Skip to main content

Recent advances in asthma genetics


There are over 100 genes that have been reported to be associated with asthma or related phenotypes. In 2006–2007 alone there were 53 novel candidate gene associations reported in the literature. Replication of genetic associations and demonstration of a functional mechanism for the associated variants are needed to confirm an asthma susceptibility gene. For most of the candidate genes there is little functional information. In a previous review by Hoffjan et al. published in 2003, functional information was reported for 40 polymorphisms and here we list another 22 genes which have such data. Some important genes such as filaggrin, interleukin-13, interleukin-17 and the cysteinyl leukotriene receptor-1 which not only were replicated by independent association studies but also have functional data are reviewed in this article.


Asthma is a disease of chronic airway inflammation that affects nearly 155 million individuals worldwide [1, 2]. Like other atopic diseases, asthma is a complex disorder caused by interactions between multiple genes of small to modest effect and equally important environmental factors. Asthma has an important genetic component but no clear pattern of inheritance, and heritability estimates of asthma vary between 36–79% [35].

It is possible to define a categorical phenotype for studies of asthma genetics. However, the heterogeneity of the disease makes this problematic. Therefore, many studies have used quantitative phenotypes as intermediates e.g. skin test responses and total or specific serum IgE. In this case, "affected" individuals can be defined as those exceeding a certain threshold at the extreme of the distribution. Alternatively, an approach called the quantitative trait locus (QTL) method allows the entire distribution to be used in the analysis. Quantitative traits are most likely due to the influence of several alleles at multiple loci interacting to cause the phenotype. In a more recent development, gene expression array technology has been employed to use gene expression as an outcome variable. For example, a genome-wide association of gene expression was performed by Dixon et al. using a cohort of families with an asthmatic proband [6]. In this study, genes involved in response to unfolded protein, regulation of progression though the cell cycle, RNA processing, DNA repair, immune responses and apoptosis showed highly heritable traits. In addition, the global map made by the study will be a excellent resource for selecting candidate genes [6].

Efforts to identify asthma genes have been carried out in various laboratories around the world and because of the complexity and heterogeneity of asthma it has been a daunting task. Two general approaches have been widely used to study the genetics of asthma: positional cloning and candidate gene approaches. The positional cloning approach in particular has been successful in identifying genes for asthma and asthma-associated phenotypes in recent years.

Multiple genome-wide linkage studies for asthma and allergy have been performed to date. Linkages have been found in specific ethnic groups, using different phenotypes and with various levels of statistical significance. Most of these regions have been replicated in more than one study. In particular, human chromosomes 2q33, 5q23-31, 6p24-21, 11q21-13, 12q24-12, and 13q14-12 have received the greatest attention, because these regions contain a large number of candidate genes [7]. However, most of these identified chromosomal regions are large, spanning 10–30 Mb, and contain several plausible candidate genes. Fine mapping can be performed in these linked regions and positional candidate cloning can be performed using high-throughput sequencing, single nucleotide polymorphism (SNP) genotyping and linkage disequilibrium (LD) mapping. This has enabled researchers to identify susceptibility genes without prior knowledge of the function of those genes e.g. a disintegrin and metalloproteinase-33 (ADAM 33), dipeptidyl dipeptidase-10, plant homeodomain finger protein-11 and G protein-coupled receptor-154 [8].

Association studies can be more powerful than linkage studies in certain circumstances. With the development of high throughput and accurate technologies for DNA sequencing and SNP genotyping the number of asthma candidate genes has increased quickly. Hoffjan et al. reviewed 64 candidate genes in 2003 [9] and the number increased to 120 [10] in 2006. There are 53 genes that were reported to be associated with asthma during 2006–2007 (see Additional file 1). Among them filaggrin is notable since seven replication studies were published in independent populations in one year. Another five genes, PTGER3, MYLK, IL17F, ECP and CYSLTR1 were replicated by other groups. The genome-wide association studies currently underway are likely to identify multiple additional genetic variants that are associated with asthma and associated traits.

Following candidate gene identification, it is important to explore the functional consequences of the associated genetic variation. It is likely that many of the genetic variants associated with asthma do not have functional consequences but are simply in LD with the causal variants. For SNPs in coding regions it is possible to predict the consequences for protein structure and function, although such predictions have to be empirically verified. However, most SNPs in the human genome are found in non-coding DNA. Variants located in promoter regions may change gene expression by altering transcription factor binding sites or by other more subtle mechanisms. Intronic variants may have an effect on the alternate splicing pattern in a given cell or tissue. It has been reported that non-coding sequence, which accounts for at least 30% of the human genome, has an important unexpected function since it is a major source of regulatory RNAs in complex organisms [11, 12]. In the 2003 review by Hoffjan et al. [9] 40 mutations had reports of functional effects and here we list other genes which have functional reports (see Additional file 2).

