Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed an extremely strong association between type 2 diabetes and a private polymorphism, namely G319S, in the hepatocyte nuclear transcription factor (HNF)-1alpha. Because HNF-1alpha is involved in the transcription of several apolipoprotein genes, we tested for an association between the private HNF1A G319S variant and plasma lipoproteins in a sample of 55 unrelated Oji-Cree subjects with type 2 diabetes and 175 unrelated Oji-Cree subjects without type 2 diabetes. In Oji-Cree subjects with type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with lower plasma concentrations of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein (apo) B. In Oji-Cree subjects without type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with higher plasma concentrations of high density lipoprotein cholesterol and apo AI. There were no associations with plasma triglycerides or lipoprotein(a). Regression analysis indicated that the HNF1A genotype accounted for approximately 10% of the variation in the apo B-related traits in the diabetic subjects and for approximately 5% of the variation in the apo AI-related traits in the nondiabetic subjects. Furthermore, the regression model indicated that the HNF1A S319 allele affected these traits in a dominant manner in subjects with and without type 2 diabetes. These findings provide the first evidence that a rare variant in a nuclear transcription factor is associated with variation in plasma lipoprotein traits.
 ...
PMID:The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree. 1063 21

In parallel experiments designed to find the genetic determinants of type 2 diabetes in Oji-Cree, we identified several linked chromosomal regions, using genomic scanning, in addition to a private diabetes-associated mutation, namely HNF1A G319S, using candidate gene sequencing. The genome scan did not identify the region harboring HNF1A as being linked with diabetes. Also, the HNF1A mutation, when used directly in sib-pair linkage analysis, was not linked with diabetes. However, HNF1A G319S was very strongly associated with diabetes, predicted the clinical severity of diabetes, and performed well as a diagnostic predictive test for diabetes in the Oji-Cree. Despite the failure of linkage analysis to identify HNF1A as a determinant of type 2 diabetes, we feel justified in interpreting that G319S has a very important pathogenic role in Oji-Cree diabetes, based upon the highly suggestive association studies. The probable etiologic heterogeneity of type 2 diabetes in the Oji-Cree created a situation in which association analysis was much more sensitive to detect a relationship between HNF1A S319 and diabetes than was linkage analysis. The effectiveness of linkage analysis will probably be limited in study samples that have an even greater complexity of genetic background and/or disease etiology. Thus, the absence of linkage does not always mean that a genomic variant is not an important determinant of a complex disease. Furthermore, our experience confirms the value of using several complementary strategies to identify susceptibility genes for a complex disease.
 ...
PMID:Disparity between association and linkage analysis for HNF1A G319S in type 2 diabetes in Canadian Oji-Cree. 1080 46

Among the Oji-Cree of northern Ontario, we previously identified a novel variant in the HNF1A gene, namely G319S, that was strongly associated with type 2 diabetes. However, the majority of subjects with diabetes did not have the HNF1A S319 variant, suggesting that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, we found that some of them had the PPARG A12 variant. After genotyping PPARG in the entire adult Oji-Cree population, we found that: 1) PPARG A12 was strongly associated with type 2 diabetes in women, but not men; 2) among women, the odds of being affected for carriers of PPARG A12 compared with noncarriers was 2.3 (95% confidence interval, 1.4-3.8); and 3) among women, affected carriers of PPARG A12 had a significantly earlier age-of-onset and/or age-at-diagnosis compared with noncarriers. When taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least two genes are involved in determining susceptibility to the disease in these people.
 ...
PMID:Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree. 1084 90

Among the Oji-Cree of northern Ontario, women have both a higher prevalence and an earlier onset of type 2 diabetes compared to men. We studied the relationship between HNF1A S319 and both the presence of and the age-of-onset of type 2 diabetes in women and men separately. We found that: 1) in women, there was a significant difference in the mean age-of-onset of type 2 diabetes according to HNF1A genotype; and 2) in men, there was no difference in the mean age-of-onset of type 2 diabetes according to HNF1A genotype. The findings indicate that HNF1A S319 is associated with increased susceptibility to type 2 diabetes in both men and women, but with earlier age-of-onset in women only. One factor that might account for the gender difference in the onset of HNF1A S319-associated type 2 diabetes is the greater prevalence and severity, and earlier onset of, obesity among female Oji-Cree.
 ...
PMID:Gender, obesity, hepatic nuclear factor-1alpha G319S and the age-of-onset of type 2 diabetes in Canadian Oji-Cree. 1095 47

