Genetic factors in lung disease: atopy and bronchial asthma

Human CD38 is a surface molecule which has been attributed the function of a signaling channel leading to cellular activation and proliferation, an ectoenzyme with multiple function as well as an inducer of Ca2+ mobilization from cytoplasmic stores. The effect mediated by CD38 have been studied in different cell populations: the results obtained in human B cells are apparently contradictory, with CD38 simultaneously leading to apoptosis in early B cells while increasing survival in cells derived from lymph node germinal center. Other effects recently reported concern a different potential in terms of signaling in early B cells and derived cell lines or in more detailed disease models of human leukemia, namely B chronic lymphocytic leukemia cells. To complete the picture of the effects mediated by CD38 in the B cell compartment, we have studied the signals elicited by ligation of the human molecule in mature B cells from circulating pool and also from spleen of normal individuals. The information obtained completes the picture of CD38 and mature B cells, where we also studied the contribution of relevant cytokines involved in maintenance and differentiation of these normal cells, namely IL-1 alpha, IL-2, IL-4 and IL-6. Our results indicate that human CD38 plays a key role as a co-receptor in mature B cells from normal individuals.     

Mechanisms of enhanced prevalence of asthma and atopy in developed countries

Atopy--a T helper 2 cell driven hypersensitivity to innocuous antigens (allergens) which causes most cases of asthma-- is of complex genetic and environmental origins. There is compelling epidemiological evidence for a rise in atopic disease in 'westernised' communities. The changing pattern of microbial exposure in early childhood is suggested to be the principal candidate mechanism for this rise.     

The epidemiology and genetics of asthma. II. Genetic aspects of the epidemiology of asthma and atopy

Asthma is regarded as a disease with a complex interaction between genetic and environmental factors. Since the end of the 1970s and during the 80s the world has seen an increase in the prevalence, morbidity and mortality linked to asthma. The rapidity of progress of this phenomenon means that it cannot be explained only by modification of genetic factors and stresses the preponderance of exogenous factors. The purpose of this review is to examine the epidemiological knowledge of these environmental factors and of the genetic factors in asthma in order to underline how these genetic and exogenous factors interact and modulate the occurrence of the asthmatic disease. In the first part of this general review we discussed the epidemiology of asthma in terms of prevalence, incidence, mortality, cost and socio-professional and scholastic repercussions and underlined for each environmental factor its causal role and/or exacerbation in asthma as well as its contribution in the increased prevalence and severity of asthma. In the second part of this general view we touch on the epidemiological knowledge of the genetics of asthma and of atopy.     

Prevalence of wheeze and asthma and relation to atopy in urban and rural Ethiopia

BACKGROUND: Asthma and allergy in developing countries may be associated with adoption of an urbanised "western" lifestyle. We compared the rates of asthma symptoms and atopy in urban populations in Jimma, southwest Ethiopia, at an early stage of economic development with those among the population of remote, rural, subsistence areas, and assessed the potential role of environmental aetiological factors leading to the differences. METHODS: Information on wheeze of 12 months' duration, diagnosed asthma, and cough for 3 months of the year was gathered by questionnaire in random household samples of 9844 people from urban Jimma and of 3032 from rural areas. Atopy was defined by allergen skin-test response to Dermatophagoides pteronyssinus and mixed threshings measured in a one-in-four subsample of those aged 5 years and older from both groups. FINDINGS: All respiratory symptoms were rare in children and were significantly less common overall in the rural than in urban group (wheeze odds ratio 0.31 [95% CI 0.22-0.43], p < 0.0001). Asthma was reported by 351 (3.6%) of the urban group, with a median reported duration of 8.5 years (IQR 4-17 years) that was unrelated to age. Atopy was a strong risk factor for asthma in urban Jimma. In the rural areas, skin sensitivity to mixed threshings was only slightly less common than in urban Jimma (0.67 [0.40-1.12], p = 0.13), whereas sensitivity to D pteronyssinus was significantly more common (3.24 [2.40-4.38], p < 0.0001), and since none of the 119 atopic individuals in the rural area reported wheeze or asthma, atopy was possibly associated with a reduction in the risk of disease among this group. Wheeze or D pteronyssinus sensitivity were positively associated with housing style, bedding materials, and use of malathion insecticide, but no single factor accounted for the urban-rural differences. INTERPRETATION: Wheeze and asthma are especially rare in rural subsistence areas, and atopy may be associated with a reduced prevalence of these symptoms in this environment. In urban Jimma, self-reported asthma seemed to emerge as a clinical problem about 10 years before our study began, which is consistent with an effect of new environmental exposures. The factor or factors leading to the increase in asthma and allergy have not been identified, although exposures related to general changes in the domestic environment are likely to be involved.     