Recently, another type of genetic variation, structural variations which are mainly found in the form of copy number variants (CNVs), has attracted a large amount of interest from complex disease researchers. Structural variations are widespread in the human genome and may have more functional impact on phenotypic variation than SNPs [13]. The high throughput genotyping of structural variations has become possible. CNVs have already been shown to be associated with susceptibility to HIV infection [14], lupus glomerulonephritis [15], and autoimmune diseases [16, 17]. There is no report concerning an association between CNVs and asthma to date but studies are likely underway.

This review focuses on several genes, which provide examples of the investigation of asthma and allergy susceptibility genes.

Asthma susceptibility genes


Filaggrin (FLG) is a key protein of the epidermis and is therefore important in the formation of the protective skin barrier. FLG was initially described as a candidate gene for atopic dermatitis in 2006 [18]. This was a breakthrough discovery because most previous allergy genetics studies were focused on immunological mechanisms and this was the first study to show that genetic variants in the skin defense system are important in allergic pathways. The skin barrier is part of the innate immune system which keeps water within the body and prevents the entrance of pathogens and allergens [19]. With a defective epidermal barrier allergen may more easily gain entrance through the skin and thus initiate local and systemic allergy and predispose to allergic disease.

FLG was initially identified as an ichthyosis vulgaris candidate gene in a study of 15 families segregating this single gene disorder [20]. There are three exons in FLG and two mutations (R501X and 2282del4) were found in the ichthyosis vulgaris patients. Both mutations are in exon 3 and stop protein translation within the first FLG repeat and result in complete loss of FLG peptide production [20]. Therefore, these two functional mutations were considered as the likely causal mutations for ichthyosis vulgaris in these families. Palmer et al. [18] observed that many individuals with either of the variations also had atopic dermatitis or asthma and therefore investigated whether the two functional variations also contribute to allergic disease. These authors examined the two mutations in three independent cohorts and found that the results were consistent in that the two nonsense mutations were highly significantly associated with atopic dermatitis (AD) but not with asthma [18]. During the following year these results were replicated by three independent studies, two from Germany [21, 22] and one from the UK [23]. In one German study, which included family-based and case-control association analyses, the two mutant alleles showed association with AD as well as asthma in the context of AD but showed no association with asthma or the presence of specific IgE in the absence of AD [22]. Another German study including 476 complete trios (mother, father and affected child) showed association between extrinsic AD but no association with intrinsic AD, the latter defined as dermatitis patients who had normal IgE and lack of sensitization towards environmental allergens [21]. A further study from Germany confirmed the association of FLG variants with AD [24]. Another three studies have shown association of extrinsic AD, asthma and rhinitis, asthma severity with the FLG variants although in some studies association was only seen with concomitant AD [21, 25, 26]. All these data suggest that the two FLG mutant alleles are important risk factors for AD but only for asthma when it is found in the context of AD. An additional seven nonsense or frame shift FLG mutations were identified in the European population and two in the Asian population [27]. There were three reasonably prevalent mutations (in addition to R501X and 2282del4) that showed association with childhood eczema [27].

To date there have been no reports showing lack of association of FLG variants and AD. However, the frequency of the two variants is low (less than 5% in Caucasians) and they are absent in Asians and Africans, and therefore only contribute to a small proportion of AD cases [22]. Most AD cases must be caused by other factors and genes that affect skin barrier development are good candidates for further studies.


Interleukin-13 (IL13) is a good candidate as an asthma susceptibility gene because it is a cytokine produced by Th2 cells and because its genetic location on chromosome 5q31 has been linked to asthma and related phenotypes in multiple linkage studies [2834]. This cytokine is capable of promoting allergen-induced bronchial hyperresponsiveness, epithelial cell damage, goblet cell hyperplasia with mucus hyperproduction, and eosinophilia. There are several studies that have shown that common polymorphisms in this gene, i.e. -1111C > T and +2043G > A (R130Q), are associated with asthma and/or related phenotypes such as increased total serum IgE, atopy, and atopic dermatitis [3541]. Other investigators have found further evidence for the role of IL13 polymorphisms in the pathogenesis of allergic disease [4246].

Tarazona-Santos et al. resequenced the whole IL13 gene and confirmed that +2043G > A, which causes replacement of a positively charged arginine (R) with a neutral glutamine (Q) at position 130, was the only nonsynonymous substitution present in all ethnic groups [47]. The 130 position is in the α-helix D segment, which has been proven to be a region where IL13 interacts with IL4 receptor-α/IL13 receptor-α1 heterodimers [48]. In the study of Chen et al. the 130Q IL13 variant (named Q110R in that paper, because the 20-amino acid signal sequence was not numbered) enhanced IL13-dependent gene induction at the cellular level and induced more significant bronchial hyperresponsiveness in mice compared with the 130R IL13 variant [49]. These authors also found that this functional variant had synergistic effects with other functional variants, e.g. 50 V and 551R in the IL4 receptor-α gene [49]. Vladich et al. investigated the function of R130Q in peripheral blood mononuclear cells from normal donors [50]. They incubated these cells with the IL13 variants and compared the STAT6 phosphorylation, CD23 expression, and hydrocortisone-dependent IgE synthesis. In these multiple functional assays IL13 130Q showed more activity than wild type IL13 and was less effectively neutralized by soluble IL13 receptor-α. From these results the authors concluded that the +2043G > A polymorphism increased the activity of IL13 and therefore enhanced the pathways leading to allergic inflammation [50]. Both of these papers offered functional evidence demonstrating that the +2043G > A polymorphism plays an important role in the pathogenesis of asthma. None of these results are definitive individually but taken together provide strong evidence that IL13 is a susceptibility gene for allergic disease.

