities can be determined, and their occurrence can be used to estimate susceptibility of the human to oxidative stress.
- genes for which polymorphisms can be associated with altered susceptibility to oxidative damage include UDP-glucuronosyltransferase 1 Al (i.e., the UGT1 Al gene), genes encoding acid phosphatase, protein phosphotyrosine phosphatase, epinephrine oxidase, ApoE4, cystathionine beta-synthase, cystathionine gamma-lyase, N5- methyl THF:homocysteine methyltransferase, methylenetetrahydrofolate reductase (MTHFR), and S-adenosylmethionine methyltransferase.
- UGT1 Al the UGT1 Al gene
- Heat shock proteins are also known to provide at least indirect protection of cells from oxidative damage, and occurrence of a heat shock protein gene polymorphism can be used as informative markers of susceptibility to oxidative damage when the polymorphism is known to be a disorder-associated polymorphism.
- It is not critical that the gene in which the occurrence of a polymorphism occurs is directly or indirectly involved in production or destruction of reactive oxygen species in the body. It is sufficient if an association can be made between the level of expression of a gene and the level of oxidative stress in the human.
- MMP matrix metalloproteinase
- polymorphisms in the foregoing genes which can be informative for susceptibility to oxidative damage include the following:
- ⁇ a polymorphism manifested as a change from an alanine residue to a valine residue at amino acid residue 9 (i.e., in the signal sequence) of MnSOD;
- ⁇ a polymorphism manifested as a change from a cytosine residue to a thymine residue at nucleotide residue -262 (i.e., in the promoter region) of the catalase gene;
- ⁇ a polymorphism in the hGPXl gene manifested as a change from a proline residue to a leucine residue at amino acid residue 198 of glutathione peroxidase; ⁇ a polymorphism in the GSTP1 gene manifested as a change from a valine residue to an isoleucine residue at amino acid residue 105 of glutathione S-transferase PI;
- ⁇ a polymorphism in the GSTTl gene manifested as a change from an alanine residue to a threonine residue at amino acid residue 21 of glutathione S-transferase theta 1; ⁇ a polymorphism in the GSTTl gene manifested as a change from an aspartic acid residue to a asparagine residue at amino acid residue 141 of glutathione S-transferase theta 1;
- ⁇ a polymorphism manifested as a change from cytosine residue to a thymine residue at nucleotide residue 677 of the gene which encodes methylenetetrahydrofolate reductase (MTHFR); " a polymorphism manifested as a change from a thymine residue to a cytosine residue at nucleotide residue -107 (i.e., in the promoter region) of the gene which encodes paraoxonase;
- MTHFR methylenetetrahydrofolate reductase
- ⁇ a polymorphism manifested as a change from a cytosine residue to a thymine residue at nucleotide residue 242 (i.e., in the coding region) of the gene encoding NAD(P)H:quinone oxidoreductase;
- ⁇ a polymorphism manifested as a change from a thymine residue to a cytosine residue at nucleotide residue 113 in exon 3 of the gene which encodes epoxide hydrolase (i.e., effecting change of from a tyrosine residue to a histidine residue in epoxide hydrolase);
- ⁇ a polymorphism manifested as a change from a guanine residue to an adenine residue at nucleotide residue -463 (i.e., in the promoter region) of the gene which encodes myeloperoxidase;
- ⁇ a polymorphism manifested as a change to an adenine residue at nucleotide residue -238 (i.e., in the promoter region) of the gene which encodes tumor necrosis factor alpha (i.e., the TNF promoter variant designated TNF2);
- ⁇ a polymorphism manifested as a change to an adenine residue at nucleotide residue -308 (i.e., in the promoter region) of the gene which encodes tumor necrosis factor alpha (i.e., the TNF promoter variant designated TNF3);
- ⁇ a polymorphism manifested as a change from a cytosine residue to a thymine residue at nucleotide residue 242 (i.e., in the coding region) of the phox gene encoding the
- ⁇ a polymorphism manifested as a 27 base pair repeat in intron 4 (i.e., between nucleotide residues 5130 and 5511) of the gene encoding nitric oxide synthase;
- ⁇ a polymorphism manifested as a change from an adenine residue to a guanine residue at nucleotide residue -290 (i.e., in the 5'-flanking region) of the gene encoding cytochrome
- P450 i.e., the polymorphism designated the CYP3A4 cytochrome P450 variant
- ⁇ a polymorphism manifested as a change from a cytosine residue to a thymine residue at nucleotide residue 699 (i.e., in the coding region) of the gene encoding cystathionine beta-synthase
- the invention includes a method of assessing the relative susceptibility of a human to oxidative damage.
