| Gene Discoveries Scratch the Surface of Crohn’s Disease |
by
David W. Sharp |
|
| WHAT'S
HOT IN MEDICINE |
| Rank |
Paper |
Citations
This Period (Jul-Aug 02) |
Rank
Last Period (May-Jun 02) |
| 1 |
J.-P. Hugot, et al.,
"Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease," Nature, 411(6837): 599-603, 31
May 2001. [14 European institutions] *437GE |
44 |
† |
| 2 |
M.P. Manns, et al., "Peginterferon alfa-2b plus ribavarin compared
with interferon alfa-2b plus ribavirin for initial
treatment of chronic hepatitis C: a randomised trial,"
Lancet, 358(9286): 958-65, 22 September 2001. [8 U.S.
and German institutions] *474YR 42 |
42 |
10 |
| 3 |
Y. Ogura, et
al., "A frameshift
mutation in NOD2 associated with
susceptibility to Crohn’s disease," Nature,
411(6837): 603-6, 13 May 2001.
[6 U.S.
institutions] *437GE |
41 |
† |
| 4 |
B.J. Druker, et al., "Efficacy and safety of a specific inhibitor of the BCR-ABL
tyrosine kinase in chronic myeloid leukemia," New
Engl. J. Med., 344(14): 1031-7, 5
April 2001. [Oregon
Hlth. Sci. U., Portland;
U. Texas, M.D. Anderson Canc.
Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover,
NJ; U. Calif.,
Los Angeles] *417XH |
58 |
1 |
| 5 |
B.J. Druker, et al., "Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and
acute lymphoblastic leukemia with the Philadelphia chromosome," New
Engl. J. Med., 344(14): 1038-42, 5
April 2001. [Oregon Hlth. Sci. U., Portland; U.
Calif., Los Angeles; U. Texas, M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover,
NJ]
*417XH |
32 |
4 |
| 6 |
E.
Lagasse, et al., "Purified hematopoietic stem cells can differentiate into hepatocytes in vivo,
" Nature Medicine, 6(11): 1229-34, November 2000. [StemCells, Sunnyvale, CA; Oregon Health Sci.
U., Portland; Baylor Coll. Med., Houston, TX; Stanford U. Sch.
Med., CA] *370GH |
31 |
5 |
| 7 |
P.E. Lipsky, et al., "Infliximab and methotrexate
in the treatment of rheumatoid arthritis," New
Engl. J. Med., 343(22): 1594-1602, 30
November 2000. [11
institutions worldwide] *377JT |
31 |
† |
| 8 |
B.M. Brenner, et al., "Effects of losartan on renal and cardiovascular outcomes in patients
with type 2 diabetes and nephropathy,"
New Engl. J. Med., 345(12):
861-9, 20 September 2001.
[8 institutions worldwide] *473JW |
31 |
† |
| 9 |
F.E.
Silverstein, et al., "Gastrointestinal toxicity with celecoxib vs nonsteroidal
anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS
study: a randomized controlled trial,"
JAMA-J. Amer. Med. Assn.,
284(10): 1247-55, 13 September 2000. [12 U.S.
institutions] *350WL |
30 |
3 |
| 10 |
M.E. Gorre, et al., "Clinical resistance to STI-571 cancer therapy caused by BCR-ABL
gene mutation or amplification,"
Science, 293(5531): 876-80, 3 August 2001. [U. Calif.,
Los Angeles] *459FU |
30 |
† |
| SOURCE:
ISI's
Hot Papers Database. Read
the full legend |
 egional ileitis is an
inflammatory disorder mostly of the small intestine. Named after Burrill B. Crohn (1932), an
accreditation that has been challenged, this severe illness remains difficult
to treat and its primary cause is unknown. A bacterial origin is a possibility;
enteric bacteria would be one candidate while another school of thought
implicates Mycobacterium paratuberculosis.
There are hints that the inflammatory cascade, including the nuclear
factor NF-kappaB, may be involved, and clinical
responses to steroids, sulfasalazine, and, more
recently, infliximab (a monoclonal antibody to
tumor-necrosis factor) support this view.
Although there are families with unusual
numbers of Crohn’s cases, any genetic link is not going to be as
clear-cut as it is with classic single-gene defects. In 1996 part of chromosome
16 was identified as being associated with susceptibility to Crohn’s disease. However, sites on at least six other
chromosomes have also been described, and the chromosome 16 region itself has
enough DNA base-pairs for a few hundred genes. Two letters to Nature in the 13 May 2001 issue narrowed the focus to a gene
called NOD2/CARD15 (paper #1 and #3).
The two groups of researchers used different methods to reach the same
conclusion—namely, that some patients with Crohn’s
disease have mutations in this gene that impair the body’s response to bacteria
and inflammation. These are recessive mutations; both alleles need to be
altered before Crohn’s susceptibility is conferred.
The gene product of NOD2 is involved
in the activation of NF-kappaB, the detection of
bacteria, and the control of the inflammatory response to them.
In his commentary on the two Nature papers, John A. Todd, University
of Cambridge, U.K. (Nature, 411[6837]: 537-9, 13
May 2001), reminded us of the likely complexity, including genetic
complexity, of susceptibility to Crohn’s disease. "This
is not the gene for Crohn’s disease," he wrote, and he estimated that 15%
of cases possess alleles (mutations) that alter this particular gene’s
functioning. The proportion in the non-Crohn’s
majority of the population is about 5%.
Publications that
climb the Science Watch charts as
rapidly as this do so because the work has prompted further studies, and those
that had appeared by November, 2002, tend to confirm the complexity that Todd
warned of. For instance, in Japan the NOD2 variants are nowhere to be seen—not
in Crohn’s disease or in the healthy population (see N. Inoue, et al., Gastroenterology,
123: 86-91, 2002). The French group (#1) subsequently
showed in a large study that half the Crohn’s
patients had at least one (of many candidate) disease-causing mutations in NOD2 and that about a third of these had
two, this double dose being associated with earlier onset and more severe
disease (see S. Lesage, et al., Am. J.
Hum. Genet.,
70: 845-57, 2002). However, possession of NOD2
variants is not predictive of whether or not a patient will respond to infliximab (see S. Vermeire, et al., Gastroenterology, 123: 106-11, 2002).
Here 33% of Crohn’s patients possessed one of the
three main gene variants, the control frequency being 15%.
So, as 2003 opens, Science Watch asked Gabriel Nunez of the University of Michigan, Ann Arbor, a senior
author with the U.S. group (# 3),
where are we? The current model, he says, is that "a deficit in a
protective innate immunity pathway regulated by NOD2 predisposes to Crohn’s disease."
However, since this gene seems to be involved in no more than 10% of Crohn’s cases in western populations, "we hypothesize
that patients with normal NOD2 alleles
may harbor mutations in other genes regulating the NOD2 pathway and/or in genes
that control some other immunity pathway that is important for the defense
against certain bacteria in the gut."
Mr.
David W. Sharp, M.A. (Cambridge), is a
contributing editor to The Lancet, London, U.K.
Science
Watch®, January/February 2003, Vol. 14, No. 1
Citing URL:
http://www.sciencewatch.com/jan-feb2003/sw_jan-feb2003_page5.htm |
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