Aσκηση- πολυπαραγοντική κληρονόμιση

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Τι σημαίνει  genome-wide techniques; σε τι μπορεί να βοηθήσουν.
Αnn N Y Acad Sci. 2010 December ; 1214: 57–69.
Modifier genes in Mendelian disorders: the example of cystic
fibrosis
Garry R. Cutting
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine,
Baltimore, Maryland
Abstract
In the past three decades, scientists have had immense success in identifying genes and their
variants that contribute to an array of diseases. While the identification of such genetic variants
has informed our knowledge of the etiologic bases of diseases, there continues to be a substantial
gap in our understanding of the factors that modify disease severity. Monogenic diseases provide
an opportunity to identify modifiers as they have uniform etiology, detailed phenotyping of
affected individuals, and familial clustering. Cystic fibrosis (CF) is among the more common life-
shortening recessive disorders that displays wide variability in clinical features and survival.
Considerable progress has been made in elucidating the contribution of genetic and nongenetic
factors to CF. Allelic variation in CFTR, the gene responsible for CF, correlates with some aspects
of the disease. However, lung function, neonatal intestinal obstruction, diabetes, and anthropometry display strong genetic control independent of
CFTR, and candidate gene studies have revealed genetic modifiers underlying these traits. The application of genome-wide
techniques holds great promise for the identification of novel genetic variants responsible for the
heritable features and complications of CF. Since the genetic modifiers are known to alter the
course of disease, their protein products become immediate targets for therapeutic intervention.
Keywords
genome wide; candidate gene; heritability; variation
Overview
It is generally recognized that genetic, environmental, and stochastic factors contribute to
phenotype variation. However, the relative effect of each component is difficult to assess,
especially for common diseases where a myriad of environmental factors may play a role.
Consider, for instance, the role of drugs (an environmental factor) in the treatment of
diseases and the effect they can have in modifying outcome. Parsing patient populations
based on multiple environmental exposures can lead to substantial drops in power to detect
the responsible genetic variants. Despite the aforementioned challenges, progress has been
made in dissecting genetic and nongenetic factors underlying disease variability for several
of the more common Mendelian disorders. The “monogenic” diseases provide unique
opportunities to dissect components as they each have a single etiology, relatively uniform
treatments, and the contribution of the disease-causing gene is known to some degree. In
many cases, some portion of phenotype variability can be associated with the nature of the
mutations in the disease-causing gene. However, disease variability in patients bearing the
same combination of mutations emphasizes the role of genetic background and environment,
which appears to be the rule rather than the exception.
2
Thus, the current challenge for many
studying monogenic disorders is to assess the relative contribution of genetic factors distinct
from the disease-causing gene and to identify those genes that modify outcome.
3
Identification of such modifier genes increases our understanding of the elements that affect
disease variability and thereby identifies new targets for therapy. Furthermore, it is possible
that genes that modify single-gene disorders contribute to the development and/or
progression of common diseases in the general population. These genes may be minimally
penetrant in healthy individuals, whereas the altered homeostasis of patients with single-
gene disorders may unmask the effect of such modifiers. Thus, the search for genetic
modifiers of single-gene disorders could benefit individuals beyond those afflicted with
monogenic conditions. Finally, by their very nature, single-gene disorders have one highly
penetrant disease-causing gene that could serve as a starting point for modeling of gene–
gene and gene–environment interactions.
Evidence for, and quantification of, genetic modifier role for CF traits
Before embarking upon a search for genetic modifiers, it is important to consider the
importance of nongenetic contributions to a phenotype. In the case of CF, the impressive
increase in mean years of survival from less than 1 year to the upper 30s currently is
attributable almost exclusively to the treatments devised for these patients. From that
perspective, environmentally mediated factors have a profound effect on disease variability.
Specific treatments such as pancreatic enzyme supplementation, nutritional support, and
vitamin supplementation have modified CF from a disease of malnutrition and early
childhood demise to a disorder marked by respiratory compromise beginning in childhood
and progressing into mid-adulthood.
6
Extension of longevity has also exposed dysfunction
of the endocrine pancreas that manifests as diabetes.
15
On the other hand, treatment does not
appear to have altered the prevalence of complications that occur in the newborn period
(e.g., neonatal intestinal obstruction or meconium ileus) or early to midchildhood (e.g.,
hepatic cirrhosis)