Another polymorphism, -1111C > T, is in the IL13 promoter region. This promoter SNP shows low levels of LD with +2043G > A in most populations [47]. Therefore, the associations between -1111C > T and asthma-related phenotypes [35, 41] are likely independent of the +2043G > A polymorphism. It was observed that the T allele of -1111C > T had increased binding of a T cell transcription factor (NFAT), which regulates IL13 and IL4 expression and -1111TT homozygosity was associated with both asthma and altered regulation of IL13 production [35]. It is still unclear whether the two polymorphisms act synergistically. However, it is possible that the increased transcription caused by -1111C > T combined with the enhanced activity caused by +2043G > A would amplify the IL13-dependent inflammatory reaction.


Unlike IL13, IL17F was discovered recently [5153]. It is one member of the IL17 gene family and the coding sequence contains 7742 bp, including three exons. IL17F was investigated as an asthma candidate gene because of its function i.e. IL17F is one of the cytokines produced by activated mast cells, CD4+ T cells, and basophils and can upregulate IL6 and IL8 transcripts and protein expression in primary bronchial epithelial cells [51]. IL17F is expressed in human liver, lung, and fetal liver tissue [51] and increased expression was oberserved in the airways of allergic asthma patients [51]. In addition, IL17F is located on chromosome 6p, which has been linked to asthma and asthma-related phenotypes in multiple genome scans [54, 55].

A Japanese case-control study reported an protective association between homozygosity for the nonsynonymous variant H161R and asthma but no association between heterozygosity for H161R or IL17F haplotypes and asthma [56]. Importantly, there were no homozygotes for 161R in the 432 asthma patients (compared with 9 homozygotes in the 435 controls). Kawaguchi et al. [56] also performed experiments to determine whether H161R was a functional variant. Recombinant wild type IL17F (containing histidine at position 161) and mutant IL17F (containing arginine at position 161) were used to stimulate BEAS-2B cells (a human bronchial epithelial cell line) and the results demonstrated that the mutant IL17F could not induce activation of a signaling pathway involving RAF1, MAP2K1/2 and MAPK1/3. The mutant isoform was also unable to stimulate the production of cytokines e.g. CSF2 and chemokines e.g. IL8, CXCL1 and CXCL5. Moreover, the mutant IL17F acted as an antagonist of wild type IL17F to block induction of IL8 expression [56]. However, despite this strong functional data, the association results were not replicated by another case-control study [57]. In this study, the authors genotyped five IL17F SNPs including H161R in 1027 white females and found no association between any SNP or haplotype with asthma [57]. The lack of consistency between the two studies may be due to differences in environmental factors or modifier genes that influence the H161R association. Thus, the results of Kawaguchi et al. [56] await confirmation in other populations and at the in vivo level.

Several additional studies have shed light on the function of IL17F and further suggested that it is a good candidate asthma susceptibility gene. It was reported that IL17F was expressed in bronchial epithelial cells and inflammatory cells in an allergic asthma mouse model but not in the lungs of control mice [58]. IL17 induced the expression of IFN-gamma-induced protein 10 (IP10) in bronchial epithelial cells [59]. IP10 has been shown to be a marker of virus-induced asthma [60, 61]. In addition, the epigenetic changes in the IL17A-IL17F locus are associated with the differentiation of the novel T helper subset, TH17 cells [62].

Cysteinyl leukotriene receptors

Cysteinyl leukotrienes are bronchoconstrictors and proinflammatory mediators of the asthma response that act through two G protein-coupled receptors: cysteinyl leukotriene receptor-1 (CYSLTR1) [63] and CYSLTR2 [64]. Both receptors are the targets of anti-asthmatic drugs. CYSLTR2 maps to chromosome 13q14, approximately 300 kb from D13S153, which was reported linked to asthma in two studies [65, 66]. The association of CYSLTR2 and asthma was replicated in two subsequent studies [67, 68] and two functional studies showed potency of leukotriene D4 on the M202V variant was lower compared with the wild-type receptor [68, 69].

