Biomedical Engineering Reference
In-Depth Information
resulting in a complete genome screen. Linkage analysis determines whether
any of the markers are inherited with the disease more often than predicted
by chance. If so, that disease is said to be ''linked'' to that marker on a cer-
tain chromosome. An advantage of linkage analysis is that completely novel
genes can be identified and implicated in the pathogenesis of a disease. This
is because linkage of a disease to a genetic marker depends only on the close
proximity of that marker with the disease-causing gene, and no data
concerning the function of the gene is required.
COPD is defined as irreversible airflow obstruction, which can be
assessed by the reduction in the level of FEV
1
and by the ratio of FEV
1
to forced vital capacity (FVC). Evaluating linkage to these quantitative
spirometric indices (FEV
1
, FVC, FEV
1
=
FVC ratio) may be a more powerful
approach for finding disease susceptibility genes and may be less subject to
genetic heterogeneity than linkage to pulmonary disease (20). To date,
several genome scan studies have been performed and a number of candi-
date regions were suggested to be in linkage to lung function levels measured
by spirometry (Table 1) (21-23).
A genome scan exploring genetic linkage to lung function was per-
formed in the Framingham Heart cohort, a longitudinal cohort started in
1948 (22). This cohort contained numerous extended pedigrees and provided
a unique population for the analysis of genetics of pulmonary function (17).
Joost et al. estimated the heritability of FEV1, FVC, and FEV1
=
FVC
and reported a suggestive linkage of FEV1 to a locus on chromosome 6q
(LOD 2.4). In a follow-up study, fine mapping for the linkage on chromo-
some 6q and assessment of the association between lung function and
specific markers supported the idea that chromosome 6q harbored a gene
that was important for lung function (23).
In addition to the study performed in Framingham Heart cohort,
another genome scan was performed in the National Heart, Lung, and
Blood Institute Family Heart Study (NHLBIFHS) cohort (24). These
authors reported different loci that may influence the variability in pulmon-
ary function (24). The FEV
1
=
FVC ratio was linked to chromosome 4 (LOD
score 3.5), and FEV1 was linked to chromosome 18 (LOD score 2.4).
The authors suggested that the discrepancy between this study and the
Framingham study might be due to differences in subject ascertainment
and spirometric data collection (24).
An additional cohort used for the linkage analysis of lung function
was composed of severe early-onset COPD probands without severe AAT
deficiency and control probands matched for age and gender (7). Owing
to the stringent enrolment criteria, the size of this cohort was not large
(585 subjects, 72 pedigrees). Both qualitative phenotypes, including airflow
obstruction and chronic bronchitis, and quantitative phenotypes, including
pulmonary function and bronchodilator responsiveness (BDR), were evalu-
ated, and several linked genomic regions were identified (25-27).
