Polymorphism in the 5′ Flanking Region of the Human Insulin Gene: A Genetic Marker for Non-Insulin-Dependent Diabetes (original) (raw)
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Science (New York, N.Y.), 1981
The arrangement of the human insulin gene in DNA from 87 individuals was analyzed by the Southern blot hybridization technique with a cloned genomic human insulin probe. Insertions of 1.5 to 3.4 kilobase pairs in the 5'-flanking region of the gene were found in DNA from 38 individuals. These insertions occurred within 1.3 kilobase pairs of the transcription initiation site. In contrast, no insertions were observed in the region 3' to the coding sequence. The prevalence of these insertions in type 2 diabetes was significantly greater than in the other groups (P less than .001). The limitation of this striking length polymorphism to a potential promoter region suggests that these insertions may play a role in insulin gene expression.
European Journal of Clinical Investigation, 1988
Abstract. Sixty-four unrelated healthy subjects were studied for the detection of a DNA polymorphism at the 5′ end of the insulin gene. No significant difference between the groups was found in blood glucose values at fasting and after an oral glucose load. A significant association was found between fasting (P < 0·05) and after load plasma C-peptide levels (P < 0·01) and the presence of a 1·6 Kb insertion at the 5′ end of the insulin gene. A gene dose-dependent effect was noted, class 3/3 individuals having the lowest after-load C-peptide concentration and class 1/3 an intermediate level (F for the linear trend: P=0·007). This might suggest that insulin gene polymorphism affects insulin secretion in healthy individuals. In order to confirm this, a subgroup of six class 3/3 and eight class 1/1 individuals subsequently underwent a hyperglycaemic clamp. The tissue sensitivity to insulin was similar in the two groups but glucose-stimulated insulin secretion was markedly impaired in homozygotes for the class 3 allele. In this group, insulin secretion was, on average, only one-third of that in class 1/1 individuals (P < 0·02). Similarly impaired in class 3/3 persons was the glucose+arginine-stimulated insulin secretion (P < 0·05). We conclude that the polymorphism at the 5′ end of the insulin gene is associated with variations in insulin secretion in healthy humans.
Journal of medical genetics, 1992
Population studies have suggested an increased frequency of small DNA insertions (class I alleles) 5' to the insulin gene in insulin dependent (type I) diabetes mellitus (IDDM). The present study examined this relationship within families. Forty-one families with at least one diabetic offspring were studied. Analysis of the insulin gene polymorphism was performed by digestion of DNA with Bg1I, SstI, RsaI, or PvuII and hybridisation with an insulin gene probe or polymorphic region specific probes. An increased frequency of class I alleles was found among the parents of diabetics (p = 0.02), as well as a trend towards increased frequency of parents homozygous for class I alleles and matings of two homozygous subjects. This increased homozygosity for class I alleles was present in non-diabetic sibs as well (p = 0.01). These results show that ascertainment through an offspring with IDDM selects for families with high frequencies of homozygosity for the class I allele and thus sugges...
Diabetologia, 1994
Previous studies have suggested an association between polymorphisms in the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Most of the studies so far have been performed in Caucasoid populations. We have investigated 418 random IDDM patients and 422 healthy control subjects from three different ethnic groups; Tanzanian blacks, Norwegian Caucasians and Japanese orientals. Our data suggest that polymorphisms in the insulin gene region confer susceptibility to IDDM in Caucasians, and that a similar tendency though not statistically significant is observed among Tanzanian blacks, while no significant contribution is seen among Japanese orientals. We further demonstrate that the disease-associated genotype INS +/+ confers susceptibility independently of HLA class II alleles associated with IDDM. Compared to the contribution of particular HLA-DQ alleles in IDDM susceptibility, the additional risk conferred by the instdin gene region polymorphism is, however, small. Genotyping of the insulin gene region will therefore most probably not be a useful tool in the prediction of IDDM. [Diabetologia (1994) 37: Wingdingsx-Wingdingsx] [Diabetologia (1994) 37: 745-749]
Diabetes, 1995
A low acute insulin response (AIR) is a predictor of non-insulin-dependent diabetes mellitus (NIDDM) in insulin-resistant Pima Indians. We have initiated a search for regions of the genome linked with the AIR using sib-pair linkage analysis as a first step in identifying genes that are determinants of this phenotype. Eighteen short tandem-repeat polymorphisms from chromosome 1 were genotyped in over 900 Pima Indians and tested for linkage with NIDDM and in a subset of Pima Indians for linkage with AIR. The anonymous DNA marker D1S198 on chromosome lp was linked with AIR (P = 0.000056) in 175 sib pairs from 60 families, all with normal glucose tolerance, but no linkage was observed between D1S198 and NIDDM (P = 0.44, 996 sib pairs). Additional markers genotyped on chromosome 1 did not show linkage with AIR or NIDDM. This study indicates that a locus on chromosome lp may be a determinant of the phenotypic variation seen in the AIR. Diabetes 44:478-481,1995
