8 research outputs found
AT1 receptor A/C1166 polymorphism contributes to cardiac hypertrophy in subjects with hypertrophic cardiomyopathy
The development of left ventricular hypertrophy (LVH) in subjects with
hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for
modifying factors such as angiotensin II. We investigated whether the
angiotensin II type 1 receptor (AT1-R) A/C1166 polymorphism, the
angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism,
and/or plasma renin influence LVH in HCM. Left ventricular mass index
(LVMI) and interventricular septal thickness were determined by
2-dimensional echocardiography in 104 genetically independent subjects
with HCM. Extent of hypertrophy was quantified by a point score (Wigle
score). Plasma prorenin, renin, and ACE were measured by immunoradiometric
or fluorometric assays, and ACE and AT1-R genotyping were performed by
polymerase chain reactions. The ACE D allele did not affect any of the
measured parameters except plasma ACE (P<0.04). LVMI was higher (P<0.05)
in patients carrying the AT1-R C allele (190+/-8.3 g/m2) than in AA
homozygotes (168+/-7.2 g/m2), and similar patterns were observed for
interventricular septal thickness (23.0+/-0.7 versus 21. 6+/-0.7 mm) and
Wigle score (7.0+/-0.3 versus 6.3+/-0.3). Plasma renin was higher (P=0.05)
in carriers of the C allele than in AA homozygotes. Multivariate
regression analysis, however, revealed no independent role for renin in
the prediction of LVMI. Plasma prorenin and ACE were not affected by the
AT1-R A/C1166 polymorphism, nor did the ACE and AT1-R polymorphisms
interact with regard to any of the measured parameters. We conclude that
the AT1-R C1166 allele modulates the phenotypic expression of hypertrophy
in HCM, independently of plasma renin and the ACE I/D polymorphism
A genome-wide search for linkage-disequilibrium with type 1 diabetes in a recent genetically isolated population from the Netherlands
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
Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura
Migraine is a common neurological disease of two main types: migraine with aura and migraine without aura. Familial clustering suggests that genetic factors are involved in the etiology of migraine. Recently, a gene for familial hemiplegic migraine, a rare autosomal dominant subtype of migraine with aura, was mapped to chromosome 19p13. We tested the involvement of this chromosomal region in 28 unrelated families with the common forms of migraine with and without aura, by following the transmission of the highly informative marker D19S394. Sibpair analysis showed that affected sibs shared the same marker allele more frequently than expected by chance. Our findings thus also suggest the involvement of a gene on 19p13 in the etiology of the common forms of migraine
Refined localization of TSC1 by combined analysis of 9q34 and 16pl3 data in 14 tuberous sclerosis families
Tuberous sclerosis (TSC) is a heterogeneous trait. Since 1990, linkage studies have yielded putative TSC loci on chromosomes 9, 11, 12 and 16. Our current analysis, performed on 14 Dutch and British families, reveals only evidence for loci on chromosome 9q34 (TSC1) and chromosome 16p13 (TSC2). We have found no indication for a third locus for TSC, linked or unlinked to either of these chromosomal regions. The majority of our families shows linkage to chromosome 9. We have refined the candidate region for TSC1 to a region of approximately 5 c M between ABL and ABO
A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees
An autosomal locus causing autoimmune disease: Autoimmune polyglandular disease type I assigned to chromosome 21
Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does not show association to specific HLA haplotypes. Unravelling the APECED locus will identify a novel gene outside the HLA loci influencing the outcome of autoimmune diseases. We have assigned the disease locus to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Linkage disequilibrium studies have significantly increased the informativeness of the analyses and helped to locate the critical DNA region for the APECED locus to just 500 kilobases, a much more precise definition than linkage analyses alone could achieve
Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group
The fragile X syndrome is an X-linked mental retardation disorder caused
by an expanded CGG repeat in the first exon of the fragile X mental
retardation (FMR1) gene. Its frequency, X-linked inheritance, and
consequences for relatives all prompt for diagnosis of this disorder on a
large scale in all affected individuals. A screening for the fragile X
syndrome has been conducted in a representative sample of 3,352
individuals in schools and institutes for the mentally retarded in the
southwestern Netherlands, by use of a brief physical examination and the
DNA test. The attitudes and reactions of (non)consenting parents/guardians
were studied by (pre- and posttest) questionnaires. A total of 2,189
individuals (65%) were eligible for testing, since they had no valid
diagnosis, cerebral palsy, or a previous test for the FMR1 gene mutation.
Seventy percent (1,531/2,189) of the parents/guardians consented to
testing. Besides 32 previously diagnosed fragile X patients, 11 new
patients (9 males and 2 females) were diagnosed. Scoring of physical
features was effective in preselection, especially for males (sensitivity
.91 and specificity .92). Major motives to participate in the screening
were the wish to obtain a diagnosis (82%), the hereditary implications
(80%), and the support of research into mental retardation (81%).
Thirty-four percent of the parents/guardians will seek additional
diagnostic workup after exclusion of the fragile X syndrome. The
prevalence of the fragile X syndrome was estimated at 1/ 6,045 for males
(95% confidence interval 1/9,981-1/ 3,851). On the basis of the actual
number of diagnosed cases in the Netherlands, it is estimated that >50% of
the fragile X cases are undiagnosed at present
Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23
Manic-depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome of two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fullfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak rod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region