Genetic markers associated with risk of diabetes mellitus
Inventors
Steinthorsdottir, Valgerdur • Thorleifsson, Gudmar • Gudbjartsson, Daniel • Masson, Gisli • Kong, Augustine
Assignees
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Publication Number
US-8796182-B2
Publication Date
2014-08-05
Expiration Date
Abstract
The invention relates to variants that predispose to risk of type 2 diabetes, basal cell carcinoma and breast cancer. It has been discovered that certain genetic variants confer risk of these diseases when inherited from one parent, but not the other. The invention provides methods of disease management, including diagnostic methods, utilizing such parental origin effects.
Core Innovation
The invention relates to determining susceptibility to type 2 diabetes in a human individual by analyzing nucleic acid from a biological sample for the identity of at least one allele of at least one polymorphic marker and by determining the parental origin of that allele. Different parental origins of the at least one allele are associated with different susceptibilities to type 2 diabetes in humans.
A key feature is that the at least one polymorphic marker is selected from rs2334499 and markers in linkage disequilibrium therewith, wherein the linkage disequilibrium is characterized by a value for r2 of at least 0.2. The method interprets the presence of a paternal origin at-risk T allele of rs2334499, or a marker allele in linkage disequilibrium therewith, as indicative of increased susceptibility, and the presence of a maternal origin protective T allele of rs2334499, or a marker allele in linkage disequilibrium therewith, as indicative of decreased susceptibility.
The invention further includes calculating a risk score that includes a relative risk (RR) or odds ratio (OR) of at least 1.1 attributed to the paternal origin at-risk allele being present in the nucleic acid, or calculating a risk score that includes a relative risk (RR) or odds ratio (OR) of less than 0.9 attributed to the maternal origin protective allele being present in the nucleic acid. The method framework supports susceptibility determination using parental-origin information associated with linkage disequilibrium markers.
Claims Coverage
One independent claim is identified: clm-00001. It covers a parental-origin allele analysis workflow for susceptibility to type 2 diabetes, anchored on rs2334499 and linkage disequilibrium markers (r2 ≥ 0.2) and mapped to susceptibility via RR/OR-based risk-score thresholds for paternal versus maternal origin.
Parental-origin allele analysis for type 2 diabetes susceptibility determination
Analyzing nucleic acid from a biological sample for the identity of at least one allele of at least one polymorphic marker, determining the parental origin of the at least one allele, and determining susceptibility to type 2 diabetes from both nucleic acid analysis and parental origin, wherein different parental origins are associated with different susceptibilities.
rs2334499 and linkage disequilibrium marker selection with r2 threshold
Selecting the at least one polymorphic marker from rs2334499 and markers in linkage disequilibrium therewith, wherein linkage disequilibrium is characterized by a value for r2 of at least 0.2.
Paternal at-risk allele detection mapped to increased susceptibility using RR/OR ≥ 1.1 risk score
Determining that a paternal origin at-risk T allele of rs2334499, or a marker allele in linkage disequilibrium therewith, is present in the nucleic acid, and including calculating a risk score that comprises a relative risk (RR) or odds ratio (OR) of at least 1.1 attributed to the paternal origin at-risk allele being present.
Maternal protective allele detection mapped to decreased susceptibility using RR/OR < 0.9 risk score
Determining that a maternal origin protective T allele of rs2334499, or a marker allele in linkage disequilibrium therewith, is present in the nucleic acid, and including calculating a risk score that comprises a relative risk (RR) or odds ratio (OR) of less than 0.9 attributed to the maternal origin protective allele being present.
Parental origin indicative interpretation of increased versus decreased susceptibility
Associating the presence of a paternal origin at-risk allele with increased susceptibility to type 2 diabetes, and associating the presence of a maternal origin protective allele with decreased susceptibility to type 2 diabetes.
The claim coverage centers on determining type 2 diabetes susceptibility by combining polymorphic marker allele identity with parental origin, using rs2334499 and linkage disequilibrium markers (r2 ≥ 0.2), and converting paternal versus maternal origin findings into susceptibility via RR/OR thresholded risk-score calculations.
Stated Advantages
Provides an approach to determine susceptibility to type 2 diabetes in a human individual based on parental origin of polymorphic marker alleles.
Supports increased susceptibility determination when a paternal origin at-risk T allele of rs2334499 is present and decreased susceptibility determination when a maternal origin protective T allele is present.
Documented Applications
Disease-association assay and diagnostic/pharmacogenomic uses based on detecting polymorphic markers and haplotypes, including determining parental origin linked to type 2 diabetes susceptibility and response to therapy, and supporting clinical trial enrichment.
Monitoring treatment progress/effectiveness by using marker- and parental-origin-linked results.
Therapeutic targeting support and drug screening for modulators of variant gene expression, including use of RNA interference, siRNA, shRNA, miRNA, and antisense.
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