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Chemokine receptor 5 (CCR5) contributes to the generation of a Th1 immune response by interacting with agonists such as RANTES, MIP-1α, and MIP-1β.1 A 32 base pair deletion (Δ32) in CCR5 has been proposed to protect individuals against HIV infection and to bias the immune system towards a Th2-driven response, thus affecting the susceptibility to develop allergic diseases such as asthma. In a study in Scottish children, Hall et al reported an association of CCR5Δ32 with a reduced risk of asthma2 but found no such association in adults with asthma.3 In addition, no association was detected with atopy or asthma/wheeze in two other studies.4,5
We examined the potential role for this deletion in the pathogenesis of asthma by an association study in a genetically untapped Indian population. Patients were diagnosed with asthma on the basis of the National Asthma Education and Prevention Program (Expert Panel Report 2) guidelines. Written consent was obtained from individuals participating in the study. Genomic DNA from patients with atopic asthma (mean (SD) age 25.2 (5.6) years) and healthy controls (27.2 (14.6) years) from Northern India was screened for CCR5Δ32 deletion. We found that only 11 of 367 controls were heterozygous for the mutation compared with 17 of 215 with atopic asthma (p = 0.0009). However, we failed to detect any homozygous individual in either group in preliminary analysis. In contrast to previous reports, individuals heterozygous for CCR5Δ32 had a 1.6 times greater risk of developing asthma than homozygous wild types.
Since heterozygous individuals may have altered disease susceptibility, we were interested in finding the inheritance pattern of this mutation in the asthmatic families. We therefore recruited 10 families (56 individuals) of the CCR5Δ32 heterozygous probands. Genotyping indicated that the mutation segregated in Mendelian fashion. In the process we found two individuals homozygous for this deletion (first report from the Indian subcontinent). Furthermore, to establish the trend of CCR5Δ32 in asthmatic families from other parts of India, 36 families (92 individuals) from the north-east and 48 families (147 individuals) from the north-west were also genotyped. Only two members of one family from north-west India were heterozygous for CCR5Δ32 deletion while no homo/heterozygous mutants were observed from north-east India.
We suggest that CCR5Δ32 is associated with asthma but its low frequency may delay the progress in establishing the role of CCR5 in predicting susceptibility to asthma. Nevertheless, our findings have important implications in understanding the global distribution of CCR5Δ32 and its possible impact on the susceptibility to developing various immunological diseases including asthma and AIDS.
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