Genetic-environmental interactions in asthma and allergy: a study in a closed population exposed to different environments.

BACKGROUND: Asthma and allergy are common chronic diseases caused by genetic and environmental factors. OBJECTIVE: To study the effect of different environments on the prevalence of both diseases in an isolated founder population that resettled in different geographic and environmental areas (namely, the genetically homogeneous population that immigrated to Israel from Cochin, India, 50 years ago). METHODS: Respiratory and allergy symptoms were recorded by a questionnaire. The relative contribution of genetic factors on asthma and allergy was established by comparing Cochin with non-Cochin Jews living in the Jerusalem mountains; the relative contribution of the environment was determined by comparing mountain Cochin Jews with those living in the desert. The study was conducted from January to October 2004. RESULTS: A total of 983 individuals (481 mountain Cochins, 353 desert Cochins, and 149 non-Cochins) were studied. The overall prevalence of asthma in Cochins was 23.7%; and of allergy, 29.5%. The rate of asthma and/or allergy in Cochins in the mountains was significantly higher than in control non-Cochins. The rates of both asthma and allergy among Cochin Jews in the mountains were significantly higher than those among Cochin Jews in the desert, the former because of a higher prevalence of allergic asthma. The rates of nonallergic asthma and allergy without asthma were similar in both environments. CONCLUSIONS: Two different asthma and allergy phenotypes were detected that share a distinct genetic background but differ in the environmental influences. Allergic asthma is strongly determined by both genetic and environmental factors, whereas nonallergic asthma or atopy without asthma is determined mainly by genetic factors and is less influenced by environmental factors.

Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.

Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.