Biomedical subjects

A Haagerup

Publications and source records attributed to A Haagerup.

11 recordsLinked to original sources

PubMed2006

Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene.

BACKGROUND: Asthma is a complex genetic disorder. Many studies have suggested that chromosome 12q harbours a susceptibility gene for asthma and atopy. Linkage on chromosome 12q24.21-q24.33 was investigated in 167 Danish families with asthma. METHODS: A two step procedure was used: (1) a genome-wide scan in one set of families followed by (2) fine scale mapping in an independent set of families in candidate regions with a maximum likelihood score (MLS) of > or =1.5 in the genome-wide scan. Polymorphisms in a candidate gene in the region on 12q24.33 were tested for association with asthma in a family based transmission disequilibrium test. RESULTS: An MLS of 3.27 was obtained at 12q24.33. The significance of this result was tested by simulation, resulting in a significant empirical genome-wide p value of 0.018. To our Knowledge, this is the first significant evidence for linkage on chromosome 12q, and suggests a candidate region distal to most previously reported regions. Three single nucleotide polymorphisms in splicing factor, arginine/serine-rich 8 (SFRS8) had an association with asthma (p < or = 0.0020-0.050) in a sample of 136 asthmatic sib pairs. SFRS8 regulates the splicing of CD45, a protein which, through alternative splice variants, has an essential role in activating T cells. T cells are involved in the pathogenesis of atopic diseases such as asthma, so SFRS8 is a very interesting candidate gene in the region. CONCLUSIONS: Linkage and simulation studies show that the very distal part of chromosome 12q contains a gene that increases the susceptibility to asthma. SFRS8 could act as a weak predisposing gene for asthma in our sample.

Asthma↗

PubMed2006

Highly significant linkage to chromosome 3q13.31 for rhinitis and related allergic diseases.

BACKGROUND: Allergic diseases such as asthma and rhinitis have closely related phenotypes and often occur with atopy. They show strong familial and intra-individual clustering, suggesting overlapping disease aetiology. Various loci and candidate genes have been suggested to underlie allergy. Many or all are still inconclusive. Following genome-wide scans on multiple phenotypes, we previously suggested that chromosome 3q13.12-q21.2 harbours an allergy locus. OBJECTIVE: To identify candidate loci in the Danish population, two additional independent sets of sib-pair families were fine-scale mapped in candidate regions showing maximum likelihood scores (MLS) > or =1.5 in the genome-wide scans. RESULTS: Twenty eight microsatellite markers in a denser map on chromosome 3q were analysed in 236 allergy sib-pair families including 125 sib pairs with rhinitis. We report significant evidence for linkage to chromosome 3q13.31 for rhinitis (MLS 5.55, identity by descent (IBD) 63.9%) and atopy (increased specific immunoglobulin E) (MLS 3.71, IBD 61.7%). We obtained an MLS of 5.1 (IBD 67.3%) at 3q13.31 when sib pairs with both rhinitis and atopy were analysed. CONCLUSION: This study reports the first statistically significant evidence for a genetic susceptibility locus for rhinitis and to our knowledge shows the most significant evidence to date of linkage for any allergy phenotype.

Asthma↗

PubMed2004

Fine-scale mapping of type I allergy candidate loci suggests central susceptibility genes on chromosomes 3q, 4q and Xp.

BACKGROUND: Type I allergy globally affects an increasing number of individuals with the consequence of considerable personal morbidity and socio-economic costs. Identification of disease susceptibility genes would render enormous medical perspectives in terms of improved diagnosis, treatment and prevention. Like for other complex disorders, achievement of the knowledge necessary depends on confirmation of reported genomic candidate regions. METHODS: We performed a two-stage fine-scale linkage analysis in 11 selected candidate regions on chromosome 3p, 3q, 4p, 4q, 5q, 6p, 9p, 12q, 12qter, 18q and Xp. We analysed 97 polymorphic markers in 424 individuals from 100 sib-pair families and evaluated the data for five phenotypes: Allergic asthma, atopic dermatitis, allergic rhinitis and total and specific immunoglobulin E. RESULTS: The highest maximum likelihood scores (MLS) were obtained on chromosomes 3q (MLS = 2.69), 4p (MLS = 2.34), 4q (MLS = 2.75), 6p (MLS = 2.22), 12qter (MLS = 2.15) and Xp (MLS = 2.23). All five phenotypes showed MLS >/= 2 in one or more of the candidate regions. CONCLUSIONS: Susceptibility genes in the 3q, 4q and Xp regions may play a central role in the inheritance of allergic disease, as positive results were obtained for all five phenotypes in these three regions.

