Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00242125 |
| Other study ID # |
05-0630-AE |
| Secondary ID |
MOP - 74621 |
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
October 18, 2005 |
| Last updated |
January 13, 2006 |
| Start date |
October 2005 |
Study information
| Verified date |
October 2005 |
| Source |
University Health Network, Toronto |
| Contact |
Catalina Coltescu |
| Phone |
416-603-5832 |
| Is FDA regulated |
No |
| Health authority |
Canada: Health Canada |
| Study type |
Observational
|
Clinical Trial Summary
Primary biliary cirrhosis (PBC) is a chronic liver disease primarily affecting middle age
women. It is characterized by immune-mediated damage to cells lining the tiny bile ducts
within the liver. Although the underlying cause of PBC is likely to be multifactorial, the
epidemiologic/population data indicate a very important role for genetic predisposition,
meaning that the disease seems to run in families. Susceptibility genes for PBC have not
been identified possibly due to limitations such as small sample size in prior studies. The
primary objective of this study is to identify these genes. This study involves obtaining
clinical and demographic data as well as collecting DNA samples from patients and their
parents, and siblings to screen for a select set of candidate genes as well as the full
genome for variants associated with PBC.
Description:
This proposal is predicated on cumulative data revealing a major role for genetic factors in
PBC and the recent positional cloning of genes for Crohn’s disease, type 2 diabetes and
rheumatoid as well as psoriatic arthritis data provide the “proof-of-principle” that
susceptibility genes for multigenic diseases can be identified by linkage and association
strategies. Our group has access to >600 patients with PBC and these individuals plus family
members provide an excellent resource for PBC gene discovery. Moreover, an International PBC
Consortium we have initiated will serve not only to validate our findings but also to serve
as a source for additional patient accrual should we be searching for genes with very small
effects. Thanks to the remarkable advances in genotyping technology and sequence data
emanating from the Human Genome Project, patient populations such as ours can now be fully
mined so as to identify susceptibility genes for common multigenic diseases. By combining
the patient resources of our group and that of other Canadian centers with available
knowledge of the full genome sequence and the extensive information on SNPs within this
sequence, as well as our expertise in high throughput genotyping and rapid computational
approaches of genetic data, we are very well positioned to begin delineating the
susceptibility alleles for PBC. As such alleles are identified, the information will then be
used to define the molecular pathophysiology of this disease, to determine whether genetic
markers can be used to predict risk and/or stratify patients in relation to prognosis and
drug responsiveness, and ultimately, to identify novel targets for improved therapeutic
intervention.
For the purposes of this study only patients with a definite diagnosis of PBC will be
recruited ie:- those that had an elevated serum alkaline phosphatase level and positive AMA
by ELISA or immunofluorescence (>1/40 titer) at the time of their initial diagnosis and who
have had a liver biopsy which confirmed the diagnosis of PBC. After signing the consent form
the patients will complete a questionnaire. With the patient’s permission the coordinator
will contact the patient’s parents and siblings that are either affected or unaffected by
PBC to ask them to participate in the study. A total of five tubes of blood will be taken
from each participant in the study. The blood samples will be used to study the liver
biochemistries and to study the inherited genetic material (DNA) in order to find out what
causes PBC. In addition we are going to review the medical records for all the patients with
PBC from TWH recruited to this study using the records held in Misys to examine and verify
their medical and surgical history, past physical exams, laboratory tests and treatments.
Each patient will also be asked to recruit unrelated (usually spouses) household members or
friends who live locally to act as controls. They will then be treated similarly with regard
to the consent form, questionnaire and blood work.
The plan is to have approximately 600 patients with PBC along with approximately 1800 of
their relatives and other unrelated healthy volunteers to take part in this study – this is
a multicentre study – sites being Toronto, London and Halifax.
Statistical Analyses/Power Calculations: The use of association analysis to identify
susceptibility alleles is highly dependent on linkage disequilibrium (LD) between the SNP
markers and the disease loci. To demonstrate the extent to which LD can be used to delineate
PBC loci, our collaborator Dr. C. Amos has carried out calculations of the power to detect
significant effects (at the p ≤ 0.05 level) in a case-control analysis assuming different
amount of LD. Dr. Amos directs a statistical genetics group at MD Anderson Cancer Centre and
is a longstanding collaborator of K. Siminovitch. He and his group members are also the
statistical advisors to several disease-mapping consortia, such as NARAC, a US-based
consortium for discovery of rheumatoid arthritis genes. To estimate the power of an
association study to identify PBC susceptibility alleles, Dr. Amos used data from Talwalkar
and Lindor, estimating PBC prevalence at 0.05% among adult females and a 15 fold increased
risk for PBC among first-degree relatives of affected individuals. Assuming that mutation
frequency for disease causation is 0.1% and also that PBC is caused by a single gene, then
this level of risk among affected first-degree relatives implies the penetrance among
carriers of PBC susceptibility alleles to be 6% and among non-carriers to be 0.4%. A single
gene model for PBC, however, is simplistic and not consistent with available epidemiologic
data. If instead, an assumption of 4 disease causative loci is made and risk is thus
assigned to each one of these loci, then the genotype-specific risk would be 2.6%, the
locus-specific relative risk would be a more modest 3.75, and the disease allelic frequency
in carriers would be 10%. In the studies proposed here, we will begin by studying 300 cases
and 300 controls for PBC association with specific candidate genes discussed above. The
power to detect association in any case-control study is highly dependent upon the LD
between the disease mutation and the SNPs at closely linked loci as well as the number of
genes studied (about 40). If we assume a high level of disequilibrium, the disequilibrium
coefficient (D’) being 0.9 and, to be conservative, apply Bonferroni’s correction for the
simultaneous evaluation of 40 loci, then achieving 5% power in this study will require
obtaining a single SNP test p-value of 0.00125. Based on a disease allele frequency of 10%
(as calculated above), and the analysis of 300 cases and 300 controls, the power to detect a
SNP marker-disease association would then be 84%. The study can be further powered by
increasing numbers of cases and/or controls. Thus, to conserve resources, genotyping will be
initially carried out using 300 cases and 300 controls, but an additional 300 controls will
be further genotyped for any markers showing significant results at the p=0.01 level.
Genome-wide association analyses will also be carried out initially on the 300 cases and
controls. However, because a genome-wide screen is likely to yield many false positive
loci-disease associations, any loci showing association at the 5% level will be confirmed
using a replicate set of 300 cases and controls and/or trio families, once 200 such families
are available.