CYSLTR1 is located on chromosome Xq21.1. Five recent studies reported that SNPs in CYSLTR1 were associated with allergic phenotypes. Among them, two studies used Caucasian samples and both of them reported significant results of the synonymous SNP, 927T > C [70, 71]. A discrepancy between these studies is that the results from the family study [70] showed that the 927T allele had a strong association with atopy severity in female subjects but the results from the case-control study showed that the minor allele, 927C, associated with asthma present with atopic dermatitis but only in males [71]. A study of a Spanish population found that the combination of 927T of CYSLTR1 and -444A of the leukotriene C4 synthase gene was less common in male patients with asthma than in controls [72]. CYSLTR1 promoter haplotypes were associated with aspirin-sensitive asthma in a Korean population, but again only in male patients [73]. CYSLTR1 promoter haplotypes have also been associated with functional effects [73, 74]. The 927T > C SNP is in strong LD with the promoter SNPs both in Caucasian and Asian populations in the HapMap database [75]. Consequently, the five studies effectively examined the same haplotype. In the Korean studies, they found that the haplotype containing the minor alleles of the promoter SNPs increased the promoter activity in three cell lines: Jurkat, A549, and U937 cells [73, 74]. This result is consistent with another paper in which the U937 cell line was used [76]. Furthermore, at the -475A > C promoter SNP, the A allele was found to bind a specific protein that was not bound by the C allele [74]. However, another study found a contradictory result in THP1 cells [77]. The authors found that the G allele of promoter SNP -336A > G (the minor allele) was associated with a twofold decrease in luciferase expression [77]. The discrepancy may have resulted from the use of different cell lines or the length of the constructs. Therefore, more studies are needed to validate these results.

A further complication is that the precise location of the CYSLTR1 promoter region is still unclear. In three papers [73, 76, 77] 5'RACE was performed using cDNA from human fetus and human leukocytes and no novel exon was found. However, in another paper two novel upstream exons were found before the previously described exon 1 using cDNA from U937 and THP-1 cells and the promoter region was identified in the region between -125 bp to -786 bp upstream of the novel exons [78]. It is possible that there are two alternative promoters in CYSLTR1 and they initiate different transcripts. There are no reports of any SNPs in the new promoter region.


In a genome-wide association study performed by Moffatt et al. SNPs in the 17q21 region showed a strong association with childhood asthma in both a UK family cohort and German case-control samples. Furthermore, the results were replicated in two independent cohorts [79]. The authors also measured global gene expression in Epstein-Barr virus-transformed lymphoblastoid cells from children in their genotyped family samples and found that the markers which showed strongest association with asthma were also consistently associated with transcript levels of ORMDL3 [79]. No other transcript levels were associated with these markers. In this study, the markers which showed association are in different LD blocks so it is possible that multiple functional variants independently contribute to the disease susceptibility. There are also many structural variants in this region that may contribute to the pathogenesis of asthma. This study is remarkable due to the use of genome-wide association analysis coupled with genome-wide gene expression analysis.

ORMDL3 is a poorly characterized gene and the underlying mechanism for the association with asthma is unclear. ORMDL3 is a member of a family of endoplasmic reticulum membrane proteins and has a ubiquitous pattern of expression in humans and Drosophila. It encodes transmembrane proteins anchored in the endoplasmic reticulum and shows conservation across species [80].


The pathogenesis of asthma, a complex disease, involves gene-gene interactions as well as gene-environment interactions. Multiple modest risk factors work synergistically to influence asthma disease susceptibility. The number of asthma-susceptibility genes identified by genetic studies is still increasing. However, most studies lack information on the mechanism by which the SNPs lead to asthma. Elucidating the functional consequences of SNPs is essential to confirm association results and to understand how the SNPs combine to influence susceptibility. Eventually, results from this important field are expected to improve preventive strategies and to aid in the development of diagnostic tools and therapies.


  1. 1.

    Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, Mitchell EA, Pearce N, Sibbald B, Stewart AW, et al.: International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995, 8:483–491.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Beasley R: The burden of asthma with specific reference to the United States. J Allergy Clin Immunol 2002, 109:S482–9.

    Article  PubMed  Google Scholar 

  3. 3.

    Duffy DL, Martin NG, Battistutta D, Hopper JL, Mathews JD: Genetics of asthma and hay fever in Australian twins. Am Rev Respir Dis 1990, 142:1351–1358.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Nieminen MM, Kaprio J, Koskenvuo M: A population-based study of bronchial asthma in adult twin pairs. Chest 1991, 100:70–75.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Hopp RJ, Bewtra AK, Watt GD, Nair NM, Townley RG: Genetic analysis of allergic disease in twins. J Allergy Clin Immunol 1984, 73:265–270.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KC, Taylor J, Burnett E, Gut I, Farrall M, Lathrop GM, Abecasis GR, Cookson WO: A genome-wide association study of global gene expression. Nat Genet 2007, 39:1202–1207.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Hoffjan S, Ober C: Present status on the genetic studies of asthma. Curr Opin Immunol 2002, 14:709–717.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Kere J, Laitinen T: Positionally cloned susceptibility genes in allergy and asthma. Curr Opin Immunol 2004, 16:689–694.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Hoffjan S, Nicolae D, Ober C: Association studies for asthma and atopic diseases: a comprehensive review of the literature. Respir Res 2003, 4:14. Print 2003..

