Insulin-gene flanking sequences, diabetes mellitus and atherosclerosis: a review

Mandrup-Poulsen, Thomas; Owerbach, David; Nerup, J.; Johansen, Klaus; Ingerslev, J.; Hansen, A. Tybjærg

doi:10.1007/bf00281989

Cited by 18 publications

(12 citation statements)

References 47 publications

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“…Some investigators have even suggested that the apparent association of NIDDM and class 3 alleles was secondary to the association with atherosclerosis (48). Some studies have suggested a 2.5-fold excess of class 3 alleles among patients with atherosclerosis, independent of hyperglycemia or abnormal glucose tolerance (49). However, the association with hypertriglyceridemia was not confirmed by groups finding an association with atherosclerosis (47)(48)(49), and at least two groups failed to confirm the association of class 3 alleles with coronary artery disease (50,51).…”

Section: Association Of Insulin-gene Polymorphisms With Diabetesmentioning

confidence: 99%

Insulin Gene in Diabetes Analysis Through RFLP

Permutt

Elbein²

1990

Diabetes Care

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Insulin deficiency is a prominent feature of non-insulin-dependent (NIDDM) and insulin-dependent (IDDM) diabetes mellitus that could result from defects in the insulin gene. Cloning of this gene has permitted molecular-genetic studies including the definition of multiple-DNA-sequence polymorphisms detected with restriction endonucleases, or restriction-fragment-length polymorphisms (RFLPs), and the mapping of the insulin gene to the short arm of chromosome 11 adjacent to the insulinlike growth factor II (IGF-II) and tyrosine hydroxylase genes. The combined RFLPs for the insulin, IGF-II, and tyrosine hydroxylase genes make this a highly informative locus for genetic studies of the insulin gene in diabetes. Early studies of an RFLP consisting of variable-number tandem repeats (VNTR) of DNA near the insulin gene suggested an association of certain alleles with approximately 170 copies of the repeat unit with NIDDM. Although subsequent studies in NIDDM did not confirm this association, an association of different alleles defined by approximately 40 copies of the repeat unit in this VNTR region with IDDM has been demonstrated in multiple studies. This VNTR region and the multiple other RFLPs for this region have been used in linkage analysis to study the segregation of insulin genes in families. These studies have failed to demonstrate a major significant role for insulin-gene defects in NIDDM, maturity-onset diabetes of the young, or IDDM in American Blacks and Whites and under various models of inheritance. Several pedigrees with diabetes and defects of the insulin gene have been described, however, and a minor role for this gene in NIDDM cannot be eliminated from available studies. Similarly, the association studies of the insulin gene and IDDM suggest a minor modifying role undetectable in pedigree studies. The role of defects in or near the insulin gene in a small subset of NIDDM or in IDDM must await direct investigation of the insulin gene in diabetic individuals with the most recent methods for gene amplification and sequence analysis.

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Section: Association Of Insulin-gene Polymorphisms With Diabetesmentioning

confidence: 99%

Insulin Gene in Diabetes Analysis Through RFLP

Permutt

Elbein²

1990

Diabetes Care

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“…Since this polymorphism has been associated with diabetes, 31 data are given for all individuals combined and for groups from which diabetics and subjects with elevated fasting blood glucose were excluded. There were no significant differences (p>0.05) in genotype distribution or allele frequencies between atherosclerotic and nonatherosclerotic men or women in any of the three studies.…”

Section: Insulin Gene Polymorphism In Atherosclerotic and Nonatheroscmentioning

confidence: 99%

“…The U-allele frequency also seems to decrease with age in the Danish population as a whole, including both atherosclerotic and nonatherosclerotic individuals. 31 This would suggest that U-allele earners die at an earlier age than L-allele earners but cannot state anything about the cause of this.…”

Section: Insulin Gene Polymorphismmentioning

confidence: 99%

Polymorphism in 5' flanking region of human insulin gene. Relationships with atherosclerosis, lipid levels, and age in three samples from Denmark.

