ADAM33 and Their Expression.
Northern blot analysis showed two transcripts (5.0 and 3.5 kb) of ADAM33, of which only one was (3.5 kb) found in cytoplasm.15,25
hybridization technique revealed that ADAM33 preferentially expressed in smooth muscles, myofibroblasts, and fibroblasts of asthmatic airway and was not found in epithelium, endothelium, and T cell or inflammatory leukocytes.46
High expression of ADAM33 is found in MRC5 (lung fibroblast), jurkat (transformed T cell), the stomach, and the small intestine. Moderate expression of ADAM33 is observed in the trachea and bronchus and low expression is shown in the lymph node and thymus.5
The potential of alternative transcript of ADAM33 gene showed marked differences in tissue expression profile of pro and protease domains, which indicates the potential for tissue-selective functions of ADAM33.9,45
However, the correlation of this phenomenon with individual SNPs is still unknown.
ADAM33 protein has two isoforms, viz.
, α and β. The α-form is found abundantly in airway fibroblasts, myofibroblasts, and smooth muscles cells. Secreted splice variants of ADAM33 are rarely found.17,45
Because of complex differential splicing property of the ADAM33 gene, a high degree of variability in gene products has been observed. The majority of variation is seen in the 5′ end of the gene and the 3′ domain is present in all transcripts.48
A study conducted by Powel et al.49
showed no clear difference in the expression of ADAM33 spliced variants in bronchial biopsy specimens between normal subjects and subjects with asthma. However, in another study, increased expression of ADAM33 has been reported in moderate and severe asthma.50
Down-regulation of the ADAM33 gene by IFN-γ has been observed in airway smooth muscles cells.51
Studies suggest that mRNA expression of ADAM33 in response to IFN-γ may be regulated by the promoter region. The difference between regulation of ADAM33 gene by IFN-γ in subjects with and without asthma may be caused by the presence of polymorphism in the upstream region of ADAM33.7,51
SNPs in ADAM33 as Indicator of Severe and Progressive Asthma.
Although the exact role of ADAM33 in the pathogenesis of asthma is unclear, studies have shown an association of ADAM33 and its related SNPs with asthma (). summarizes the results of studies conducted in various populations. In the original description of ADAM33 as an asthma candidate gene, Van Eerdewegh et al.25
identified a locus on the short arm of chromosome 20 and assessed 135 polymorphisms of 23 genes in this region and reported ADAM33 gene to be significantly associated with asthma association of ADAM33 SNPs with asthma as reported in published studies, are summarized in .
Reported single nucleotide polymorphisms in the ADAM33 gene. Exons (black rods) and introns of the ADAM33 gene are shown. The association results of a case–control study in different populations shown in .
Previously reported association results with ADAM33 gene polymorphisms with asthma and BHR
In another case–control study, Howard et al.8
assessed association of eight SNPs of ADAM33 gene, namely S1, S2, ST + 4, ST + 7, T1, T2, V-1, and V4, with asthma in four unique ethnic groups with asthma viz
: U.S. white, Dutch white, black American, and Hispanic. Significant associations of SNPs were observed in all four studied population, but no single SNP was consistently associated with a specific asthma phenotype across all of the ethnicities. They observed significant associations with asthma in the Dutch population with SNPs ST + 7 and V4 by using a codominant model (p
= 0.0093 and p
= 0.0009, respectively). Associations with asthma were also observed in black Americans with SNP S2 (p
= 0.03), U.S. white populations with SNPs ST + 7 (p
= 0.017), T1 (p
= 0.03), T2 (p
= 0.02) and in U.S. Hispanic populations with SNPs S2 (p
= 0.04) and T2 (p
Lind et al.52
working on six SNPs, viz.
, S1, T1, T2, V-1, V1, and V4, of the ADAM33 gene used the transmission disequilibrium test to analyze associations between the ADAM33 gene variants and asthma, asthma severity, bronchodilator responsiveness, and total IgE levels using single SNPs, two to six SNP combinations, specific haplotypes but were unable to establish an association of any SNPs either with asthma or other outcomes. Raby et al.48
assessed 17 SNPs of ADAM33 gene, viz.
, G-1, Il, KL + 3, M + 1, N1, S2, S + 1, ST + 4, ST + 5, T1, T2, V-2, V-1, V3, and V4, but failed to detect association in a family-based study of white, black Americans, and Hispanic trios representative of North American children with mild-to-moderate asthma. However, two SNPs in strong linkage disequilibrium (T1 and T + 1) were marginally associated with asthma in the Hispanic cohort only (p
= 0.04). Wernar et al.53
analyzed 15 SNPs of the ADAM33 gene, viz.
, F + 1, Il, M + 1, Q-1, S1, S2, S + 1, ST + 4, ST + 5, ST + 7, T1, T2, T + 1, V-1, and V4, and observed a statistically significant association of asthma with SNPs F + 1, ST + 4, and ST + 5 in a family-based study. Significant association of SNP, ST + 7, was found in the case–control study.
Blakey et al.6
conducted transmission disequilibrium and case–control studies in Icelandic and Nottingham study populations but did not find any association with asthma; however, after performing meta-analysis, all existing data showed either positive or negative association results with asthma and showed that F + 1 and ST + 7 SNPs were significantly associated with asthma.6
Schedel et al.54
analyzed 10 SNPs of ADAM33, viz.
, F + 1, M + 1, S1, S2, ST + 4, ST + 5, ST + 7, T1, T2, and V4, and found none to be significantly associated with asthma in both case–control and cohort study designs in a German population.
A study conducted on a Chinese population by Wang et al.55
did not find any association of SNPs, viz.
, S + 1, T1, and F + 1, with asthma. Another study on a Chinese Han population analyzing six SNPs of the ADAM33 gene, viz.
, V4, T + 1, T2, T1, S1, and Q-1, for association with allergic asthma, found that V4, T2, T1, and Q-1 increased risk of susceptibility.56
Kedda et al.40
did a study on an Australian population and were unable to find association of SNPs of ADAM33, viz.
, F + 1, Q-1, S1, ST + 4, ST + 7, V-2, V-1, V2, V4, and V5, with asthma.
Thongngarm et al.57
conducted a study in a Thai population on eight SNPs of ADAM33, viz.
, S1, S2, ST + 4, ST + 7, T1, V-1, and V4, and found a positive association between ADAM33 polymorphisms S2 and ST + 4 with asthma susceptibility. A study by Vergara et al.58
using six SNPs of ADAM33, viz.
, S2, ST + 7, T1, T2, V-1, and V4, in population of Cartagena, Colombia, were unable to find association of any SNPs with asthma. However, they found association of TT genotype of ST + 7(C/T) SNP with asthma (p
= 0.05) that disappeared after correcting for multiple testing. They also identified eight common haplotypes; among them, H4 (GCAGGG) was associated with asthma in the family group (Z
score, −2.049; p
A study by Bijanzadeh et al.59
in children as well as adults, also failed to find an association between asthma and the T1 SNP of ADAM33 gene in a southern Indian population. However, another recent case–control study, conducted in Northern India to assess association of ADAM33 gene polymorphisms, viz.
, F + 1, S2, ST + 4, ST + 5, and V4, with asthma in children aged 1–15 years, showed significant association of all of them with the disease.60
Certain studies have shown that multiple SNPs may act together to increase the risk of asthma; haplotype analysis found a significant association which was not found during individual SNPs analysis.40,47,58
However, it is still unclear which of the identified SNPs relate causatively to asthma.