Promoter Polymorphism in the <i>MS4A2</i> Gene and Asthma in the Indian Population

Abstract

Background: A previous study from our laboratory identified 3-locus risk and protective haplotypes of the MS4A2 gene, a prime candidate for asthma and atopy, that were associated with differential histamine release profiles from basophils and FcεRIβ transcript levels in the Indian population. Methods: To explore the role of promoter polymorphisms in the observed association, 4 additional promoter polymorphisms (–752C/T, –654C/T, –426T/C and –109T/C) were investigated in 240 nuclear families with atopic asthma, 237 atopic asthmatics and 221 unrelated controls, all of whom were clinically well characterized. The β-subunit transcript levels were measured for 15 individuals and were correlated with the associated promoter polymorphisms. Results: We observed a significant association of the –752C/T and –109T/C polymorphisms with asthma, in addition to the already reported association for the INT2 G/A, intron 5 (CA)_n and 3′-UTR C/T polymorphisms. Additionally, the allele T of the –109T/C polymorphism was associated with a reduced risk of asthma and lower percent peripheral blood eosinophils, thereby pointing towards a protective role for this allele in asthma. Further, the 7-locus haplotypes C_C_T_C_A_16_C and T_C_T_T_G_18_T were identified as the major risk/susceptibility and protective haplotypes, respectively (p < 0.05). Three-locus sliding-window haplotype analysis also identified the –426T/C, –109T/C and INT2 G/A polymorphisms to be in regions of high priority (p < 0.00001). Indeed, the –109T allele was found to be associated with reduced expression levels for FcεRIβ. Conclusions: A promoter-dependent mechanism with altered transcriptional regulation of FcεRIβ may be involved for its association with asthma. These results, therefore, could be useful in predicting the genetic susceptibility of individuals for developing asthma.

Mast cells in airway diseases and interstitial lung disease

“…Indeed, polymorphisms have been reported to be linked to asthma susceptibility in the promoter region of MS4A2 , which could affect expression levels of FcεRIβ (Sharma et al, 2009). In addition, mutations within regions recognised by the spliceosome could differentially affect isoform expression.…”

Comments on ‘Association of FcϵRIβ polymorphisms with risk of asthma and allergic rhinitis: evidence based on 29 case–control studies’

“…Fourth, the reported genotype frequency for the C-109T or E+237G polymorphisms of FcεRIβ gene in two studies of Guo et al .’s paper [ 1 ] were not in agreement with the ones in their original papers [ 22 , 23 ]. In Sharma and Ghosh’s study, the CC, CT, and TT genotype frequency for C-109T polymorphism in case/control groups were (89, 108, and 40)/(34, 118, and 69), respectively [ 22 ], which were wrongly counted as (87, 113, and 37)/(39, 108, and 74), respectively, in Guo et al .’s paper [ 1 ]. In Amo et al .’s published article, the EE, EG, and GG genotype frequency in control group for E+237G polymorphism were 487, 39, and 0, respectively [ 23 ], which were wrongly counted as 144, 277, and 105, respectively [ 1 ].…”

“…The main characteristics of the eligible studies [ 2–17 , 19 , 20 , 22–42 ], including the first author, publication year, country where individual study was conducted, ethnicity of study population, atopic disease category, sample size of case/control groups, the detailed genotype frequency, and the P -values for Hardy–Weinberg Equilibrium (HWE) test, were shown in Table 1 . There were 36 case–control studies about the association between E+237G variant and allergic diseases risk [ 2–4 , 6–15 , 17 , 19 , 20 , 23–28 , 30–33 , 36 , 38 , 39 , 41 , 42 ], and 15 were about the correlation of C-109T polymorphism with allergic diseases risk [ 5 , 8 , 12 , 14 , 17 , 19 , 22 , 23 , 29 , 34 , 35 , 37 , 38 , 40 ].…”

Exploration of the Genetic Epidemiology of Asthma: a review, with a Focus on Prevalence in Children and Adolescents in the Caribbean

“…As a consequence, FcεRIβ mediates asthma by activating inflammatory cells (14,16,22). Further studies in the Indian population confirmed that a promoter-dependent mechanism mediates FcεRIβ's pathway, leading to asthma (23). In a study of gene association in Italian families with allergic asthma, a hierarchical genotyping design was used to isolate G-protein-coupled receptor for asthma [GPRA] (24).…”