- This susceptibility can be calculated relative to a hypothetical human whose genome does not contain a single disorder-associated polymorphism in a gene associated with oxidative stress.
- susceptibility can be calculated relative to another human who may have one or more different disorder-associated polymorphism than the human being assessed.
- the basis upon which raw susceptibility scores are calculated is immaterial, so long as the same basis is used for all humans whose scores are to be compared (i.e., so that the scores are relatable to one another).
- the relative susceptibility of a human to oxidative damage permits assessment of risks and benefits of a variety of compositions, conditions, and interventions.
- the susceptibility of a human to oxidative damage can be used to determine whether the human would benefit by supplementing nutritional intake with a composition that contains one or more anti-oxidants.
- the relative susceptibility of the human to oxidative damage can indicate an appropriate dose of such an anti-oxidant- containing composition.
- suitability of a condition or intervention for a human e.g., administration to the human of hyperbaric oxygen or a pharmaceutical agent known to induce generation of toxic species of oxygen
- Occurrence of every disorder-associated polymorphisms in a gene related to oxidative stress is not necessarily equally indicative of susceptibility to oxidative stress.
- a weighting factor can be assigned to each polymorphism detected in the methods and kits described herein.
- four genes MnSOD, CZSOD, CAT, and GP are known to have very significant roles in oxidative stress in humans. All else being equal, disorder-associated polymorphisms that occur in one of these four genes are more significant than polymorphisms that occur in genes having less significant roles in oxidative stress.
- a greater weighting factor can be assigned to these polymorphisms than to others.
- the weighting factor assigned to these four polymorphisms can be 1 to 10 times greater than the weighting factor assigned to disorder- associated polymorphisms (having equal correlation with the corresponding disorder, as discussed below) in other genes.
- the weighting factor assigned to polymorphisms in the MnSOD, CZSOD, CAT, and GP genes is twice that assigned to disorder-associated polymorphisms in other genes.
- Another factor which can influence the significance that is assigned to occurrence of a disorder-associated polymorphism in a human's genome is the degree to which the polymorphism is correlated with the corresponding disorder.
- Some disorders are highly correlated with occurrence of a genetic polymorphism, and other disorders exhibit lower correlation with a polymorphism.
- a polymorphism When a polymorphism is reported to be associated with a disorder (i.e., with a disease or pathological condition), a degree of correlation between the polymorphism and the disorder is often reported.
- One useful way of calculating a factor that describes correlation between a polymorphism and a disorder is to calculate an odds ratio that describes the likelihood that an individual in whose genome the disorder-associate polymorphism occurs will exhibit or develop the disorder. Because the kits and methods described herein can be used to detect whether the human is homozygous for the disease-associated polymorphism, odds ratios calculated for homozygous individuals can also be used, if they are available.
- Odds ratios can be calculated as described in the art.
- the odds ratio can be calculated as follows. First, the odds of being afflicted with the disorder are calculated for a first population in whom the polymorphism occurs by dividing the number of afflicted individuals in the first population by the total number of individuals in the first population. Second, the odds of being afflicted with the disorder are calculated for a first population in whom the polymorphism does not occur by dividing the number of afflicted individuals in the second population by the total number of individuals in the second population. Third, the odds ratio is calculated by dividing the odds for the first population by the odds for the second population.
- An overall oxidative stress susceptibility score for a human can be determined as follows.
- a significance score can be assigned to each disorder-associated polymorphism that is detected in the human's genome using a method or kit described herein.
- the significance score is a constant (e.g., 1.00), and is multiplied by any significance factor (e.g., 1-10, preferably 2, for the MnSOD, CZSOD, CAT, and GP genes) and by any correlation factor that is available.
- That correlation factor should be used in place of the correlation factor for mere occurrence of the polymorphism, at least if the method or kit is used to rule out occurrence in the subject's genome of corresponding non-disorder-associated polymorphisms. If significance and correlation factors are not available, then values of 1.00 should be assigned to each. An overall score is determined by summing the significance score for each disorder-associated polymorphism that is detected using the method or kit.
- This overall oxidative stress susceptibility score can be compared with the values obtained from other subjects, or it can be compared with the value (i.e., zero) which would be expected to occur in a human whose genome does not include any disorder-associated polymorphism in a gene associated with oxidative stress.