Adult↗

PubMed2002

Asthma and atopy - a total genome scan for susceptibility genes.

BACKGROUND: Allergic asthma is an increasingly common disease of complex inheritance. Several studies have suggested candidate regions, but genetic heterogeneity, ethnic differences and varying study designs may in part explain the lack of identified and confirmed susceptibility genes. Investigation of different populations will further clarify the topic. We therefore evaluated allergic asthma and increased total and specific IgE in 39, 45 and 57 sib-pairs from 100 Danish allergy families. METHODS: Affected sib-pairs meeting a narrow phenotype definition were selected for the three phenotypes atopy, allergic asthma and increased total IgE. We performed a total genome scan using 446 microsatellite markers and obtained nonparametric linkage results from the MAPMAKER/SIBS computer program. RESULTS: Our study revealed four candidate regions (MLS > 2) on chromosome 1p36, 3q21-q22, 5q31 and 6p24-p22, and 15 candidate regions (1 < MLS < 2) that may contain susceptibility genes for asthma and atopy. We did not find linkage to the candidate genes TNF-beta, FcER1beta and Il4R-alpha, except for weak support for linkage of the asthma phenotype to TNF-beta (MLS = 1.18). CONCLUSIONS: We found evidence for two new asthma and atopy loci, 1p36 and 3q21-q22, and supported linkage in the Danish population to seven previously reported candidate regions.

Asthma↗

PubMed2001

No linkage and association of atopy to chromosome 16 including the interleukin-4 receptor gene.

BACKGROUND: Several susceptibility genes for atopy have been suggested in recent years. Few have been investigated as intensively as the interleukin-4-receptor alpha (IL4Ralpha) gene on chromosome 16. The results remain in dispute. Therefore, in a robust design, we tested for association of type I allergy to the IL4R variations I50V and Q576R, and investigated chromosome 16 for atopy candidate regions in general. METHODS: We identified 100 Danish allergy sib-pair families. Five conservative phenotypes for type I allergy were defined and evaluated. The IL4R variations were genotyped in trios and evaluated by the transmission disequilibrium test (TDT). Multipoint linkage analysis and exclusion mapping were conducted with sib-pairs analyzed for 17 microsatellite markers. RESULTS: No evidence for association or linkage to the IL4R polymorphisms was found (P values: 0.12-0.90). Linkage analysis did not support linkage of any of the phenotypes to chromosome 16. Major parts of chromosome 16 were excluded as candidate regions harboring oligogenes for type I allergy. CONCLUSION: We found chromosome 16 unlikely to harbor strong candidate genes for type I allergy. The role of the IL4Ralpha gene in the inheritance of atopy was insignificant in the Danish population. The use of conservative allergy phenotypes in the search for genes predisposing to atopic disease was discussed.

Child↗

PubMed2001

A new locus for Seckel syndrome on chromosome 18p11.31-q11.2.

Seckel syndrome (MIM 210600) is a rare autosomal recessive disorder with a heterogeneous appearance. Key features are growth retardation, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance. We have performed a genome-wide linkage scan in a consanguineous family of Iraqi descent. By homozygosity mapping a new locus for the syndrome was assigned to a approximately 30 cM interval between markers D18S78 and D18S866 with a maximum multipoint lod score of 3.1, corresponding to a trans-centromeric region on chromosome 18p11.31-q11.2. This second locus for Seckel syndrome demonstrates genetic heterogeneity and brings us a step further towards molecular genetic delineation of this heterogeneous condition.

Abnormalities, Multiple↗

PubMed2001

Allergic rhinitis--a total genome-scan for susceptibility genes suggests a locus on chromosome 4q24-q27.

