New ways in respiratory genetics.
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Alleles↗
Biomedical subjects
M Kabesch
Publications and source records attributed to M Kabesch.
[Childhood allergies are increasing enormously. Is it genetics or the environment?].
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Age Factors↗
[Genetics and allergies: consequences for the practitioner?].
Atopic disorders (asthma, hay fever, atopic dermatitis) may develop on the basis of a genetic predisposition towards environmental factors. These complex genetic conditions do not follow Mendelian inheritance patterns. Rather, the genetic predisposition for atopic diseases is based on a combination of changes affecting several genes which are involved in a variety of pathophysiological mechanisms. A number of candidate genes for asthma and allergies have already been identified. Today, it seems possible to identify genetic risk profiles related to specific environmental conditions which should lead to an improvement in diagnostic, preventive and therapeutic measures. However, before genetic diagnostic can be implemented in clinical practice, further studies are needed.
Asthma↗
Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample.
BACKGROUND: Atopic diseases are characterized by immunoglobulin E (IgE)-mediated immune responses towards common allergens, many of which are proteases. Recently it has been suggested that a proteinase inhibitor gene, SPINK5, which is located on chromosome 5q31, may play a role in the pathogenesis of atopic diseases. OBJECTIVE: We investigated the association between the polymorphism G1258A leading to a putative amino acid change (Glu420Lys) in serine protease inhibitor, kazal type 5 (SPINK5) and phenotypes of atopic diseases in a large general population sample of German children. METHODS: Parental questionnaires were used and children underwent skin prick testing, pulmonary function testing and bronchial challenge. Blood was collected for serum IgE measurements and DNA extraction. In total, 1161 children were genotyped for the SPINK5 Glu420Lys polymorphism and association studies were performed. RESULTS: A significant association between SPINK5 420Lys and the development of asthma was observed (OR 1.77; 95%CI: 1.02-3.06, P=0.041 for 420Lys homocygotes). Atopic carriers of SPINK5 420Lys showed an increased risk for asthma and asthma symptoms (OR 2.06; 95%CI: 1.01-4.20, P=0.047). When children with a combination of asthma and atopic dermatitis were compared with normal controls, the SPINK5 420Lys genotype was more prevalent in the disease group (OR 4.56; 95%CI: 1.370-15.12, P=0.007). No association between SPINK5 420Lys genotypes and total serum IgE levels, skin prick test (SPT) reactivity or atopic dermatitis was observed. CONCLUSION: These results suggest that SPINK5 Glu420Lys polymorphism may be associated with certain asthma phenotypes characterized by the concomitant expression of asthma and atopic dermatitis or SPT reactivity.
Asthma↗
A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases.
BACKGROUND: A polymorphism in the promoter region of the CD14 gene, C-159T, has been shown to be associated with increased levels of soluble CD14 (sCD14) and decreased serum immunoglobulin E (IgE) and the expression of a more severe atopic phenotype in previous studies. METHODS: To test if these associations are consistently found in different populations and different age groups, we genotyped 2048 children of different age groups as well as 888 adults from different regions of Germany for the CD14 C-159T polymorphism. RESULTS: While an association between this promoter polymorphism and levels of sCD14 could be confirmed in our study population (CC: 1017 ng/ml vs TT: 1370 ng/ml, P = 0.03), no association between CD14 C-159T genotypes and IgE levels or the prevalence of atopic diseases was seen. CONCLUSIONS: The lack of association between CD14 genotypes and IgE as well as atopic outcomes in this large German study population seems to indicate that CD14 genotypes may not directly be involved in the development of allergies during childhood.
Adult↗
Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults.
BACKGROUND: Several studies have shown linkage of chromosome 12q 13-24 with atopy related phenotypes. Among candidate genes in this region is STAT6 (signal transducer and activator of transcription), which is essential for Th2 cell differentiation, recruitment, and effector function. METHODS: We evaluated six polymorphisms of STAT6 for evidence of associations with serum IgE levels and atopic diseases in a population based cross sectional cohort of 1407 German adults. Genotyping was performed using the matrix assisted laser desorption ionisation-time of flight mass spectrometry method. Haplotypes were estimated using the SAS/Genetics module, and population-derived IgE percentiles (50% IgE>53 kU/l, 66% IgE>99 kU/l and 90% IgE>307 kU/l) were modelled as outcome variables in haplotype trend regression analysis. RESULTS: All polymorphisms were genotyped successfully. Haplotype reconstruction revealed 8/64 possible haplotypes, reaching estimated frequencies of 1% or more. One polymorphism in intron 2 (rs324011) showed a significant association with total serum IgE (p = 0.015). A STAT6 risk haplotype for elevated IgE showing odds ratios of 1.7 (p = 0.015) for IgE cut-off 100 kU/l, and 1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE percentiles 50%, 66%, and 90%, respectively was detected. The increased risk of this haplotype was confirmed by linear haplotype trend regression on log transformed IgE values (p = 0.007). Analysis further revealed a risk haplotype for specific sensitisation and a risk haplotype for asthma. CONCLUSION: The data indicate that genetic variants within STAT6 contribute significantly to IgE regulation and manifestation of atopic diseases.
Adult↗
Glutathione S transferase deficiency and passive smoking increase childhood asthma.