- the Kimura reference describes two corresponding polymorphisms that occur in the MnSOD gene (i.e., occurrence of either C or T at a particular position in the MnSOD gene). Individuals in whose genome the disorder- associated polymorphism occur exhibit an odds ratio of 1.43 for the disorder (a form of macular degeneration), and individuals who are homozygous for the same polymorphism exhibit an odds ratio of 10.14.
- occurrence of the disorder-associated polymorphism described in Kimura can be assigned a significance of 2.86, and exclusive occurrence of that polymorphism (i.e., homozygosity) can be assigned a significance of 20.28.
- any particular disorder-associated polymorphism or non-disorder-associated polymorphism
- Numerous methods of detecting occurrence of a polymorphism are known in the art, and substantially any of those methods can be used in the kits and methods described herein.
- the reagents included in the kit will vary depending on the method to be used to detect the polymorphisms. Examples of some suitable polymorphism detection methods are provided below.
- a pair of oligonucleotide primers are used to amplify a portion of the gene that includes a polymorphic region.
- Detection of one or more of the polymorphisms that occur at the polymorphic region can be achieved by contacting the amplified portion with an oligonucleotide having a sequence that it will anneal under stringent conditions with the amplified portion only if one polymorphism occurs at the portion, but will not anneal with the amplified portion if another polymorphism occurs at that portion.
- oligonucleotide having a sequence that it will anneal under stringent conditions with the amplified portion only if one polymorphism occurs at the portion, but will not anneal with the amplified portion if another polymorphism occurs at that portion.
- stringent conditions are known in the art, and can be modified by the skilled artisan as appropriate to any particular amplified portion/oligonucleotide pair.
- one or more molecular beacon oligonucleotides are used to detect polymorphisms (disorder-associated, non-disorder-associated, or both) in a sample that contains a copy of the subject's genome, a fraction of the subject's genome, or amplification products generated from the subject's genome (e.g., amplified portions of oxidative stress-associated genes in which portions polymorphisms are known to occur).
- Molecular beacon probes are single-stranded oligonucleotides having a fluorescent label (e.g. rhodamine, FAM, TET, VIC, JOE, or HEX) attached to the 5'-end thereof and a fluorescence quencher (e.g. TAMRA or DABCYL) attached to the 3'-end thereof (or vice versa), as described (Kostrikis et al., 1998, Science 279:1228-1229).
- the sequence of each molecular beacon probe is selected to include two complementary hairpin regions, whereby the probe can self-anneal to form a hairpin structure. The 5'- and 3'- ends are brought into close association when the hairpin structure forms.
- the probe also comprises a targeting portion which is selected to be complementary to a target sequence (e.g. a single polymorphism of an oxidative-stress-associated gene).
- a targeting portion which is selected to be complementary to a target sequence (e.g. a single polymorphism of an oxidative-stress-associated gene).
- the targeting portion and at least one of the hairpin regions are located in close proximity to one another, meaning that the targeting portion either overlaps the hairpin region or flanks it, having no more than about 5 nucleotide residues therebetween.
- the probe does not fluoresce, because the hairpin structure forms and the fluorescence quencher attached to one end of the probe quenches fluorescence of the label attached to the other end of the probe. If the targeting portion of the probe anneals with a region of a nucleic acid having the target sequence, then formation of the hairpin structure is inhibited, the fluorescence quencher is not brought into association with the fluorescent label, and the probe fluoresces.
- Multiple molecular beacon probes can be used in a single reaction mixture, and fluorescence associated with the probes can be differentiated if the molecular beacon probes are spectrally distinct.
- one or more molecular beacon probes are used, each having targeting portion which is complementary to a target region (e.g. 20 to 40 nucleotide residues, more preferably 20 to 30 residues) of one polymorphism of an oxidative stress- associated gene (e.g., one of the genes disclosed herein).
- a target region e.g. 20 to 40 nucleotide residues, more preferably 20 to 30 residues
- one polymorphism of an oxidative stress- associated gene e.g., one of the genes disclosed herein.
- the target region includes, and preferably is approximately centered around, the nucleotide residue at which the polymorphism occurs.
- two such probes are used, one having a targeting region completely complementary to the target region of one polymorphism of the gene (e.g., one of two polymorphisms of an SNP), and the other having a targeting region completely complementary to the target region of a corresponding polymorphism of the gene (e.g., the other polymorphism of the SNP).
- oligonucleotide primers which are complementary to a region adjacent a characteristic residue of the polymorphism are extended using a polymerase enzyme, and the identity of the nucleotide residue that is added to the primer in the position complementary to the characteristic residue is determined.
- the primer can be extended in the presence of non-extendable nucleotide residues in order to ensure that a limited number of (or only one) nucleotide residues are incorporated into the primer.
