IGFs are important regulators of pancreatic beta-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, ...birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI.
A Genome-Wide Search for Linkage-Disequilibrium With Type 1 Diabetes in a Recent Genetically Isolated Population From the
Netherlands
Norbert Vaessen 1 ,
Peter Heutink 1 ,
Jeanine J. ...Houwing-Duistermaat 1 ,
Pieter J.L.M. Snijders 1 ,
Tessa Rademaker 1 ,
Leon Testers 1 ,
Manou R. Batstra 2 ,
Lodewijk A. Sandkuijl 1 ,
Cornelia M. van Duijn 1 and
Ben A. Oostra 1
1 Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Department of Clinical Genetics, Erasmus Medical
Center Rotterdam, Rotterdam, the Netherlands
2 Department of Pediatrics, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
Abstract
Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ
region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome scans have identified >18 other genomic regions
that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the
genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in
mapping susceptibility loci than in complex outbred populations. We describe a genome-wide search in a recently Dutch isolated
population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a
genome-wide scan using a combined linkage- and association-based approach. In addition to the HLA locus, evidence for type
1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and
17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved
ancestral haplotype was found for chromosome 8q24.
Footnotes
Address correspondence and reprint requests to Prof. Dr. B.A. Oostra, Genetic Epidemiology Unit, Department of Clinical Genetics,
Erasmus Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands. E-mail: oostra{at}kgen.fgg.eur.nl .
Received for publication 29 June 2001 and accepted in revised form 15 November 2001.
DIABETES
Increased serum iron is found to be a risk factor for stroke. Carriers of HFE C282Y and H63D mutations have elevated serum iron levels and may have an increased risk for stroke. We studied the ...association between HFE gene mutations, carotid atherosclerosis, and stroke.
We compared the frequency of the HFE C282Y and H63D gene mutations in 202 prevalent and incident cases of stroke with that of 2730 controls from a population-based study, the Rotterdam Study. The influence of HFE mutations on the relationship between hypertension, smoking, and stroke was studied by use of a logistic regression model. In the analyses of hypertension, we used noncarriers and nonhypertensives as reference; in the analysis of smoking, we used noncarriers and those who never smoked as the reference group. Furthermore, we studied the mean intima-media thickness of the common carotid artery in relation to hypertension, smoking, and the HFE genotype in subjects without stroke.
The percentage of both C282Y and H63D carriers in cases (43.7%, n=87) did not differ significantly (P=0.09) from that of controls (37.6%, n=986). The odds ratio for stroke for HFE carriers who also suffered from hypertension was 3.0 (95% CI, 1.9 to 4.6), and for HFE carriers who were also smokers, the odds ratio for stroke was 2.6 (95% CI, 1.4 to 5.0). The mean+/-SD intima-media thickness of the carotid artery was 0.77+/-0.14 mm for noncarriers without a history of hypertension or smoking compared with 0.81+/-0.17 mm for HFE carriers who smoked (P<0.004) and 0.84+/-0.20 mm for HFE carriers who were hypertensive (P<0.001).
Mutations in the HFE gene were not significantly related to stroke or atherosclerosis in the carotid artery. The HFE gene may modify the relationship between smoking and stroke.
The role of estrogens in Alzheimer's disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) ...alpha gene and the risk of AD in a prospective study of 6056 Caucasian older men and women aged 55 years and over. In a subset of 468 participants, we assessed volumes of the hippocampus and amygdala, which have a high density of ER alpha, with brain magnetic resonance imaging (MRI) (1.5 T MR unit). During a total of 35 405 person-years of follow-up (mean per persons 5.8 years), 312 new cases of dementia were detected, of whom 230 were diagnosed with AD. Neither the PvuII nor the XbaI polymorphism or haplotypes thereof were associated with the risk of all-cause dementia or AD. In contrast, we found that nondemented women who carried the PvuII p allele or haplotype 'px' had smaller amygdalar volumes on MRI in an allele-dose-dependent fashion. Total amygdalar volume was 4.50 (SE 0.10) in PP genotype, 4.45 (SE 0.06) in Pp genotype, and 4.18 ml (SE 0.08) in pp genotype (P trend=0.008). Further studies are required to investigate whether this smaller amygdalar volume has functional significance.
In this paper a nonlinear elliptic-parabolic system which arises in a two-dimensional groundwater flow problem is studied. Abstract results on evolution equations are employed to obtain existence and ...uniqueness results. Regularity and stability properties of the solution are also considered.
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