CORRESPONDENCE
Multiple sclerosis and
type 1 diabetes in Sardinia
Sir—M G Marrosu and colleagues
(April 27, p 1461)1 report on the risk of
type 1 diabetes in patients who have
multiple sclerosis, in Sardinia, Italy,
which is further discussed by
A Lernmark in his April 27 Commen-
tary.2 We have assessed HLA patterns in
individuals who have both diseases
compared with those with only one
disease.
To test the hypothesis of mutually
exclusive HLA-patterns, we did a
case-control study in 66 patients who
had type 1 diabetes and multiple
sclerosis (33), or multiple sclerosis
only (33). We analysed blood
samples for HLA class I and class II
alleles in all patients. For comparison
with type 1 diabetes only we
referred to published data. HLA-typing
was done by conventional serology
(immunomagnetic beads) and geno-
typing (SSP-PCR, Dynal SSP, Oslo,
Norway; low/high resolution).
The individuals with type 1 diabetes
and multiple sclerosis had the expected
HLA pattern associated with type 1
diabetes (76% carried DRB1*04, 70%
carried DQB1*0302, 42% were
DR4/DR3 heterozygous), but not the
expected multiple sclerosis HLA pattern
(none carried DQB1*0602 or
DRB1*1501, 3·1% carried DQA
1*0102). In the multiple sclerosis only
patients, we saw the expected multiple-
sclerosis-associated HLA pattern for
white people (42% carried DR
B1*1501-DQ B1*0602, 58% DQA
1*0102), but the prevalence of type 1
diabetes susceptibility and resistance
alleles did not differ from that in the
general population. The allele
frequencies of DRB1*1501, DQB
1*0602, and DQA 1*0102 were, in
multiple sclerosis only patients, 24%,
24%, and 27%, respectively, and, in
patients with type 1 diabetes and
multiple sclerosis, 0%, 0%, and 1·5%,
respectively.
Hence, our data3 support the
hypothesis of mutually exclusive HLA
patterns for type 1 diabetes and multiple
sclerosis, and are consistent with a very
low rate of comorbidity of both diseases
in Europe and elsewhere, except for
Sardinia.
*B M Lobnig, E Chantelau
Department of Metabolic Diseases and Nutrition,
WHO Collaborating Centre for Diabetes,
Heinrich-Heine-Universität Düsseldorf,
Postfach 10 10 07, D-40001 Düsseldorf,
Germany
(e-mail: Lobnig@med.uni-duesseldorf.de)
1 Marrosu MG, Cocco E, Lai M,
Spinnicci G, Pischedda MP, Contu P.
Patients with multiple sclerosis and risk of
THE LANCET • Vol 360 • October 19, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
type-1 diabetes mellitus in Sardinia, Italy:
a cohort study. Lancet 2002; 359:
1461–65.
2 Lermark A. Multiple sclerosis and type 1
diabetes: an unlikely alliance. Lancet 2002;
359: 1450–51.
3 Lobnig MB, Chantelau E, Vidgren G, et al.
HLA-patterns in patients with multiple
sclerosis and type-1 diabetes mellitus:
evidence for possible mutual exclusion of
both diseases. Diabetes Metab (Paris) (in
press).
Sir—M G Marrosu and colleagues1
note that in Sardinian families with
genetic inheritance of multiple
sclerosis, type-1 diabetes is three to
five times more prevalent than in
families without a history of multiple
sclerosis. This higher prevalence is
seen in the multiple sclerosis patients
and in their healthy siblings. The
investigators conclude that common
genes probably contribute to
susceptibility for both diseases. In
discussion of the findings, they
conclude that non-HLA genetic
factors must be involved in this
association. They do not point,
however, to what direction.
When considering an immuno-
genetic explanation of this obser-
vation, the innate immune system
immediately comes to mind.
Cytokines are key players in this
immune process. We have previously
shown that production capacity of the
cytokine interleukin 10 is under tight
genetic control, with heritability
estimates as high as 75%.2 We have
also shown that risk of typical multiple
sclerosis is four-fold higher in families
with an innate low production capacity
of interleukin 10 and high production
capacity of tumour necrosis factor
than in families with the opposite
cytokine profile.3 In addition, in older
individuals with a low interleukin 10
production capacity, we have noted a
three-fold increased risk of developing
type 2 diabetes.4
Evidence suggests that dimeric
pMHC (peptide-major histocompati-
bility complex) class II chimera can
prevent autoimmune diabetes in mice
and can even reverse diabetes in
animals that already have the disease.5
This effect can probably be attributed
to formation of T-regulatory type 1
cells, for which interleukin 10 is an
essential growth factor. Therefore, low
innate interleukin 10 production
might contribute to insufficient
formation of these T-regulatory type 1
cells.
We think the tight genetic control of
interleukin 10 production and the
involvement of interleukin 10 in
multiple sclerosis and type 1 diabetes
makes low interleukin 10 production a
very likely candidate as one of the
common genetic factors for both
multiple sclerosis and type 1 diabetes.
*Anton J M de Craen, Tom W J Huizinga,
Rudi G J Westendorp
Departments of *General Internal Medicine
and Rheumatology, Leiden University Medical
Centre, PO Box 9600, 2300 RC Leiden,
Netherlands
(e-mail: A.J.M.de_Craen@lumc.nl)
1 Marrosu MG, Cocco E, Lai M,
Spinnicci G, Pischedda MP, Contu P.
Patients with multiple sclerosis and risk of
type 1 diabetes in Sardinia, Italy: a cohort
study. Lancet 2002; 359: 1461–65.
2 Westendorp RGJ, Langermans JA,
Huizinga TWJ, et al. Genetic influence on
cytokine production and fatal
meningococcal disease. Lancet 1997; 349:
170–73.
3 de Jong BA, Schrijver HM, Huizinga TWJ,
et al. Innate production of interleukin 10
and tumor necrosis factor affects the risk of
multiple sclerosis. Ann Neurol 2000; 48:
641–46.
4 van Exel E, Gussekloo J, de Craen AJM,
et al. Low production capacity of
interleukin-10 associated with the
metabolic syndrome and type 2 diabetes.
Diabetes 2002; 51: 1088–92.
5 Casares S, Hurtado A, McEvoy RC,
Sarukhan A, von Boehmer H,
Brumeanu TD. Down-regulation of
diabetogenic CD4+ T cells by a soluble
dimeric peptide—MHC class II chimera.
Nat Immunol 2002; 3: 383–91.
Outcomes after off-pump
and on-pump heart surgery
Sir—Gianni Angelini and colleagues
(April 6, p 1194)1 report a prospective,
randomised, controlled study com-
paring outcomes after off-pump with
on-pump coronary artery bypass
grafting (CABG) surgery, an approach
that has previously been used by few
workers.
Most previous studies are flawed by
selection and treatment bias.2 Angelini
and colleagues have overcome this
bias, which, as they acknowledge,
could account for at least some of the
differences in short-term outcomes.
What is reassuring from their data is
that, in the medium-term, cardiac
outcome is no different whether
CABG surgery is with or without
cardiopulmonary bypass. This
information is useful, since any gains
obtained from reducing short-term
morbidity would be quickly off-set by a
small number of patients having an
adverse long-term cardiac outcome.
The situation is analogous to the use of
epidural analgesia for on-pump CABG
surgery, which can lower the frequency
of chest infection and dysrhythmias3
that are of a similar magnitude to those
in Angelini and colleagues’ study.
There remains, however, an as yet
unquantified risk of epidural haema-
toma in patients who are heparinised,
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