- Methods of this type are known in the art (e.g., the SNP-IT® technology of Orchid Biocomputer, Inc.) and are described, for example in U.S. Patents numbers 6,013,431 and 6,004,744.
- An patient's susceptibility to oxidative stress is predictive of the patient's susceptibility to individual disorders that are associated with or known to be caused by oxidative stress and its physiological consequences.
- development, progression, or both, of Alzheimer's disease is thought to be influenced by oxidative damage sustained by the patient's tissues, including brain tissues.
- the rate or likelihood of development and progression of oxidative damage-associated disorders can be estimated by assessing the overall susceptibility of a patient to oxidative stress.
- Alzheimer's disease-associated polymorphism of a single gene ApoE4
- susceptibility to Alzheimer's disease can be associated with occurrence in a patient of disorder-associated polymorphisms in genes that have no previously known connection with Alzheimer's disease.
- susceptibility of a patient to Alzheimer's disease can be assessed by detecting occurrence in the patient of disorder- associated polymorphisms in any of the genes described herein, such as those in the groups herein designated a)-g).
- the individual disorders for which susceptibility can be assessed using these methods are not limited to Alzheimer's disease.
- the methods can be used to assess susceptibility to substantially any disorder which is presently known to be associated with, caused by, or exacerbated by oxidative stress or the physiological consequences of oxidative stress.
- autoimmune disorders such as macular degeneration and psoriasis; bacterial, viral, fungal, and parasitic infections; age-related loss of skin thickness, resilience, and flexibility; allergies; hair loss; hair discoloration (e.g., graying); tumorigenesis; brain degenerative disorders such as Alzheimer's, Lou Gherig's, Huntington's, and Parkinson's diseases; other neurodegenerative disorders such as Friedreich's ataxia, hereditary spastic paraplegia, cerebellar degeneration, and amyotrophic lateral sclerosis; respiratory disorders such as asthma; inflammatory disorders such as pancreatitis. [0077] Kits for Assessing Oxidative Stress
- the invention includes a kit for assessing the relative susceptibility of a human to oxidative stress.
- the kit contains reagents for performing one or more of the methods described herein.
- the reagents used in certain embodiments of the methods described herein are indicated above. Reagents useful for performing those methods using a variety of alternative sample preparation and polymorphism detection methods or chemistries are apparent to the skilled artisan.
- Kits for detecting polymorphisms in individual genes are known in the art, and the kit of the invention can have similar components. However, a critical feature of the kit is that it includes reagents that permit its user to detect disorder-associated polymorphisms in at least three genes associated with oxidative stress. Preferably the kit includes reagents that permit detection of disorder-associated polymorphisms in at least 4, 6, 8, 10, 15, 20, or 30 or more such genes. [0080] In one embodiment, the kit includes a plurality of oligonucleotides which anneal under stringent conditions with a disorder-associated polymorphism of one of the genes, but not with a non-disorder associated-polymorphism.
- Each of the oligonucleotides is preferably attached to a surface in order to facilitate handling of the oligonucleotide.
- the oligonucleotides can be linked with a plurality of surfaces (e.g., oligonucleotides for a particular polymorphism being attached to a particle discrete from a particle to which oligonucleotides for another polymorphism are attached), or they can be attached to discrete regions of a single surface (e.g., as in the GENECHIPTM device of Affymetrix, Inc.). Annealing between individual oligonucleotides and the polymorphism corresponding thereto can be detected using standard methods.
- the kit can also comprise oligonucleotides that are useful as molecular beacon probes or as extendable primers.
- the kit further comprises a DNA collection kit or apparatus, such as that described in co-pending U.S. patent application number 09/302,623 (allowed).
- DNA collected using the kit or apparatus can be stored or archived, and subjected to additional testing as previously unknown polymorphisms are discovered in genes associated with oxidative stress, or as the significance of previously unappreciated polymorphisms is realized.
- the invention also relates to a method of assessing the advisability that a human should employ a skin care product comprising an anti-oxidant ingredient.