The incidence of coronary heart disease (CHD) among aboriginal people in northern Ontario has tripled over the past 20 years. This is inextricably linked to the remarkably high prevalence of type 2 diabetes in these native communities. Approximately 40% of the Oji-Cree of northern Ontario have typical obesity-related type 2 diabetes, which represents a drastic increase from virtually unreportable levels 50 years ago. The Oji-Cree have a private mutation in the HNF1A gene, namely G319S, which is absent from other ethnic groups and aboriginal populations. The most compelling reasons that HNF1A S319 is a diabetes-susceptibility allele are its consistent statistical association with the presence and severity of diabetes. Also, HNF1A S319 has specificity and positive predictive values of 97% and 95%, respectively, for the development of diabetes in the Oji-Cree by 50 years of age. This makes the HNF1A G319S genotype the most specific predictive genetic test for diabetes in any human population. HNF1A S319 has all the attributes of a thrifty allele in the Oji-Cree. It is possible that the recent increase in CHD in the aboriginal people of northern Ontario is the result of the expression of diabetes susceptibility due to HNF1A S319 as a consequence of rapid changes in environment and lifestyle.
 ...
PMID:Genes and environment in type 2 diabetes and atherosclerosis in aboriginal Canadians. 1128 43

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A, which encodes hepatic nuclear factor-1alpha (HNF-1alpha), was associated with Oji-Cree type 2 diabetes and was found in approximately 40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1alpha to activate transcription by approximately 50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant negative effect of the mutant protein. The impact of the G319S mutation at the population level was assessed by classifying subjects with type 2 diabetes according to HNF1A genotype and plotting the cumulative age of onset of diabetes. Disease onset was modeled satisfactorily by two-parameter sigmoidal functions for all diabetic subjects and all three HNF1A genotypes. Pairwise statistical comparisons showed significant between-genotype differences in t50 (all P < 0.00001), corresponding to the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by approximately 7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for HNF1A G319S provides a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health dilemma. The findings also show that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young.
 ...
PMID:HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. 1190 71

Maturity onset diabetes of the young (MODY) is a genetically heterogeneous form of type 2 diabetes that is characterized by autosomal dominant inheritance, onset in early adulthood and a primary defect in insulin secretion. Mutations in at least six genes have been shown to underlie MODY, including mutations in GCK (encoding glucokinase, also called MODY2) and mutations in HNF1A (encoding hepatocyte nuclear factor-1alpha, also called MODY3). We sequenced genomic DNA from probands of seven Canadian MODY families. In four probands, we detected four novel GCK mutations, namely IVS2-7G>A, G72R, T206R and S263P. In three other probands, we detected three HNF1A mutations, of which two were novel, namely 1051delCA and Q250X, and one had been previously reported, namely R131Q. The novel mutations expand the spectrum of MODY mutations. In addition, knowledge of the specific defect can be used to pre-symptomatically identify family members at risk for developing MODY.
 ...
PMID:GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY). 1244 80

The prevalence of type 2 diabetes in Canadian Oji-Cree is among the highest in the world. Our research has uncovered genetic determinants of Oji-Cree type 2 diabetes and related metabolic traits. The most important genetic discovery by far was the private G319S mutation in transcription factor HNF-1alpha, encoded by the HNF1A gene. HNF1A G319S was discovered by candidate gene sequencing and would have been missed using the currently favored strategy of genome-wide scanning. G319S was associated with increased odds of having type 2 diabetes across the whole study sample and in all subgroups, including adolescent Oji-Cree. Furthermore, G319S had specificity and positive predictive value of 97% and 95%, respectively, for developing type 2 diabetes by age 50. The protein bearing the G319S mutation had impaired function in vitro. Sigmoidal modeling showed that each dose of the G319S allele accelerated the median age of diabetes onset by about 7 yr. This approach also showed that environment more strongly accelerated the median age-of-onset of Oji-Cree diabetes onset than did G319S, which could have implications for intervention strategies to reduce the burden of this epidemic. There is also evidence for genetic determination of related metabolic traits in the Oji-Cree.
 ...
PMID:Genes, environment and Oji-Cree type 2 diabetes. 1272 23

Maturity-onset diabetes of the young is a genetically heterogeneous autosomal dominant form of diabetes mellitus, characterized by an early age at onset and a primary defect in beta-cell function. Forty families with a clinical presentation suggestive of MODY were screened for the most common MODY subtypes caused by mutations in the genes encoding glucokinase (GCK, MODY2) and hepatocyte nuclear 1-alpha (HNF1A/TCF1, MODY3). Overall, 14 mutations were found (35%) giving a relative frequency of 22.5% and 12.5% for MODY2 and MODY3, respectively. Five of the nine GCK mutations identified were novel and included two deletions, two nonsense, and one splice site mutation. The GCK splice donor mutation was shown to result in an aberrant transcript owing to the recruitment of a cryptic splice site. The translated protein is predicted to contain an in frame insertion of nine amino acids. Among the five HNF1A mutations identified, three were novel comprising one missense mutation, one deletion, and one insertion. In addition, several novel polymorphisms within GCK were identified and their allele frequencies estimated. Knowledge of the genetic cause of MODY has significant impact on therapeutic decision making and may help to identify family members at risk for diabetes.
 ...
PMID:Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY). 1584 81

Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r(2)< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.
 ...
PMID:Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns. 1693 1


1 2 3 4 5 6 7 8 9 Next >>