HUMAN CC10 GENE-EXPRESSION IN AIRWAY EPITHELIUM AND SUBCHROMOSOMAL LOCUS SUGGEST LINKAGE TO AIRWAY DISEASE

The CC10 gene encodes the Clara cell 10-kDa protein, which is expresse d in airway epithelial cells. Quantification of CC10 gene expression i n freshly isolated human proximal airway epithelial cells demonstrated very high mRNA levels, approximately fivefold greater than gamma-acti n mRNA, and in situ hybridization localized CC10 mRNA to nonciliated a irway epithelial cells. Sequence analysis demonstrated that the human CC10 gene is comprised of three short exons separated by a long first and short second intron, and with a 5' flanking region typical of a re gulated gene. Three Alu repeats were observed in intron 1 and one in i ntron 2. Two polymorphic regions within the introns were identified. F irst, a microsatellite was localized 5' to the third Alu repeat in int ron 1 with a variable number of 4- and 5-base pair (bp) repeats and a heterozygosity of 0.71. Second, in 3% of the 168 chromosomes examined, there was the insertion of a human-specific Alu repeat in intron 2, 4 5 bp 3' to the exon 2-intron junction. In three Centre d'Etude du Poly morphisme Humain families, meiotic breakpoint analysis using these two polymerphic loci localized the CC10 gene to 11 p12-q13 between marker s D11S16 and D11S97, a region recently linked to atopy and to the beta -subunit of the high-affinity immunoglobulin E receptor. The observati ons in the present study of high-level expression of the CC10 gene in the epithelium of conducting airways and a subchromosomal localization of the gene to a region potentially linked to inflammatory airway dis ease, together with the reported anti-inflammatory and immune-modulati ng properties of the protein, suggest the CC10 gene product may be imp ortant in modulating inflammation within the airways. If so, the highl y heterozygous microsatellite described in the present study should fa cilitate analysis of a possible linkage of the CC10 gene with an inher ited susceptibility to asthma.