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Identification of SNPs associated with hyperlipidemia, dyslipidemia and defective carbohydrate metabolism

A technology for hyperlipidemia, dyslipidemia, applied in the field of diagnostic compositions, capable of solving problems such as impossible diagnosis or treatment of patients

Inactive Publication Date: 2007-04-04
NAT PUBLIC HEALTH INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Results It is currently not possible to diagnose or treat patients affected by familial mixed hyperlipidemia (FCHL)

Method used

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  • Identification of SNPs associated with hyperlipidemia, dyslipidemia and defective carbohydrate metabolism
  • Identification of SNPs associated with hyperlipidemia, dyslipidemia and defective carbohydrate metabolism
  • Identification of SNPs associated with hyperlipidemia, dyslipidemia and defective carbohydrate metabolism

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Example 1: The test program of Examples 2-5. All FCHL families analyzed have probands with severe CHD and lipid phenotype, and an average of 5-6 family members with FCHL. These FCHL families showing extreme and well-defined disease phenotypes were analyzed to identify potential genes on 1q21 that cause FCHL. We selected the regional candidate gene method and sequenced 4 candidate genes of functionally related regions on 1q21. The TXNIP, USF1, retinoic acid X receptor gamma (RGRG) and apolipoprotein A2 (APOA2) genes were sequenced to identify all possible variants. Among these genes, TXNIP initially represented the most promising position candidate gene, because it has been shown to be the basis for the genotype of mixed hyperlipidemia in mice. 17 . Based on their functional candidacy and the close locations (4 , And the 10 most promising SNPs from an expanded sample of 721 family members from 60 FCHL families (see below). The results of the 60 SNPs are shown in Supplementar...

Embodiment 2

[0181] Example 2: USF1 gene as a candidate gene

[0182] We identified a total of 23 SNPs of the 5867bp sequence of the USF1 gene (Supplementary Table 2): 3 of them are silent variants in exons, and the rest are located in non-coding regions and putative promoters. Eight of the 23 SNPs are new. Initially, we genotyped the SNPs in the USF1 gene: usf1s1 (exon 11), usf1s2 (intron 7) and usf1s7 (exon 2) (Table 2-3 shows the genotyped The corresponding rs number of SNPs).

[0183] Table 1: Multipoint HHRR and gamete competition analysis of usf1s1 (=RS3737787) and usf1s2 (=RS2073658) SNPs

[0184] TCHL all

TG all

FCHL men

TG man

Multiple HHRR

Gamete competition

ns(ns)

0.00002

(0.005)

0.05(ns)

0.00006 (0.008)

0.009(ns)

0.0004

0.04)

0.00003(0.003)

0.0000009

(0.004)

Progressive p-value

Gamete competition

0.00004

0.00006

0.0004

0.00001

(Gene drooping)

Test p value

[0...

Embodiment 3

[0197] Example 3: Haplotype analysis of JAM-USF1 gene region

[0198] Using the HBAT program, we obtained evidence of shared haplotypes in the usf1s1 and usf1s2 regions (Table 3). These observations are supported by multiple HHRR analysis (Table 3). For haplotype 1-1 (1 indicates a common allele), using -o selection results in a p-value of 0.0007.

[0199] Table 3 Haplotype analysis in men affected by TG using the HBAT program (the results of multi-locus GENO-PDT and multiple HHRR are given below for comparison)

[0200] Test

[0201] This choice not only measures the preferential inheritance of sensitive haplotypes to the sick, but also estimates its less preferential inheritance to the unaffected, making it useful here, because the unaffected individuals in these expanded families also contain important information. Table 3 also shows the results of HBAT-e selection and the correlation test for specific linkages. Since this test counts the implicit conditions in the li...

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Abstract

The present invention relates to a nucleic acid molecule comprising a chromosomal region contributing to or indicative of hyperlipidemias and / or dyslipidemias or defective carbohydrate metabolism, wherein said nucleic acid molecule is selected from the group consisting of: (a) a nucleic acid molecule having or comprising the nucleic acid sequence of SEQ ID NO: 1, wherein said nucleic acid sequence has one or more mutations having an effect on USFI function; (b) a nucleic acid molecule having or comprising the nucleic acid sequence of SEQ ID NO: 1, wherein said nucleic acid sequence is characterized by comprising a guanine or an adenine residue in position 3966 in intron 7 of the USF1 sequence; and / or (c) a nucleic acid molecule having or comprising the nucleic acid sequence of SEQ ID NO: 1, wherein said nucleic acid sequence is characterized by comprising a cytosine or a thymine residue in position 5205 in, exon 11 of the USF1 sequence; wherein said nucleic molecule extends, at a maximum, 50000 nucleotides over the 5' and / or 3' end of the nucleic acid molecule of SEQ ID NO: 1. The present invention further relates to a diagnostic composition comprising a nucleic acid molecule encoding USF1 or a fragment thereof, the nucleic acid molecule disclosed herein, the vector, the primer or primer pair of the present invention or an antibody specific for USF1. Finally, the present invention relates to the use of the nucleic acid molecule of the invention for the preparation of a pharmaceutical composition for the treatment of hyperlipidemia, dyslipidemia, coronary heart disease, type II diabetes, metabolic syndrome, hypertension or atherosclerosis.

Description

Technical field [0001] The present invention relates to a nucleic acid molecule comprising a chromosomal region that promotes or indicates hyperlipidemia, dyslipidemia and glucose metabolism defects, wherein the nucleic acid molecule is selected from: (a) having or containing the nucleic acid sequence of SEQ ID NO:1 A nucleic acid molecule, wherein the nucleic acid has one or more mutations that affect the function of USF1; (b) a nucleic acid molecule having or comprising SEQ ID NO: 1, wherein the nucleic acid is characterized by an intron in the USF1 sequence 7 contains a guanine or adenine residue at position 3966; and / or (c) has or contains a nucleic acid molecule of SEQ ID NO: 1, wherein the nucleic acid is characterized in that it contains at position 5205 of exon 11 of the USF1 sequence Cytosine or thymine residues; wherein the nuclear molecule extends a maximum of 50,000 nucleotides at the 5'and / or 3'end of the nucleic acid molecule of SEQ ID NO:1. The present invention fur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/47C12Q1/68A61K38/17A61K39/395
CPCC12Q2600/156C12Q2600/172C12Q1/6883C12Q2600/158C07K14/4705A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12
Inventor 黎那·皮尔托南-帕洛蒂玛丽亚-丽塔·塔斯基宁拜依维·派杰坎塔克里斯帝安·艾亨霍姆
Owner NAT PUBLIC HEALTH INST
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