Genetics

Why some patients with asthma require high-dose corticosteroid therapy and others continue to have refractory symptoms is an important question. In vitro, corticosteroid insensitivity can be induced in peripheral blood mononuclear cells by IL-2 and IL-4, suggesting that the inflammatory milieu might be important. Torrego and coworkers showed that this phenomenon was not related to an increased expression of the inhibitory corticosteroid receptor GR-ß in peripheral blood mononuclear cells from control subjects and subjects with stable and unstable asthma. Interestingly, peripheral blood mononuclear cells from subjects with unstable asthma had increased mRNA for the active glucocorticoid receptor GR- ${alpha}$ , but demonstrated a reduced antiproliferative effect of dexamethasone, suggesting impaired function of GR- ${alpha}$ . The authors speculated that this effect reflects IL-2– and IL-4–induced activation of the p38 mitogen-activated protein kinase, resulting in phosphorylation of GR and reduced glucocorticoid binding affinity and nuclear translocation of the GR.

Recent evidence suggests that alterations in the helper T-cell type 1 (Th1) cytokine pathway may be associated with susceptibility to allergic asthma. Birkisson and colleagues examined a number of genes and protein expression in the Th1 pathway involved with IL-12 and IFN- ${gamma}$ , their subunits, and receptors, and found no evidence for a defect in these cytokine genes and responses as a primary event in asthma.

The IL-1 cluster on the human chromosome 2q12-2q14 has promising candidate genes for asthma and other inflammatory diseases. Gohlke and coworkers conducted a study of single-nucleotide polymorphisms (SNPs) and found the diagnosis of asthma to be associated with SNPs in the IL-1 receptor antagonist and transforming growth factor ß₁ (TGF-ß₁) genes, respectively.

TGF-ß₁ is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Silverman and colleagues performed a case-control study of 527 patients with asthma and 170 without asthma. In the case of TGF-ß₁, the T allele of C-509T was not only associated with a diagnosis of asthma but also appeared to enhance gene transcription. Genes involved in the innate immune system were also explored.

Toll-like receptor 10 is a potential asthma candidate gene, because in early life, innate immune responses to inhaled allergens and pathogen-associated molecular patterns may influence asthma susceptibility. Lazarus and colleagues reported that two SNPs in Toll-like receptor 10 were associated with asthma in two different populations (Nurses' Health Study and Childhood Asthma Management Program).

In a case-control analysis, Hizawa and colleagues examined the genetic influence of promoter polymorphisms on the development of atopy and asthma in a Japanese population (n = 584). The authors reported that two different functional variations in the macrophage migration inhibitory factor (MIF) gene (–173G/C and –794[CATT]_5–8 repeat polymorphism) were associated with atopy but not asthma.

Genome scans for asthma have identified suggestive or significant linkages on 17 different chromosomes, including chromosome 12, region q13-23, housing the vitamin D receptor (VDR) gene. Poon and colleagues reported that six variants of the vitamin receptor gene falling into two haplotype blocks were associated with asthma and four variants were associated with atopy in a Quebec cohort.

VDR polymorphisms have been associated with several immune-related diseases, and VDR and vitamin D itself modulate T-cell differentiation. VDR maps to chromosome 12q, near a region commonly linked to asthma.

Raby and colleagues evaluated VDR as part of a 12q positional candidate survey and in response to observations of VDR polymorphism associating with asthma and atopy in a founder population of Quebec. Four of six variants were associated with asthma. Interestingly, and confusingly, one of these variants (and associated haplotype) was also seen in an increased frequency in a second cohort (517 females with asthma and 519 matched control subjects), but the association was reversed (i.e., appeared to confer protection rather than risk). Clearly, the relationships between genetic variability in the VDR and asthma are complex and not well understood.

The ADAM33 gene, located on the short arm of chromosome 20, was recently identified as contributing to asthma. Because the earlier study was conducted exclusively in white subjects recruited from the United States and Britain, Lind and coworkers investigated whether the ADAM33 gene is associated with asthma in Puerto Ricans (who have the highest asthma prevalence in the United States) and Mexicans (who have the lowest asthma prevalence). Genotyping of six single-nucleotide polymorphisms (SNPs) revealed no associations with asthma severity, bronchodilator response, or IgE levels. The transmission equilibrium test and genotyping of matched control samples (to permit case-control analyses) did not reveal significant associations in either the Puerto Rican or Mexican population. The authors conclude that the ADAM33 gene is not an important risk factor for asthma or for asthma-associated phenotypes in Mexicans or Puerto Ricans.