Is the increase in asthma prevalence occurring in children without a family history of atopy?

We investigated the familial associations of asthma and atopic disease in a population in which the prevalence of asthma and atopy is increasing. Interviewer administered abbreviated family history questionnaires were applied in 416 families with a total of 1005 children ascertained through index children attending fracture and dressing clinics. The prevalence of reported asthma (22.5%), eczema (24%) and hayfever (20%) in the children was high but similar to previous studies in this population. Asthma was reported in 20.8% of children of parents without a history of asthma and 18% of children of parents without any history of atopic disease. Logistic regression analysis of outcomes in the index children showed increased risk of atopic disease associated with parental history of the same atopic disease. The presence of an affected sibling was associated with an increased risk of eczema (OR 3.04 CI 1.83-5.05) or hayfever (OR 1.79 CI 0.97-3.3) but not asthma (OR 1.18 CI 0.66-2.08). Increasing number of siblings was associated with reduced risk although this was significant only for hayfever (OR 0.62 CI 0.41-0.86). Although the presence of affected relatives is associated with an increased risk of atopic disease the high prevalence of reported atopic disease, particularly asthma. in children of parents without a family history of atopic disease suggests that much of the increase in asthma prevalence is occurring in children without a significant genetic predisposition. Childhood asthma developing in what would previously have been regarded as low risk families may differ in its aetiology from classical atopic asthma.     

Prevalence of occupational asthma among automobile and furniture painters in the center of Eskisehir (Turkey): the effects of atopy and smoking habits on occupational asthma

BACKGROUND: Occupational asthma (OA) is a respiratory disorder characterized by airway hyperreactivity caused by agents present in the workplace. For determination of the prevalence of OA among car and furniture painters exposed to isocyanate in the center of Eskisehir, Turkey, a clinical and epidemiologic prospective study in three phases was done, incorporating 312 (89.4%) of the painters. METHODS: Of these subjects, 190 (61%) were furniture painters and 122 (39%) automobile painters. In the first phase of the study, a modified questionnaire and pulmonary function test (PFT) were done. During the second phase, peak expiratory flow rate (PEFR) was monitored in 52 subjects whose complaints were confirmed and who agreed to a month of such monitoring. In the third phase, nonspecific bronchial provocation tests (NSBPT) with histamine were done on 23 of the PEFR-monitored workers. RESULTS: Finally, through questionnaire, typical history, PFT, PEFR monitoring, and NSBPT, 30 workers (9.6%) were diagnosed as having OA. Smoking habits and atopy in the OA-diagnosed workers were found to be statistically significantly high in comparison to the other workers. CONCLUSIONS: It was concluded that OA is a common disorder among automobile and furniture painters, and smoking habits and atopy were seen to have a significant effect on OA occurrence.     

