Genetic Modifiers in Cystic Fibrosis

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     Drumm and colleagues (Oct. 6 issue)identified sequence variants in the TGF{beta}

    1 gene as genetic modifiers of lung disease in cystic fibrosis. TGF{beta}

    1 is encoded on chromosome 19q13, 4.5 Mbp from the CFM1 locus that confers a risk of meconium ileus.We scanned this region on 19q13 with use of single-nucleotide polymorphisms (SNPs) and microsatellites in a cohort of sibling pairs homozygous for the {Delta}

    F508 mutation with extreme clinical phenotypesfor a modulator of disease severity. Neither the two TGF{beta}

    1 SNPs (–509 and codon 10)nor the microsatellite D19S112 at CFM1was associated with disease severity in our cohort.

    Interrogation of the region between TGF{beta}

    1 and CFM1 by four microsatellites, however, revealed a significant transmission disequilibrium in clinically discordant sibling pairs (a peak at D19S197, P=0.003), suggesting a modulation of factors acting in trans(Figure 1). The region contains the CEACAM gene family encoding cell-adhesion molecules involved in the binding of pathogens and the regulation of differentiation, angiogenesis, and cancer. The TGF{beta}

    1–CEACAM region apparently contains at least one clinically relevant genetic modifier of cystic fibrosis.

    http://www.100md.com/html/DirDu/2006/07/03/02/42/78.htm