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Abstract
Description
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Priority Applications (7)
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EP02736545A EP1386001A4 (en) | 2001-04-05 | 2002-04-05 | Kits and methods for assessing oxidative stress |
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AU2002309543A AU2002309543B2 (en) | 2001-04-05 | 2002-04-05 | Kits and methods for assessing oxidative stress |
JP2002578795A JP2004528840A (en) | 2001-04-05 | 2002-04-05 | Kits and methods for evaluating oxidative stress |
US10/247,935 US7211383B2 (en) | 2001-04-05 | 2002-09-20 | Kits and methods for assessing skin health |
US11/731,180 US8313930B2 (en) | 2001-04-05 | 2007-03-30 | Kits and methods for assessing skin health |
US13/668,842 US20130130247A1 (en) | 2001-04-05 | 2012-11-05 | Kits and Methods for Assessing Skin Health |
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US10/247,935 Continuation-In-Part US7211383B2 (en) | 2001-04-05 | 2002-09-20 | Kits and methods for assessing skin health |
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Cited By (6)
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WO2003102178A1 (en) * | 2002-05-31 | 2003-12-11 | Takara Bio Inc. | Method of typing gene polymorphisms |
EP1581094A2 (en) * | 2002-09-20 | 2005-10-05 | Genelink, Inc. | Kits and methods for assessing skin health |
WO2009127073A1 (en) * | 2008-04-18 | 2009-10-22 | Gen Sod2 Foundation | Cosmetic preparation tailored to an individual and method for the production thereof |
WO2009150856A1 (en) * | 2008-06-13 | 2009-12-17 | 株式会社ヤクルト本社 | Gene that imparts oxygen resistance and application thereof |
WO2013093407A1 (en) * | 2011-12-20 | 2013-06-27 | Gene Onyx Limited | Product selection using genetic analysis |
US9747685B2 (en) | 2013-09-25 | 2017-08-29 | The Proctor & Gamble Company | Method and system for skin care consultation |
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JP2007225607A (en) * | 2006-01-27 | 2007-09-06 | Prima Meat Packers Ltd | Method of screening antistress agent, and method of determining effectiveness thereof |
JP6986793B1 (en) * | 2021-02-04 | 2021-12-22 | 日本メナード化粧品株式会社 | How to determine the genetic predisposition of stress susceptibility |
-
2002
- 2002-04-05 EP EP02736545A patent/EP1386001A4/en not_active Ceased
- 2002-04-05 JP JP2002578795A patent/JP2004528840A/en not_active Withdrawn
- 2002-04-05 AU AU2002309543A patent/AU2002309543B2/en not_active Ceased
- 2002-04-05 WO PCT/US2002/010682 patent/WO2002080755A2/en active IP Right Grant
- 2002-04-05 CA CA002443395A patent/CA2443395A1/en not_active Abandoned
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AHMED ET AL.: 'Increased reactive oxygen species in familial amyotropic lateral sclerosis with mutations in SOD1' JOURNAL OF THE NEUROLOGICAL SCIENCES vol. 176, June 2000, pages 88 - 94, XP002967149 * |
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Cited By (11)
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US8313930B2 (en) | 2001-04-05 | 2012-11-20 | Genelink, Inc. | Kits and methods for assessing skin health |
WO2003102178A1 (en) * | 2002-05-31 | 2003-12-11 | Takara Bio Inc. | Method of typing gene polymorphisms |
EP1581094A2 (en) * | 2002-09-20 | 2005-10-05 | Genelink, Inc. | Kits and methods for assessing skin health |
EP1581094A4 (en) * | 2002-09-20 | 2008-04-23 | Genelink Inc | Kits and methods for assessing skin health |
WO2009127073A1 (en) * | 2008-04-18 | 2009-10-22 | Gen Sod2 Foundation | Cosmetic preparation tailored to an individual and method for the production thereof |
WO2009150856A1 (en) * | 2008-06-13 | 2009-12-17 | 株式会社ヤクルト本社 | Gene that imparts oxygen resistance and application thereof |
WO2013093407A1 (en) * | 2011-12-20 | 2013-06-27 | Gene Onyx Limited | Product selection using genetic analysis |
GB2501640A (en) * | 2011-12-20 | 2013-10-30 | Gene Onyx Ltd | Product selection using genetic analysis |
CN104114717A (en) * | 2011-12-20 | 2014-10-22 | 基因奥尼克斯有限公司 | Product selection using genetic analysis |
GB2501640B (en) * | 2011-12-20 | 2015-06-17 | Gene Onyx Ltd | Product selection using genetic analysis |
US9747685B2 (en) | 2013-09-25 | 2017-08-29 | The Proctor & Gamble Company | Method and system for skin care consultation |
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CA2443395A1 (en) | 2002-10-17 |
WO2002080755A9 (en) | 2003-03-06 |
WO2002080755A3 (en) | 2003-10-30 |
EP1386001A4 (en) | 2005-07-20 |
JP2004528840A (en) | 2004-09-24 |
EP1386001A2 (en) | 2004-02-04 |
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