Early BCG vaccination and development of atopy

BACKGROUND: The increase in atopic diseases may be partly explicable by a decline of certain infectious diseases, or changes in childhood vaccination programmes, or both. We investigated whether BCG vaccination against tuberculosis influences the development of atopy. METHODS: We did a retrospective cohort study of 216 children with atopic heredity, born in Stockholm between 1989 and 1992, who received BCG vaccination when they were younger than 6 months, and 358 age-matched controls who had not been vaccinated. Both groups attended Sachs' Children's Hospital, Stockholm, Sweden, during 1995-96 for assessment of atopic history and clinical signs of atopic disease. All children also underwent skin-prick testing (SPT) and serum was analysed for allergen-specific IgE antibodies. Serum from parents was also analysed for IgE antibodies. FINDINGS: 77 (36%) children in the BCG group and 145 (41%) in the control group had a positive history or clinical signs of atopic disease. In the vaccinated group, 26 (12%) children had one or more positive SPT, and 61 (31%) had circulating allergen-specific IgE antibodies, whereas in the control group, the numbers were 35 (10%) and 84 (27%) respectively. Atopy was confirmed by serology in parents of almost two-thirds of the children in each group. Other risk factors for atopic disease were evenly distributed between the two groups. INTERPRETATION: Early BCG vaccination in children with atopic heredity does not seem to affect the development of atopic disease before school age.     

European study of asthma. Prevalence of atopy in young adults of 5 areas in Spain. Spanish Group of European Asthma Study

BACKGROUND: The aim of the current study is to show the prevalence of atopy in five Spanish areas, and its variability according to area, age and gender. PATIENTS AND METHODS: From a populational based sample of 16,884 individuals aged 20 to 44 years-old, we obtained a randomized 20% subsample (n = 3,310). Participants performed specific IgE measurements, skin prick tests, forced spirometries and metacholine challenges to measure bronchial hyperresponsiveness. The response rate was 40%, and 1,313 individuals were finally included in the study. Specific atopy to the following aeroallargens was determined: cat dander, Cladosporium, Dermatophagoides, Phleum, Parietaria, birch, Alternaria, ambrosia, olive, rye grass and dog dander. RESULTS: The global prevalence of atopy (detectable specific antibodies IgE in serum and/or skin reactivity) widely varied by area, skin reactivity ranking in males from a minimum in Albacete (24.6%; 95% CI: 18-33) to a maximum in Huelva (39.6%; 95% CI: 30-53), and in females ranking from a minimun in Galdakao (10.3%; 95% CI: 6-17) to a maximum in Barcelona (28.8%; 95% CI: 19-43). Considering separately seropositivity and skin reactivity we observed a similar trend. Males showed a higher prevalence of global atopy (40.1%) than females (29.4%). Our data indicate that there is a decrease in the prevalence of atopy according to age in the general population, but only significant in men. Dermatophagoides pteronyssinus is the most common allergen in all ares but Albacete, where the most common allergen is the olive pollen. CONCLUSIONS: By means of a standard methodology, we report population data of the prevalence of atopy in five Spanish areas. The distribution of the prevalence of atopy varies widely in the five areas surveyed, according to the composition of the most common environmental allergens.     

Genetics and allergy

Complex diseases, including diseases of allergic origin (asthma, rhinitis, dermatitis), tend to cluster in families, suggesting the existence of a genetic predisposition that has been confirmed by the family and twin studies. However, it is difficult to establish a clear Mendelian pattern of inheritance and it is accepted that multiple genes exist which have an additive effect (polygeny) and interact with environmental factors (multifactorial polygenic mechanism) to cause not only the atopic constitution but also the pathology that derives from it. Advances in genetics and molecular biology, through linkage studies in chosen family nuclei and different population groups, are facilitating the location of chromosomal regions related with allergic pathology. The genes situated in these regions are considered candidate genes, and the genes themselves and the functions that they control are studied in relation to allergic disease. Although there are regions and candidate genes distributed throughout the genome, chromosomes 5, 6, 11, and 14 contain genes whose responsibility for susceptibility to atopy, asthma and bronchial hyperreactivity is accepted and whose polymorphisms could be risk factors. The study of these genes and many other candidate genes may clarify some etiopathogenic aspects of diseases of allergic origin and improve their prophylaxis and therapy.     