Tybjærg‐Hansen¹,

Gerdes²,

Overgaard³

et al. 1990

Arteriosclerosis

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VariationsIn the DNA sequence flanking the 5' region of the human Insulin gene (U-and L-alleles) were studied in relation to atherosclerosis, lipid levels, and age In three groups of atherosclerotic Individuals and in nonatherosclerotlc controls. The atherosclerotic groups comprised a postmyocardlal infarction group with a mean age of 48 years, a group of Individuals operated on for carotid stenosis with a mean age of 62 years, and a group of 85-year-olds with clinical coronary disease, peripheral arterial disease, or both. All 331 individuals were unrelated Caucasians of Danish ancestry. There were no significant differences (p>0.05) In genotype distribution or allele frequencies between atherosclerotic and nonatherosclerotlc Individuals, but In the 85-year-olds, there was evidence (p<0.10) for a lower U-allele frequency in nonatherosclerotlc women compared to atherosclerotic women. In nonatherosclerotlc women, there was a significant decrease In U-allele frequency with age (60 to 85 years). This decrease does not prove conclusively, but Is compatible with, the hypothesis that the U-allele predisposes to, or the L-allele protects against, atherosclerosis. The possible effect of the U-allele on the development of atherosclerosis does not seem to be mediated through conventional risk factors. (Arteriosclerosis 10:372-378, May/June 1990)

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“…Genomic analyses in man have revealed restriction fragment length polymorphisms (RFLPs) for these loci. Various RFLPs were found with higher frequencies in disease groups than in controls (Mandrup-Poulsen et al 1985, Rees et al 1985b, Ordovas et al 1986, Hegele e t al. 1986).…”

mentioning

confidence: 92%

“…In addition to exogenous factors, genetic factors appear to be involved in the pathogenesis of coronary heart disease (CHD) (Berg 1985). Sequence variations in the apoprotein genes (Humphries 1988) and in the 5' flanking region of the insulin gene (Mandrup-Poulsen et al 1985) were thought t o be candidates for playing a part in coronary risk. Genomic analyses in man have revealed restriction fragment length polymorphisms (RFLPs) for these loci.…”

mentioning

confidence: 99%

Restriction fragment length polymorphisms at the apoprotein genes AI, CIII and B‐100 and in the 5‘ flanking region of the insulin gene as possible markers of coronary heart disease

1995

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Several sequence variations were examined for being endogenous “risk markers” in the development of CHD. The “markers” in this study included: the PstI‐SstI RFLPs in the apo AI‐CIII gene cluster, the EcoRI‐MspI RFLPs in the apo B100 gene and the SstI RFLP in the 5‘ flanking region of the insulin gene. The study population comprised 700 individuals of German origin. A strong association of these “markers” to the disease phenotype predicts their loss in healthy individuals with ages above that of the prevalent incidence of CHD. In contrast, these “markers” should accumulate in diseased persons. A significant age‐dependent selection was observed for the EcoRI RFLP in the apo B100 gene. This was the case when the allele and genotype frequencies of healthy old individuals were compared with those of newborns. In contrast, no RFLP showed significant differences in allele and genotype distributions between patients defined by coronary angiography and controls. In the group of patients, but not controls, several RFLP genotypes were found to be associated with significantly higher serum levels of cholesterol and triglycerides. This was true in the case of serum cholesterol comparing the genotypes S1S2 with those of S1S1 (p=0.05) observed for the SstI polymorphic site in the 3’ noncoding region of the apo CIII gene. Significantly higher levels of triglycerides were found within the heterozygous patients P1P2 (p=0.045) and S1S2 (p=0.02) than in the homozygotes P1P1 and S1S1 for the PstI‐SstI RFLPs at the apo AI‐CIII gene cluster. The SstI RFLP in the 5‘ flanking region of the insulin gene also revealed significantly higher values of triglycerides among the patients with the genotype UU compared to the heterozygotes LU (p=0.005) and to the homozygotes LL (p=0.0008). Among the patients, the combined genotype P1P2 S1S2 for the PstI‐SstI RFLPs at the apo AI‐CIII genes first had higher serum cholesterol levels than the genotype P1P2 S1S1 (p=0.02) and secondly had higher values of serum triglycerides compared to the genotypes: P1P1 S1S1 (p=0.01), P1P2 S1S1 (p=0.02) and P1P1 S1S2 (p=0.03).

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Insulin-gene flanking sequences, diabetes mellitus and atherosclerosis: a review

Cited by 18 publications

References 47 publications

Insulin Gene in Diabetes Analysis Through RFLP

Insulin Gene in Diabetes Analysis Through RFLP

Polymorphism in 5' flanking region of human insulin gene. Relationships with atherosclerosis, lipid levels, and age in three samples from Denmark.

Restriction fragment length polymorphisms at the apoprotein genes AI, CIII and B‐100 and in the 5‘ flanking region of the insulin gene as possible markers of coronary heart disease

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