A Brief History of Asthma Genetics

This entry is based on one that I wrote previously for a blog by Dr. Ann Wu, a pediatrician and health services researcher who studies asthma. If you are a patient with asthma, I recommend taking a look at her blog. There are many helpful posts that give insights into how to manage and treat asthma.

Everybody knows asthma “runs in families,” but that is only part of the story. Asthma is a complex disease that is not caused by a single gene or even a small group of genes.  It is strongly influenced by other factors, most notably environmental ones. Here is a brief history of asthma genetics studies.

Since the mid-90s, there have been experimental techniques available to widely study human genetics of complex diseases. The initial studies of asthma genetics were performed between 1996 and 2005, and they were so-called linkage and candidate gene association studies. During this time, researchers published in 492 papers associations of over 100 genes with asthma and related traits. Of this long list of genes, only about 10 seemed very important because the associations were found frequently (>10 times) in independent populations (the gold standard for gene association studies to be deemed reliable is that they consistently replicate in large independent studies) [1]. The 10 most salient genes that arose in this time span are: IL4, IL13, CD14, ADRB2, HLA-DRB1, HLA-DQB1, TNF, FCER1B, IL4RA, ADAM33.

Starting in 2007, as newer technologies were developed and became cheaper, genome-wide association studies (GWAS) of asthma have been conducted. Unlike the candidate gene studies, GWAS look at common genetic variants across the entire genome. Initially, asthma GWAS were conducted in relatively small cohorts, and these GWAS mostly reported different “top” associations with little replication across studies. One exception, and the region of the genome that has most strongly been associated with asthma, is the ORMDL3 and GSDMB gene region. To date, strong associations in this region have been reported in over 15 independent cohorts. Most recently, many of the investigators who had reported individual cohort GWAS, became part of large multi-center collaboration efforts. In Europe, this collaboration was called GABRIEL [2], while in the US, it was called EVE [3]. These large-scale GWAS have begun to consistently identify genes that are strongly associated with asthma. Such genes include GSDMB-ORMDL3 locus, HLA-DQ, IL1RL1, IL18RL1, IL33, TSLP, SLC22A5, SMAD3, and RORA.The reproducibility of the latest asthma GWAS findings is promising, but much work remains to be done in asthma genetics. Most importantly, we have yet to identify the function of most of the variants that have been identified.

 

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References

  1. C. Ober, and S. Hoffjan, "Asthma genetics 2006: the long and winding road to gene discovery.", Genes and immunity, 2006. http://www.ncbi.nlm.nih.gov/pubmed/16395390
  2. M.F. Moffatt, I.G. Gut, F. Demenais, D.P. Strachan, E. Bouzigon, S. Heath, E. von Mutius, M. Farrall, M. Lathrop, and W.O.C.M. Cookson, "A large-scale, consortium-based genomewide association study of asthma.", The New England journal of medicine, 2010. http://www.ncbi.nlm.nih.gov/pubmed/20860503
  3. D.G. Torgerson, E.J. Ampleford, G.Y. Chiu, W.J. Gauderman, C.R. Gignoux, P.E. Graves, B.E. Himes, A.M. Levin, R.A. Mathias, D.B. Hancock, J.W. Baurley, C. Eng, D.A. Stern, J.C. Celedón, N. Rafaels, D. Capurso, D.V. Conti, L.A. Roth, M. Soto-Quiros, A. Togias, X. Li, R.A. Myers, I. Romieu, D.J. Van Den Berg, D. Hu, N.N. Hansel, R.D. Hernandez, E. Israel, M.T. Salam, J. Galanter, P.C. Avila, L. Avila, J.R. Rodriquez-Santana, R. Chapela, W. Rodriguez-Cintron, G.B. Diette, N.F. Adkinson, R.A. Abel, K.D. Ross, M. Shi, M.U. Faruque, G.M. Dunston, H.R. Watson, V.J. Mantese, S.C. Ezurum, L. Liang, I. Ruczinski, J.G. Ford, S. Huntsman, K.F. Chung, H. Vora, X. Li, W.J. Calhoun, M. Castro, J.J. Sienra-Monge, B. del Rio-Navarro, K.A. Deichmann, A. Heinzmann, S.E. Wenzel, W.W. Busse, J.E. Gern, R.F. Lemanske, T.H. Beaty, E.R. Bleecker, B.A. Raby, D.A. Meyers, S.J. London, . , F.D. Gilliland, . , E.G. Burchard, . , F.D. Martinez, . , S.T. Weiss, . , L.K. Williams, . , K.C. Barnes, . , C. Ober, and D.L. Nicolae, "Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.", Nature genetics, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21804549