Predictability of early atopy by cord blood-IgE and parental history

BACKGROUND: Atopic family history and cord blood IgE have been used as predictors of atopic disease in newborns for about 20 years, but at least for cord blood IgE the sensitivity has been shown to be very low. The objective of this paper was to evaluate whether parental history and cord blood-IgE were more accurate predictors for the appropriate atopic phenotypes in the infants rather than for any atopy. METHODS: A total of 1314 newborn infants was recruited in six German obstetric departments in 1990 and followed-up for 2 years. Four hundred and ninety-nine (38%) were at high risk for atopy with at least two first degree atopic family members and/or elevated cord-blood IgE concentrations. RESULTS: The cumulative incidence of atopic dermatitis over the first 2 years of life (AD24) amounted to 20.1%, and there was a significant association with AD history of the mother (OR 2.5, 95%CI 1.46-4.26) and of the father (OR 3.53, 95%CI 1.90-6.54). The cumulative incidence of recurrent wheezing in the first 2 years of life (RW24) amounted to 16.1%, and was positively associated with asthma history (OR 2.11, 95%CI 1.33-3.60) and sensitization history (OR 1.64, 95%CI 1.34-2.36) of the mother, but with neither for the father. RW24 was less prevalent in girls than in boys (OR 0.64, 95%CI 0.47-0.89). Thirty-one per cent of infants were sensitized (CAP test value > 0.35 kU/L) against at least one of nine food or inhalative allergens (S24) and this was significantly associated with cord blood-IgE value (OR 2.43, 95%CI 1.69-3.49), and sensitization history of the mother (OR 1.64, 95%CI 1.18-2.41). Using multiple logistic regression analysis, the prediction of AD24 by AD of parents, of RW24 by asthma of parents, and of sensitization by cord blood IgE was of low accuracy. CONCLUSION: The predictive capacity of parental history and cord blood IgE is not high enough to recommend them as screening instruments for primary prevention. The majority of atopic manifestations and of sensitization occur in infants with no demonstrable risk at birth.     

Genetics of aging and immunity

The influence of alcohol (ethanol) on sleep was investigated in 10 men. Polysomnography (PS) was recorded on a baseline night (BL-N) and an ethanol (0.8 g/kg) night (Et-N). On visual score rapid eye movement (REM) sleep was reduced, REM latency was prolonged on Et-N as compared to BL-N. Using the fast Fourier transformation method, electroencephalographic power density of REM sleep in delta frequencies band and in the 10-12 Hz range of non-REM sleep were enhanced. REM sleep and non-REM sleep changes were prominent in the second-half and first-half of the night, respectively.     

Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma

Founder populations offer many advantages for mapping genetic traits, particularly complex traits that are likely to be genetically heterogeneous. To identify genes that influence asthma and asthma-associated phenotypes, we conducted a genome-wide screen in the Hutterites, a religious isolate of European ancestry. A primary sample of 361 individuals and a replication sample of 292 individuals were evaluated for asthma phenotypes according to a standardized protocol. A genome-wide screen has been completed using 292 autosomal and three X-Y pseudoautosomal markers. Using the semi-parametric likelihood ratio chi2 test and the transmission-disequilibrium test, we identified 12 markers in 10 regions that showed possible linkage to asthma or an associated phenotype (likelihood ratio P < 0.01). Markers in four regions (5q23-31, 12q15-24.1, 19q13 and 21q21) showed possible linkage in both the primary and replication samples and have also shown linkage to asthma phenotypes in other samples; two adjacent markers in one additional region (3p24.2-22) showing possible linkage is reported for the first time in the Hutterites. The results suggest that even in founder populations with a relatively small number of independent genomes, susceptibility alleles at many loci may influence asthma phenotypes and that these susceptibility alleles are likely to be common polymorphisms in the population.