Serum levels of eosinophil cationic protein, which is produced by activated eosinophils, reflect the degree of activation of the circulating pool of eosinophils. Because some patients with asthma do not have elevated levels of this protein, Noguchi and coworkers screened 137 Japanese families (identified through children with asthma) for polymorphisms in the gene for eosinophil cationic protein. Three polymorphisms were identified: -393 C/T, -138C/A, and 124 Arg/Thr. The transmission disequilibrium test did not reveal an association between these polymorphisms and asthma. Serum levels of eosinophil cationic protein were lower in subjects with the -393T allele than in subjects with the -393C allele. Gel shift assay revealed that the C/eosinophil cationic protein is capable of binding the -393C/T polymorphic site. The authors conclude that a significant amount of the variance in baseline serum levels of eosinophil cationic protein can be explained by -393C/T polymorphism, although this polymorphism is not involved in the development of asthma.

Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are detoxifying enzymes induced in response to oxidative stress, as occurs during ozone exposure. To examine the relationship between significant polymorphisms in NQO1 and GSTM1 and risk of asthma, David and coworkers studied 218 case-parent triads in children from Mexico City (which has the highest ozone levels in North America). The Pro187Ser polymorphism in NQO1 was not associated with risk of asthma. Among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at reduced risk of asthma as compared with Pro/Pro homozygotes. The authors conclude that children who live in an area with high exposure to ozone and who carry at least one NQO1 Ser allele and are homozygous for the GSTM1 deletion are at a decreased risk of asthma.

Variation in levels of exhaled nitric oxide in patients with asthma may arise from sequence variants in the genes for nitric oxide synthase. To determine whether a sequence variant in the gene for endothelial nitric oxide synthase (NOS3), an enzyme constitutively expressed in endothelial cells, could explain some of the variation in exhaled nitric oxide, Storm van's Gravesande and coworkers studied 73 patients with mild to moderate asthma. A strong association was found between exhaled nitric oxide and a known functional NOS3 missense sequence variant in the endothelial nitric oxide gene (G894T). Age- and sex-adjusted levels of exhaled nitric oxide were lowest in patients with the TT genotype (7.2 ppb) and higher in patients with either the GT genotype (17.1 ppb) or the GG genotype (12.1 ppb). The G894T DNA variant explained 16% of the residual variance in levels of exhaled nitric oxide. The authors conclude that a missense variant of the gene for endothelial nitric oxide synthase explains about one-sixth of the variation in levels of exhaled nitric oxide among patients with asthma.

Citations 1-12 of 12 total displayed.

Association of Vitamin D Receptor Gene Polymorphisms with Childhood and Adult Asthma

Benjamin A. Raby, Ross Lazarus, Edwin K. Silverman, Steven Lake, Christoph Lange, Mathias Wjst, and Scott T. Weiss
Am. J. Respir. Crit. Care Med. 170: 1057 -1065. First published online as doi:10.1164/rccm.200404-447OC [Abstract] [Full text]

Association of Vitamin D Receptor Genetic Variants with Susceptibility to Asthma and Atopy

Audrey H. Poon, Catherine Laprise, Mathieu Lemire, Alexandre Montpetit, Donna Sinnett, Erwin Schurr, and Thomas J. Hudson
Am. J. Respir. Crit. Care Med. 170: 967 -973. First published online as doi:10.1164/rccm.200403-412OC [Abstract] [Full text]

TOLL-like Receptor 10 Genetic Variation Is Associated with Asthma in Two Independent Samples

Ross Lazarus, Benjamin A. Raby, Christoph Lange, Edwin K. Silverman, David J. Kwiatkowski, Donata Vercelli, Walt J. Klimecki, Fernando D. Martinez, and Scott T. Weiss
Am. J. Respir. Crit. Care Med. 170: 594 -600. First published online as doi:10.1164/rccm.200404-491OC [Abstract] [Full text]

Glucocorticoid Receptor Isoforms ${alpha}$ and ß in in Vitro Cytokine-induced Glucocorticoid Insensitivity

Alfons Torrego, Laura Pujols, Jordi Roca-Ferrer, Joaquim Mullol, Antoni Xaubet, and César Picado
Am. J. Respir. Crit. Care Med. 170: 420 -425. First published online as doi:10.1164/rccm.200308-1143OC [Abstract] [Full text]