    Article  Google Scholar 

  10. 10.

    Ober C, Hoffjan S: Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 2006, 7:95–100.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Lu C, Tej SS, Luo S, Haudenschild CD, Meyers BC, Green PJ: Elucidation of the small RNA component of the transcriptome. Science 2005, 309:1567–1569.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Mattick JS: The functional genomics of noncoding RNA. Science 2005, 309:1527–1528.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Chen Q, Book M, Fang X, Hoeft A, Stuber F: Screening of copy number polymorphisms in human beta-defensin genes using modified real-time quantitative PCR. J Immunol Methods 2006, 308:231–240.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, Nibbs RJ, Freedman BI, Quinones MP, Bamshad MJ, Murthy KK, Rovin BH, Bradley W, Clark RA, Anderson SA, O'Connell R J, Agan BK, Ahuja SS, Bologna R, Sen L, Dolan MJ, Ahuja SK: The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005, 307:1434–1440.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Aitman TJ, Dong R, Vyse TJ, Norsworthy PJ, Johnson MD, Smith J, Mangion J, Roberton-Lowe C, Marshall AJ, Petretto E, Hodges MD, Bhangal G, Patel SG, Sheehan-Rooney K, Duda M, Cook PR, Evans DJ, Domin J, Flint J, Boyle JJ, Pusey CD, Cook HT: Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 2006, 439:851–855.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Fanciulli M, Norsworthy PJ, Petretto E, Dong R, Harper L, Kamesh L, Heward JM, Gough SC, de Smith A, Blakemore AI, Froguel P, Owen CJ, Pearce SH, Teixeira L, Guillevin L, Graham DS, Pusey CD, Cook HT, Vyse TJ, Aitman TJ: FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 2007, 39:721–723.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B, Hebert M, Jones KN, Shu Y, Kitzmiller K, Blanchong CA, McBride KL, Higgins GC, Rennebohm RM, Rice RR, Hackshaw KV, Roubey RA, Grossman JM, Tsao BP, Birmingham DJ, Rovin BH, Hebert LA, Yu CY: Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 2007, 80:1037–1054.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006, 38:441–446.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Elias PM: Stratum corneum defensive functions: an integrated view. J Invest Dermatol 2005, 125:183–200.

    CAS  PubMed  Google Scholar 

  20. 20.

    Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O'Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH: Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 2006, 38:337–342.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, Klopp N, Wagenpfeil S, Zhao Y, Liao H, Lee SP, Palmer CN, Jenneck C, Maintz L, Hagemann T, Behrendt H, Ring J, Nothen MM, McLean WH, Novak N: Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006, 118:214–219.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Marenholz I, Nickel R, Ruschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, Gruber C, Lau S, Worm M, Keil T, Kurek M, Zaluga E, Wahn U, Lee YA: Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 2006, 118:866–871.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Barker JN, Palmer CN, Zhao Y, Liao H, Hull PR, Lee SP, Allen MH, Meggitt SJ, Reynolds NJ, Trembath RC, McLean WH: Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol 2007,127(3):564–567.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Ruether A, Stoll M, Schwarz T, Schreiber S, Folster-Holst R: Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany. Br J Dermatol 2006, 155:1093–1094.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Morar N, Cookson WO, Harper JI, Moffatt MF: Filaggrin mutations in children with severe atopic dermatitis. J Invest Dermatol 2007, 127:1667–1672.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, McLean WH, Mukhopadhyay S: Filaggrin null mutations are associated with increased asthma severity in children and young adults. J Allergy Clin Immunol 2007, 120:64–68.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, Janecke AR, Elias PM, van Steensel MA, Nagtzaam I, van Geel M, Steijlen PM, Munro CS, Bradley DG, Palmer CN, Smith FJ, McLean WH, Irvine AD: Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007, 39:650–654.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Postma DS, Meyers DA, Jongepier H, Howard TD, Koppelman GH, Bleecker ER: Genomewide screen for pulmonary function in 200 families ascertained for asthma. Am J Respir Crit Care Med 2005, 172:446–52. Epub 2005 May 18..

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Noguchi E, Shibasaki M, Arinami T, Takeda K, Maki T, Miyamoto T, Kawashima T, Kobayashi K, Hamaguchi H: Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population. Am J Respir Crit Care Med 1997, 156:1390–1393.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Martinez FD, Solomon S, Holberg CJ, Graves PE, Baldini M, Erickson RP: Linkage of circulating eosinophils to markers on chromosome 5q. Am J Respir Crit Care Med 1998, 158:1739–1744.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Shek LP, Tay AH, Chew FT, Goh DL, Lee BW: Genetic susceptibility to asthma and atopy among Chinese in Singapore--linkage to markers on chromosome 5q31–33. Allergy 2001, 56:749–753.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Xu J, Postma DS, Howard TD, Koppelman GH, Zheng SL, Stine OC, Bleecker ER, Meyers DA: Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet 2000, 67:1163–73. Epub 2000 Oct 6..

