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Genetic linkage analysis of pulmonary fibrotic response to silica in mice

Dept of Pulmonary Medicine, School of Medicine, Fukushima Medical University, Fukushima, Japan.

CORRESPONDENCE: Y. Ohtsuka, Dept of Internal Medicine, Iwamizawa Rosai Hospital, 4-jyo, Higashi 16-chome 5, Iwamizawa, Hokkaido 068-0004, Japan. Fax: 81 126221304. E-mail: yohtsuka{at}kvf.biglobe.ne.jp

Keywords: C57BL/6J, CBA/J, hydroxyproline, intercross, quantitative trait locus

Received: November 11, 2005
Accepted June 29, 2006

Inter-individual variations in the development of silicosis, even within the same environments, have been reported, which suggest the contribution of genetic factors in silicosis aetiology. The aim of the present study was to determine whether there is any significant genetic influence on the development of silicosis. Furthermore, which genetic loci are responsible for the pulmonary response to silica exposure?

Eight strains of inbred mice were used to examine the genetic influence on the lung fibrotic response to silica exposure. After intercross-breeding between the most susceptible and most resistant strains, a genome-wide linkage analysis of quantitative trait loci (QTL) was performed. Hydroxyproline was applied as an index, and genotypes of 167 marker genes were analysed by fragment analysis using a capillary-type sequencer.

There was significant inter-strain difference in the mean concentration of hydroxyproline contents among the eight strains of mice. Breeding studies were conducted between the most susceptible, C57BL/6J, and the most resistant strain, CBA/J. A genome-wide linkage analysis of silica-exposed intercrossed cohorts identified significant QTL on chromosome 4 and suggestive QTL on chromosomes 3 and 18.

The present study demonstrates that genetic factors may play a significant role in fibrotic-lung responses to silica; one significant and two suggestive quantitative trait loci were identified.

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