Allergic rhinitis is a common disease of complex inheritance and is characterised by mucosal inflammation caused by allergen exposure. The genetics of closely related phenotypes such as asthma, atopy and to some extend atopic dermatitis has attracted attention in recent years. Genetic reports of allergic rhinitis on the contrary have as yet been most sparse. To identify candidate regions holding genes for allergic rhinitis we performed a total genome-scan on affected sib-pair families. From 100 Danish sib-pair families selected for allergy, families containing sib-pairs matching a phenotype definition of both clinical allergic rhinitis and confirmed specific allergy were chosen. Thirty-three affected sib-pair families qualified for the scan that was undertaken using 446 microsatellite markers. Non-parametric linkage results were obtained from MAPMAKER/SIBS computer program. The study revealed one major candidate region on chromosome 4q24-q27 (LOD=2.83) and eight minor candidate regions 2q12-q33, 3q13, 4p15-q12, 5q13-q15, 6p24-p23, 12p13, 22q13, and Xp21 (LOD=1.04-1.63) likely to contain susceptibility genes for allergic rhinitis. Our findings did not support a previous report of linkage of allergic rhinitis to chromosome 12q14-q24 but they added positive evidence to the asthma and atopy candidate regions 2q33 and 6p23. Further identification of the specific genes involved in allergic rhinitis will give opportunities for improved diagnosis and treatment.

Adolescent↗

PubMed2000

Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population.

The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.

Adolescent↗

PubMed1998

[Multiple carboxylase deficiency].

Biotinidase deficiency and holocarboxylase synthetase deficiency are two autosomal recessively inherited disorders of biotin metabolism affecting children below the age of two years. Both cause multiple carboxylase deficiency resulting in defects of fatty acid synthesis, gluconeogenesis and amino acid catabolism. The clinical picture involves the nervous system, the skin, the respiratory system, the digestive system and the immune system, but great individual variations often makes the clinical diagnosis difficult. Early diagnosis and treatment with biotin are essential in order to prevent death from metabolic acidosis or irreversible damage to the central nervous system. Two patients with biotinidase deficiency, two patients with holocarboxylase synthetase deficiency and a review of the literature are presented. Neonatal screening for biotinidase deficiency or a higher degree of metabolic screening of the urine in children below the age of one year with seizures and unexplained clinical course are discussed.

Biotin↗

PubMed1997

Biotinidase deficiency: two cases of very early presentation.

Two infants with early presentation of biotinidase deficiency (age 3 weeks and 2 weeks) are described. On admission, both children had severe neurological symptoms. In the first patient, magnetic resonance imaging (MRI) of the brain showed frontal and temporal atrophy, and in the second patient, CT of the brain showed diffuse periventricular hypodensities, particularly in the frontal region. Oral treatment with biotin (15mg and 10mg per day respectively) made all symptoms disappear within a few weeks. On follow-up 13 and 16 months later, both children were still asymptomatic on this treatment. Their psychomotor development was normal. MRI and CT of the brain had normalized. Later, a moderate hearing loss was detected in the first patient. In biotinidase deficiency, early diagnosis and treatment with oral biotin are essential in order to prevent irreversible damage to the central nervous system and early death from metabolic acidosis. Neonatal screening for biotinidase deficiency would fulfil this goal.

Amidohydrolases↗

PubMed1992

Pericentric inversion of chromosome 12; a three family study.

A pericentric inversion of chromosome 12 has been followed in three large independently ascertained Danish families. Out of a total number of 52 persons examined, 25 were found to carry the inversion. The breakpoints in all three families were localized to p13 and q13, resulting in more than one-third of the total length of the chromosomes being inverted. However, no chromosomal aberrations arising because of meiotic crossing-over inside the inverted area have been found among the offspring of the carriers. The percentage of spontaneous abortions among carriers is found to be high, viz. 33%. The segregation rate is calculated to be 0.58, which is not significantly different from an expected segregation rate of 0.5. In family 3, an additional inversion of a chromosome 9 has been found in 4 individuals. Our results are discussed in relation to previous findings and with respect to the genetic counselling of families with pericentric inversions.

Abortion, Spontaneous↗