Association of the Interleukin-1 Receptor Antagonist Gene with Asthma

Henning Gohlke, Thomas Illig, Margret Bahnweg, Norman Klopp, Elisabeth André, Janine Altmüller, Nicole Herbon, Monika Werner, Michael Knapp, Lydia Pescollderungg, Attilio Boner, Giovanni Malerba, Pier Franco Pignatti, and Matthias Wjst
Am. J. Respir. Crit. Care Med. 169: 1217 -1223. First published online as doi:10.1164/rccm.200302-281OC [Abstract] [Full text]

Genetic Approaches to Assessing Evidence for a T Helper Type 1 Cytokine Defect in Adult Asthma

Illugi F. Birkisson, Eva Halapi, Unnur S. Bjornsdottir, Dana L. Shkolny, Elva Adalsteinsdottir, Thor Arnason, David Gislason, Thorarinn Gislason, Jeffrey Gulcher, Kari Stefansson, and Hakon Hakonarson
Am. J. Respir. Crit. Care Med. 169: 1007 -1013. First published online as doi:10.1164/rccm.200302-228OC [Abstract] [Full text]

Functional Polymorphisms in the Promoter Region of Macrophage Migration Inhibitory Factor and Atopy

Nobuyuki Hizawa, Elsuro Yamaguchi, Daisuke Takahashi, Jun Nishihira, and Masaharu Nishimura
Am. J. Respir. Crit. Care Med. 169: 1014 -1018. First published online as doi:10.1164/rccm.200307-933OC [Abstract] [Full text]

Transforming Growth Factor-ß₁ Promoter Polymorphism C–509T Is Associated with Asthma

Eric S. Silverman, Lyle J. Palmer, Venkat Subramaniam, Arlene Hallock, Sheeba Mathew, Joseph Vallone, Debora S. Faffe, Toshiki Shikanai, Benjamin A. Raby, Scott T. Weiss, and Stephanie A. Shore
Am. J. Respir. Crit. Care Med. 169: 214 -219. First published online as doi:10.1164/rccm.200307-973OC [Abstract] [Full text]

ADAM33 Is Not Associated with Asthma in Puerto Rican or Mexican Populations

Denise L. Lind, Shweta Choudhry, Ngim Ung, Elad Ziv, Pedro C. Avila, Keyan Salari, Connie Ha, Elizabeth G. Lovins, Natasha E. Coyle, Sylvette Nazario, Jesus Casal, Alfonso Torres, Jose R. Rodriguez-Santana, Henry Matallana, Craig M. Lilly, Jorge Salas, Moises Selman, Homer A. Boushey, Scott T. Weiss, Rocio Chapela, Jean G. Ford, William Rodriguez-Cintron, Edwin K. Silverman, Dean Sheppard, Pui-Yan Kwok, and Esteban González Burchard
Am. J. Respir. Crit. Care Med. 168: 1312 -1316. First published online as doi:10.1164/rccm.200306-877OC [Abstract] [Full text]

Nicotinamide Adenine Dinucleotide (Phosphate) Reduced:Quinone Oxidoreductase and Glutathione S-Transferase M1 Polymorphisms and Childhood Asthma

Gloria L. David, Isabelle Romieu, Juan Jose Sienra-Monge, William J. Collins, Matiana Ramirez-Aguilar, Blanca Estela del Rio-Navarro, Norma Isabel Reyes-Ruiz, Richard W. Morris, Jacqueline M. Marzec, and Stephanie J. London
Am. J. Respir. Crit. Care Med. 168: 1199 -1204. First published online as doi:10.1164/rccm.200305-684OC [Abstract] [Full text]

Association of a Missense Mutation in the NOS3 Gene with Exhaled Nitric Oxide Levels

Karin Storm van's Gravesande, Michael E. Wechsler, Hartmut Grasemann, Eric S. Silverman, Louis Le, Lyle J. Palmer, and Jeffrey M. Drazen
Am. J. Respir. Crit. Care Med. 168: 228 -231. First published online as doi:10.1164/rccm.200212-1491BC [Abstract] [Full text]

The Promoter Polymorphism in the Eosinophil Cationic Protein Gene and Its Influence on the Serum Eosinophil Cationic Protein Level

Emiko Noguchi, Asushi Iwama, Kazunori Takeda, Tetsuya Takeda, Masashi Kamioka, Kunio Ichikawa, Toshiko Akiba, Tadao Arinami, and Masanao Shibasaki
Am. J. Respir. Crit. Care Med. 167: 180-184. [Abstract] [Full text]

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