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 FcepsilonRIbeta 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 beta-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 FcepsilonRIbeta.
Conclusions: A promoter-dependent mechanism with altered transcriptional regulation of FcepsilonRIbeta may be involved for its association with asthma. These results, therefore, could be useful in predicting the genetic susceptibility of individuals for developing asthma.