Clinical Genetics, 2008
The significance of genetic factors for insulin release after glucose infusion was studied in 155 nuclear families of which 59 were control families and 96 had been ascertained through a parent with onset of diabetes after 30 years of age. Fasting insulin and glucose as well as three principal components of the insulin and glucose curves were submitted to path analysis and complex segregation analysis. The three principal components were considered to reflect the magnitude, the degree of response and the persistence of the curves. The genetic heritability of the insulin variables varied between 0.47-0.93 and that of the glucose variables between 0.20-0.54. There were considerable intergenerational differences in the genetic heritability for the persistence of the glucose curve and for the degree of response and persistence of the insulin curve. The cultural heritability was found to be of minor importance, while the non-transmitted sibling environment was large. There was significant evidence for a major locus for the persistence of the insulin curve. The best fit was for a completely recessive autosomal gene with the gene frequency 0.21. The phenotype distribution of this variable showed significant kurtosis which could simulate a major locus. However, the significant evidence for such a locus remained after an analysis using partial quantitation. The diabetics were significantly different from the non-diabetics for all the variables studied, but a complete discrimination between the diabetics and non-diabetics could not be obtained. There was no significant difference between the children of the diabetics and non-diabetics for any of the variables studied.
Arteriosclerosis, Thrombosis, and Vascular Biology, 1990
Variations in 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 nonatherosclerotic controls. The atherosclerotic groups comprised a postmyocardial 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 greater than 0.05) in genotype distribution or allele frequencies between atherosclerotic and nonatherosclerotic individuals, but in the 85-year-olds, there was evidence (p less than 0.10) for a lower U-allele frequency in nonatherosclerotic women compared to atherosclerotic women. In nonatherosclerotic women, there was a significant decrease in U-alle...
Human Genomics, 2011
Type 2 diabetes represents an increasing health burden. Its prevalence is rising among younger age groups and differs among racial/ethnic groups. Little is known about its genetic basis, including whether there is a genetic basis for racial/ethnic disparities. We examined a multi-ethnic sample of 253 healthy children to evaluate associations between insulin-related phenotypes and 142 ancestry-informative markers (AIMs), while adjusting for sex, age, Tanner stage, genetic admixture, total body fat, height and socioeconomic status. We also evaluated the effect of measurement errors in the estimation of the individual ancestry proportions on the regression results. We found that European genetic admixture is positively associated with insulin sensitivity (S I), and negatively associated with the acute insulin response to glucose, fasting insulin levels and the homeostasis model assessment of insulin resistance. Our analysis revealed associations between individual AIMs on chromosomes 2, 8 and 15 and these phenotypes. Most notably, marker rs3287 at chromosome 2p21 was found to be associated with S I (p ¼ 5.8 Â 10 25). This marker may be in admixture linkage disequilibrium with nearby loci (THADA and BCL11A) that previously have been reported to be associated with diabetes and diabetes-related phenotypes in several genome-wide association and linkage studies. Our results provide further evidence that variation in the 2p21 region containing THADA and BCL11A is associated with type 2 diabetes. Importantly, we have implicated this region in the early development of diabetes-related phenotypes, and in the genetic aetiology of population differences in these phenotypes.
Prevalence of beta allele of the insulin gene in type II diabetes mellitus
Human Genetics, 1994
Fifty-two patients and 36 controls were compared in a search for insulin gene variants among type II diabetic patients with fasting hyperinsulinemia (above 90 ~tU/ml) and a fasting C-peptide to insulin molar ratio between 1.11 and 1.50. Alpha and beta alleles of the insulin gene were characterized by restriction analysis of polymerase chain reaction (PCR) products and direct sequencing. The more frequent occurrence of the alpha allele of the insulin gene within the control population as compared with a prevalence of the beta allele in the diabetic patients (P, 0.05) was observed. The beta allele, usually described as the rare allele, seems to be associated with the disease.