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B, Gidley H, Kurtz B, Lee J, Nance M, Pettersson A, Prescott J, Richardson A, Schlenker E, Summerhill E, Willadsen S, Parry R: Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum Mol Genet 1998, 7:1393–1398.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Hizawa N, Freidhoff LR, Chiu YF, Ehrlich E, Luehr CA, Anderson JL, Duffy DL, Dunston GM, Weber JL, Huang SK, Barnes KC, Marsh DG, Beaty TH: Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: a genome-wide multipoint linkage analysis in families recruited through 2 asthmatic sibs. Collaborative Study on the Genetics of Asthma (CSGA). J Allergy Clin Immunol 1998, 102:436–442.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    van der Pouw Kraan TC, van Veen A, Boeije LC, van Tuyl SA, de Groot ER, Stapel SO, Bakker A, Verweij CL, Aarden LA, van der Zee JS: An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun 1999, 1:61–65.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Liu X, Nickel R, Beyer K, Wahn U, Ehrlich E, Freidhoff LR, Bjorksten B, Beaty TH, Huang SK: An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). J Allergy Clin Immunol 2000, 106:167–170.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Graves PE, Kabesch M, Halonen M, Holberg CJ, Baldini M, Fritzsch C, Weiland SK, Erickson RP, von Mutius E, Martinez FD: 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. J Allergy Clin Immunol 2000, 105:506–513.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Heinzmann A, Mao XQ, Akaiwa M, Kreomer RT, Gao PS, Ohshima K, Umeshita R, Abe Y, Braun S, Yamashita T, Roberts MH, Sugimoto R, Arima K, Arinobu Y, Yu B, Kruse S, Enomoto T, Dake Y, Kawai M, Shimazu S, Sasaki S, Adra CN, Kitaichi M, Inoue H, Yamauchi K, Tomichi N, Kurimoto F, Hamasaki N, Hopkin JM, Izuhara K, Shirakawa T, Deichmann KA: Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet 2000, 9:549–559.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Leung TF, Tang NL, Chan IH, Li AM, Ha G, Lam CW: A polymorphism in the coding region of interleukin-13 gene is associated with atopy but not asthma in Chinese children. Clin Exp Allergy 2001, 31:1515–1521.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    DeMeo DL, Lange C, Silverman EK, Senter JM, Drazen JM, Barth MJ, Laird N, Weiss ST: Univariate and multivariate family-based association analysis of the IL-13 ARG130GLN polymorphism in the Childhood Asthma Management Program. Genet Epidemiol 2002, 23:335–348.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Howard TD, Whittaker PA, Zaiman AL, Koppelman GH, Xu J, Hanley MT, Meyers DA, Postma DS, Bleecker ER: Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol 2001, 25:377–384.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Leung TF, Chan IH, Wong GW, Li CY, Tang NL, Yung E, Lam CW: Association between candidate genes and lung function growth in Chinese asthmatic children. Clin Exp Allergy 2007, 37:1480–1486.

    CAS  PubMed  Google Scholar 

  43. 43.

    Hosseini-Farahabadi S, Tavakkol-Afshari J, Rafatpanah H, Farid Hosseini R, Khaje Daluei M: Association between the Polymorphisms of IL-4 Gene Promoter (-590C>T), IL-13 Coding Region (R130Q) and IL-16 Gene Promoter (-295T>C) and Allergic Asthma. Iran J Allergy Asthma Immunol 2007, 6:9–14.

    CAS  PubMed  Google Scholar 

  44. 44.

    Bernstein DI, Wang N, Campo P, Chakraborty R, Smith A, Cartier A, Boulet LP, Malo JL, Yucesoy B, Luster M, Tarlo SM, Hershey GK: Diisocyanate asthma and gene-environment interactions with IL4RA, CD-14, and IL-13 genes. Ann Allergy Asthma Immunol 2006, 97:800–806.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Battle NC, Choudhry S, Tsai HJ, Eng C, Kumar G, Beckman KB, Naqvi M, Meade K, Watson HG, Lenoir M, Burchard EG: Ethnicity-specific gene-gene interaction between IL-13 and IL-4Ralpha among African Americans with asthma. Am J Respir Crit Care Med 2007, 175:881–887.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Hunninghake GM, Soto-Quiros ME, Avila L, Su J, Murphy A, Demeo DL, Ly NP, Liang C, Sylvia JS, Klanderman BJ, Lange C, Raby BA, Silverman EK, Celedon JC: Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood. J Allergy Clin Immunol 2007, 120:84–90.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Tarazona-Santos E, Tishkoff SA: Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus. Genes Immun 2005, 6:53–65.

    CAS  PubMed  Google Scholar 

  48. 48.

