Miriam F. Moffatt

A large-scale, consortium-based genomewide association study of asthma

BACKGROUNDnSusceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease.nnnMETHODSnWe carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma.nnnRESULTSnWe observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma.nnnCONCLUSIONSnAsthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined Pu2009value of Pu2009<u200910-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (Pu2009<u200910-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Gene polymorphism in Netherton and common atopic disease

Atopic dermatitis (AD) and asthma are characterized by IgE-mediated atopic (allergic) responses to common proteins (allergens), many of which are proteinases. Loci influencing atopy have been localized to a number of chromosomal regions, including the chromosome 5q31 cytokine cluster. Netherton disease is a rare recessive skin disorder in which atopy is a universal accompaniment. The gene underlying Netherton disease (SPINK5) encodes a 15-domain serine proteinase inhibitor (LEKTI) which is expressed in epithelial and mucosal surfaces and in the thymus. We have identified six coding polymorphisms in SPINK5 (Table 1) and found that a Glu420→Lys variant shows significant association with atopy and AD in two independent panels of families. Our results implicate a previously unrecognized pathway for the development of common allergic illnesses.

Extent and distribution of linkage disequilibrium in three genomic regions

The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.

A Genome-Wide Association Study on African-Ancestry Populations For Asthma

BACKGROUNDnAsthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed.nnnOBJECTIVESnWe sought to test the hypothesis that some genes might contribute to the profound disparities in asthma.nnnMETHODSnWe performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma.nnnRESULTSnA meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated.nnnCONCLUSIONSnThis study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Contributing factors to the pathobiology : The genetics of asthma

Markers in 19 chromosomal regions have shown some evidence of linkage to asthma, atopy, or related phenotypes in multiple independent genome-wide searches. Linkages to five of these regions (5q, 6p, 11q, 12q, and 13q) have also been reported in non-genome-wide screens. In addition, at least two independent studies have reported linkages to markers on 16p. Numerous candidate genes in these regions have shown varying levels of association to asthma or atopic phenotypes, potentially implicating them as disease susceptibility loci. These include the IL4, CD14, and B2ADR genes on 5q, the HLA-DRB1 and TNF genes on 6p, the FCERB1 and CC16 genes on 11q, and the IL4RA gene on 16p. It still remains to be determined whether polymorphisms in these genes account for the reported linkages in these regions. Studies are underway in laboratories around the world to identify the disease-causing variations in these genes that account for the linkages just discussed. Identifying specific genetic polymorphisms that influence asthma and atopic phenotypes will shed light on the molecular pathways involved in these complex disorders and provide a better understanding of the pathophysiology of asthma and atopy.

The genetics of atopic dermatitis

Purpose of reviewAtopic dermatitis is typified by itchy, inflamed skin. It is increasingly common in the developed world and is a major cause of morbidity in infants and young children. Most children with the disease have high levels of immunoglobulin E and many have concomitant asthma. The cause of the disease is unknown, but it is highly heritable. Identification of the genes and genetic variants underlying atopic dermatitis may lead to new treatments and better classification of children with the disease. Recent findingsPreliminary genetic studies have identified genes or clusters of genes that are expressed in the outermost layer of the skin to be just as important as genes that may modify the atopic process. These genes may influence other diseases, including psoriasis. Genome screens in mouse models seem to indicate involvement of some of the equivalent chromosomal regions as for human disease. SummaryThe findings suggest that atopy in atopic dermatitis may be a secondary process, rather than the cause of the disease. The barrier function of the skin is seen not to be merely passive. Identification of the genes underlying atopic dermatitis is feasible and likely within a few years.

Competing Functions Encoded in the Allergy-Associated FcϵRIβ Gene

Allergic reactions are triggered via crosslinking of the high-affinity receptor for immunoglobulin E, F(c)epsilonRI. In humans, F(c)epsilonRI is expressed as a tetramer (alphabetagamma(2)) and a trimer (alphagamma(2)). The beta subunit is an amplifier of F(c)epsilonRI surface expression and signaling. Here, we show that as a consequence of alternative splicing, the F(c)epsilonRIbeta gene encodes two proteins with opposing and competing functions. One isoform is the full-length classical beta, the other a novel truncated form, beta(T). In contrast to beta, beta(T) prevents F(c)epsilonRI surface expression by inhibiting alpha chain maturation. Moreover, beta(T) competes with beta to control F(c)epsilonRI surface expression in vitro. We propose that the relative abundance of the products of the beta gene may control the level of F(c)epsilonRI surface expression and thereby influence susceptibility to allergic diseases.

Genes in asthma: new genes and new ways.

Purpose of reviewAsthma is a disease of unknown aetiology characterized by intermittent inflammation of the small airways of the lung. Asthma is familial due to an interaction between strong genetic and environmental factors. This article aims to review the current understanding of the genetic factors underlying asthma, looking historically as well as highlighting the latest developments in the field. Recent findingsFindings from recent candidate gene studies and microsatellite genome screens have continued to highlight the importance of the epithelial barrier and its defence mechanisms in asthma. Completion of the human genome sequence and the advent of genome-wide association studies have resulted in the identification of two novel asthma susceptibility genes, ORMDL3 and CHI3L1, in the past year. SummaryWith the advances in genetics and genomics substantial steps have been taken in the last decade in understanding the genetic factors underlying asthma. Studies have highlighted the importance of the role of the epithelium with many of the genes so far identified being expressed in this key barrier. With the application of genome-wide expression, microRNA studies, metagenomics, proteomics and metabolomics the next decade will undoubtedly result in a further substantial increment in our understanding of the mechanisms underlying asthma.

Genetics of asthma and inflammation: the status.

Genome-wide screens are consistently finding linkage between asthma-associated traits and specific chromosomal loci. Several loci coincide with linkages to other inflammatory diseases, suggesting the presence of common pathways in their pathogenesis. Candidate-gene studies have found an association between a CD14 polymorphism and IgE levels, suggesting a mechanism for the increased prevalence of allergic disease. A polymorphism in Fc epsilon RI-beta shows parent-of-origin effects when associated with severe infantile eczema, further illustrating the complexity of gene-environment effects on the developing immune system.