Introduction
This is one of a group of Interactive Research Project Grant applications
which have the broad objective of clarifying the role of genes in alcohol
dependence and related disorders. Alcohol dependence is a common condition with
a substantial genetic component. This application focuses on pre-clinical
alcoholic liver disease in a community-based sample and will complement
published studies on patients with more advanced disease. The objective is to
identify risk factors able to predict which hazardous drinkers are at risk of
eventual progression to liver disease. Successful identification of risk
factors for alcoholic liver disease will lead to improvements in early
identification of people at risk from their drinking, and early intervention
to prevent progression to clinical disease. Known risk factors include
lifetime quantity of alcohol consumed, and gender (women are more susceptible
to alcoholic liver disease than men). The postulated risk factors to be
studied are based on a small number of published studies on patients, and on
our preliminary work with community samples. They include obesity and related
metabolic disorders; iron overload; and allelic variation in a range of
candidate genes concerned with alcohol metabolism, inflammatory response
within the liver, fatty liver and fibrosis. The specific aims are to test
whether the postulated risk factors affect the probability of liver
dysfunction in hazardous drinkers, using biochemical liver function tests to
detect pre-clinical liver damage. The enzyme liver function tests are
abnormal in a substantial proportion (~ 30-40%) of hazardous drinkers and
offer an opportunity for noninvasive testing in
large numbers of subjects. Subjects will be drawn from twins and their families
who have participated in previous studies of alcohol use and dependence. They
will have met DSM-IV criteria for alcohol dependence and/or have reported
hazardous levels of alcohol intake in the previous studies. They will provide
information on recent alcohol intake, and blood samples will be taken for
biochemical testing and as a source of DNA
for genotyping. Data will be analyzed using
standard methods for twin studies and tests will be included for the effects
of postulated phenotypic risk factors, for heritability of liver abnormality
conditional on hazardous drinking, and for allelic association at candidate
genes.
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