    Madhankumar AB, Mintz A, Debinski W: Alanine-scanning mutagenesis of alpha-helix D segment of interleukin-13 reveals new functionally important residues of the cytokine. J Biol Chem 2002, 277:43194–205. Epub 2002 Aug 19..

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Chen W, Ericksen MB, Levin LS, Khurana Hershey GK: Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants. J Allergy Clin Immunol 2004, 114:553–560.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Vladich FD, Brazille SM, Stern D, Peck ML, Ghittoni R, Vercelli D: IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation. J Clin Invest 2005, 115:747–754.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Kawaguchi M, Onuchic LF, Li XD, Essayan DM, Schroeder J, Xiao HQ, Liu MC, Krishnaswamy G, Germino G, Huang SK: Identification of a novel cytokine, ML-1, and its expression in subjects with asthma. J Immunol 2001, 167:4430–4435.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Starnes T, Robertson MJ, Sledge G, Kelich S, Nakshatri H, Broxmeyer HE, Hromas R: Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J Immunol 2001, 167:4137–4140.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Hymowitz SG, Filvaroff EH, Yin JP, Lee J, Cai L, Risser P, Maruoka M, Mao W, Foster J, Kelley RF, Pan G, Gurney AL, de Vos AM, Starovasnik MA: IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. Embo J 2001, 20:5332–5341.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Haagerup A, Bjerke T, Schiotz PO, Binderup HG, Dahl R, Kruse TA: Asthma and atopy - a total genome scan for susceptibility genes. Allergy 2002, 57:680–686.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Wjst M, Fischer G, Immervoll T, Jung M, Saar K, Rueschendorf F, Reis A, Ulbrecht M, Gomolka M, Weiss EH, Jaeger L, Nickel R, Richter K, Kjellman NI, Griese M, von Berg A, Gappa M, Riedel F, Boehle M, van Koningsbruggen S, Schoberth P, Szczepanski R, Dorsch W, Silbermann M, Wichmann HE, et al.: A genome-wide search for linkage to asthma. German Asthma Genetics Group. Genomics 1999, 58:1–8.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Kawaguchi M, Takahashi D, Hizawa N, Suzuki S, Matsukura S, Kokubu F, Maeda Y, Fukui Y, Konno S, Huang SK, Nishimura M, Adachi M: IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol 2006, 117:795–801.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Ramsey CD, Lazarus R, Camargo CA Jr., Weiss ST, Celedon JC: Polymorphisms in the interleukin 17F gene (IL17F) and asthma. Genes Immun 2005, 6:236–241.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Suzuki S, Kokubu F, Kawaguchi M, Homma T, Odaka M, Watanabe S, Ieki K, Matsukura S, Kurokawa M, Takeuchi H, Sasaki Y, Huang SK, Adachi M, Ota H: Expression of interleukin-17F in a mouse model of allergic asthma. Int Arch Allergy Immunol 2007, 143 Suppl 1:89–94.

    Article  PubMed  Google Scholar 

  59. 59.

    Kawaguchi M, Kokubu F, Huang SK, Homma T, Odaka M, Watanabe S, Suzuki S, Ieki K, Matsukura S, Kurokawa M, Adachi M: The IL-17F signaling pathway is involved in the induction of IFN-gamma-inducible protein 10 in bronchial epithelial cells. J Allergy Clin Immunol 2007, 119:1408–1414.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Spurrell JC, Wiehler S, Zaheer RS, Sanders SP, Proud D: Human airway epithelial cells produce IP-10 (CXCL10) in vitro and in vivo upon rhinovirus infection. Am J Physiol Lung Cell Mol Physiol 2005, 289:L85–95.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Wark PA, Bucchieri F, Johnston SL, Gibson PG, Hamilton L, Mimica J, Zummo G, Holgate ST, Attia J, Thakkinstian A, Davies DE: IFN-gamma-induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations. J Allergy Clin Immunol 2007, 120:586–593.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Akimzhanov AM, Yang XO, Dong C: Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 2007, 282:5969–5972.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Lynch KR, O'Neill GP, Liu Q, Im DS, Sawyer N, Metters KM, Coulombe N, Abramovitz M, Figueroa DJ, Zeng Z, Connolly BM, Bai C, Austin CP, Chateauneuf A, Stocco R, Greig GM, Kargman S, Hooks SB, Hosfield E, Williams DL Jr., Ford-Hutchinson AW, Caskey CT, Evans JF: Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999, 399:789–793.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Takasaki J, Kamohara M, Matsumoto M, Saito T, Sugimoto T, Ohishi T, Ishii H, Ota T, Nishikawa T, Kawai Y, Masuho Y, Isogai T, Suzuki Y, Sugano S, Furuichi K: The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT(2) receptor. Biochem Biophys Res Commun 2000, 274:316–322.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR, Faux JA, Ryan GF, le Souef PN, Lathrop GM, Musk AW, Cookson WO: A genome-wide search for quantitative trait loci underlying asthma. Nature 1996, 383:247–250.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Kimura K, Noguchi E, Shibasaki M, Arinami T, Yokouchi Y, Takeda K, Yamakawa-Kobayashi K, Matsui A, Hamaguchi H: Linkage and association of atopic asthma to markers on chromosome 13 in the Japanese population. Hum Mol Genet 1999, 8:1487–1490.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Fukai H, Ogasawara Y, Migita O, Koga M, Ichikawa K, Shibasaki M, Arinami T, Noguchi E: Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13q14 and atopic asthma. Pharmacogenetics 2004, 14:683–690.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Pillai SG, Cousens DJ, Barnes AA, Buckley PT, Chiano MN, Hosking LK, Cameron LA, Fling ME, Foley JJ, Green A, Sarau HM, Schmidt DB, Sprankle CS, Blumenthal MN, Vestbo J, Kennedy-Wilson K, Wixted WE, Wagner MJ, Anderson WH, Ignar DM: A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma. Pharmacogenetics 2004, 14:627–633.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Thompson MD, Storm van's Gravesande K, Galczenski H, Burnham WM, Siminovitch KA, Zamel N, Slutsky A, Drazen JM, George SR, Evans JF, O'Dowd BF: A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha. Pharmacogenetics 2003, 13:641–649.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Hao L, Sayers I, Cakebread JA, Barton SJ, Beghe B, Holgate ST, Sampson AP, Holloway JW: The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma. Clin Exp Allergy 2006, 36:735–741.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Arriba-Mendez S, Sanz C, Isidoro-Garcia M, Davild I, Laffond E, Horeno E, Avila C, Lorente F: 927T>C polymorphism of the cysteinyl-leukotriene type-1 receptor (CYSLTR1) gene in children with asthma and atopic dermatitis. Pediatr Allergy Immunol 2006, 17:323–328.