BACKGROUND: It has been suggested that the genetically determined deficiency of glutathione S transferase (GST) enzymes involved in the detoxification of environmental tobacco smoke (ETS) components may contribute to the development of asthma. METHODS: A large population of German schoolchildren (n = 3054) was genotyped for deficiencies of the GST isoforms M1 and T1. The association between GSTM1 and GSTT1 genotypes and asthma as well as atopy was investigated with respect to current and in utero ETS exposure. RESULTS: In children lacking the GSTM1 allele who were exposed to current ETS the risk for current asthma (OR 5.5, 95% CI 1.6 to 18.6) and asthma symptoms such as wheeze ever (OR 2.8, 95% CI 1.3 to 6.0), current wheezing (OR 4.7, 95% CI 1.8 to 12.6) and shortness of breath (OR 8.9, 95% CI 2.1 to 38.4) was higher than in GSTM1 positive individuals without ETS exposure. Hints of an interaction between ETS exposure and GSTM1 deficiency were identified. In utero smoke exposure in GSTT1 deficient children was associated with significant decrements in lung function compared with GSTT1 positive children not exposed to ETS. CONCLUSIONS: GSTM1 and GSTT1 deficiency may increase the adverse health effects of in utero and current smoke exposure.
Asthma↗
[Prevention of asthma in childhood].
SUMMARY: Environmental factors during early childhood seem to influence the onset of asthma, a disease that affects 10% of all German children, respectively. Prevention strategies are needed to reduce the burden of the disease. Breast feeding and the avoidance of environmental tobacco smoke exposure are recommended for primary prevention. Furthermore, secondary prevention measurements are suggested to reduce the onset of symptoms, once the disease is present.
Air Pollution, Indoor↗
Clinical, biochemical and molecular genetic data in five children with Gitelman's syndrome.
Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT). The main clinical symptoms are: muscular weakness, carpopedal spasm, constipation and short stature. The diagnosis was suspected in five children according to clinical criteria. All patients exhibited carpopedal spasm during febrile illness, three patients had short stature. Biochemical features were: metabolic alkalosis, hypokalemia, hypomagnesemia, low IGF-I levels, hyperkaliuria, hypernatriuria, hypocalciuria and normoprostaglandinuria. Three patients had elevated plasma renin activity and hyperaldosteronism. Mutational analysis of the NCCT gene confirmed the diagnosis in all five patients. Different forms of therapy, potassium and magnesium substitution, spironolactone and indomethacin failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized IGF-I levels in the three patients with short stature. During therapy, clinical symptoms disappeared. We conclude that Gitelman's syndrome is a disorder with a variable symptom profile, but can be suspected on clinical signs already in early childhood. The early diagnosis is essential in preventing complications.
Adolescent↗
A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children.
BACKGROUND: Increased levels of total serum IgE are a strong risk factor for the development of asthma. IgE is also involved in host defenses against parasites and fungi. Linkage of total serum IgE with markers located close to the 3 Mb cluster of cytokine genes in chromosome 5q31 has been reported. IL-4 or IL-13 are regarded as essential for IgE synthesis. OBJECTIVE: We tested whether polymorphisms in the IL-13 gene might explain the linkage between chromosome 5q31 and total serum IgE levels. METHODS: We used denaturing HPLC to detect polymorphisms in overlapping PCR fragments of the IL-13 gene including promoter and 3' untranslated regions. After sequencing was performed to identify the locations of the polymorphisms, PCR and primer-induced restriction site assays were used to genotype subjects in 3 unselected populations. RESULTS: We report here 7 polymorphisms (6 novel) in IL-13. Four of these polymorphisms are tightly linked to a variant in the terminal portion of the coding region of the gene that results in a predicted amino acid change in residue 130 (Arg130Gln). The Gln form is strongly associated (P =.000002) with increased serum IgE levels in 3 different populations comprising a total of 1399 children. Two additional polymorphisms in the promoter region of IL-13 are more loosely linked to Arg130Gln and are also less significantly associated with total serum IgE levels. CONCLUSION: These data suggest that the Arg130Gln polymorphism in IL-13, or others in close linkage with it, is associated with the development of the elevated serum IgE phenotype.
Asthma↗
Lower prevalence of asthma and atopy in Turkish children living in Germany.
Ethnic origin has been reported to affect the prevalence of atopic diseases in several studies in different parts of the world. However, little is known about the prevalence of asthma and atopy in immigrants living in Europe. The objective of this study was to evaluate the prevalence of asthma and atopy in Turkish children living in Germany and to investigate the role of ethnic origin on the development of asthma and atopy in this population. In a cross-sectional survey the prevalence of physician-diagnosed asthma, atopy, skin-prick tests and bronchial hyperresponsiveness (BHR) to cold dry air challenge was assessed in 7,445 school children aged 9-11 yrs, living in Munich, south Germany. Questionnaires were distributed to the parents for self-completion and children underwent skin prick tests and cold air hyperventilation challenge. The Turkish children showed a significantly lower prevalence of asthma (5.3 versus 9.4%, p<0.05) than their German peers. Furthermore, atopy, as assessed by skin prick tests (24.7 versus 36.7%, p<0.001) and BHR (3.9 versus 7.7%, p<0.001), was less common in Turkish children. In multivariate regression models controlling for potential explanatory factors, Turkish origin still showed a significantly lower risk of developing asthma, atopic sensitization and BHR. The prevalence of childhood asthma was therefore shown to be lower in Turkish children living in Germany than in Turkey. These findings suggest that the lower prevalence of asthma and allergy in Turkish children living in Germany might be attributable to a selection bias affecting the parents of these children, as healthy individuals may have decided to come to Germany for work.
Age Distribution↗