    Article  PubMed  Google Scholar 

  72. 72.

    Sanz C, Isidro-Garcia M, Davila I, Moreno E, Laffond E, Lorente F: Analysis of 927T> C CYSLTRI and -444A > C LTC4S polymorphisms in patients with asthma. J Investig Allergol Clin Immunol 2006, 16:331–337.

    CAS  PubMed  Google Scholar 

  73. 73.

    Kim SH, Oh JM, Kim YS, Palmer LJ, Suh CH, Nahm DH, Park HS: Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males. Clin Exp Allergy 2006, 36:433–439.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Kim SH, Yang EM, Park HJ, Ye YM, Lee HY, Park HS: Differential Contribution of the CysLTR1 Gene in Patients with Aspirin Hypersensitivity. J Clin Immunol 2007, 27:613–619.

    Article  PubMed  Google Scholar 

  75. 75.

    The International HapMap Project [] 2003.

  76. 76.

    Zhang J, Migita O, Koga M, Shibasaki M, Arinami T, Noguchi E: Determination of structure and transcriptional regulation of CYSLTR1 and an association study with asthma and rhinitis. Pediatr Allergy Immunol 2006, 17:242–249.

    Article  PubMed  Google Scholar 

  77. 77.

    Duroudier NP, Sayers I, Castagna CC, Fenech AG, Halapi E, Swan C, Hall IP: Functional polymorphism and differential regulation of CYSLTR1 transcription in human airway smooth muscle and monocytes. Cell Biochem Biophys 2007, 47:119–130.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Woszczek G, Pawliczak R, Qi HY, Nagineni S, Alsaaty S, Logun C, Shelhamer JH: Functional characterization of human cysteinyl leukotriene 1 receptor gene structure. J Immunol 2005, 175:5152–5159.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO: Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007, 448:470–473.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Hjelmqvist L, Tuson M, Marfany G, Herrero E, Balcells S, Gonzalez-Duarte R: ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol 2002, 3:RESEARCH0027.

    Article  PubMed  PubMed Central  Google Scholar 

Download references


This study was supported by a grant from the Canadian Institutes of Health Research.

JZ is supported by a CIHR/HSFC IMPACT Strategic Training Program Grant and a Canadian Lung Association Fellowship Award. AJS is supported by a Tier 2 Canada Research Chair and a Michael Smith Foundation for Health Research Scholar Award.

Author information



Corresponding author

Correspondence to Andrew J Sandford.

Additional information

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

JZ drafted the manuscript. PP conceived of the review and edited the manuscript. AS edited the manuscript. All authors read and approved the final manuscript.

Electronic supplementary material


Additional file 1: Novel candidate genes in 2006–2007. The table lists all the novel candidate asthma gene studies published during 2006–2007 (DOC 530 KB)


Additional file 2: Studies to detect functional SNPs. The table lists all the genes with functional studies published during 2005–2007 (DOC 140 KB)

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Zhang, J., Paré, P.D. & Sandford, A.J. Recent advances in asthma genetics. Respir Res 9, 4 (2008).

Download citation


  • Asthma
  • Atopic Dermatitis
  • Bronchial Epithelial Cell
  • IL13 Variant
  • Plant Homeodomain Finger