Gene deficiency increases risk of thrombosis in SLE

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Gene deficiency increases risk of thrombosis in SLE

Rheumawire

Jul 14, 2004 17:00

Nainggolan

Copenhagen, Denmark - Danish researchers have shown that patients with

systemic lupus erythematosus (SLE) who also have a variant form of the

mannose-binding-lectin gene are up to 7 times as likely to suffer

arterial thromboses [1].

These findings suggest that mannose-binding-lectin genotyping should be

undertaken in patients with SLE to help guide preventive therapy, say Dr

Tommy Ohlenschlaeger (Bispebjerg Hospital, Copenhagen) and colleagues in

their paper in the July 15, 2004 issue of the New England Journal of

Medicine.

" All hospitals that have genetic testing capabilities should be able to

do this; it's a simple test, " 1 of the authors, Dr Garred

(Rigshospitalet, Copenhagen), told rheumawire. " If you can pinpoint the

lupus patients who have this deficiency you can use more aggressive,

directed therapy to help prevent thromboses. "

Garred says the gene deficiency may also indicate poor prognosis in

other conditions, such as rheumatoid arthritis (RA) and sepsis and in

critically ill patients in intensive care. " We plan to do a similar

study to look for the deficiency in RA patients, " he noted.

Ohlenschlaeger et al explain that patients with SLEwho are often quite

younghave a much higher rate of coronary artery disease than age-matched

controls and that this increased risk is not fully accounted for by

traditional atherosclerotic risk factors.

Meanwhile, patients with defects in mannose-binding lectin have been

shown to have atherosclerotic disease that has an earlier onset and is

more severe than in people with normal mannose-binding lectin; they also

have altered expression of autoimmune diseases such as SLE and RA, the

researchers say. " We hypothesized that homozygosity for

mannose-binding-lectin variant alleles is associated with an increased

risk of clinically detectable arterial thrombotic events in patients

with SLE. "

They genotyped 91 patients with SLE and found that 54 had no

mannose-binding-lectin variant alleles (A/A genotype), 30 were

heterozygous (A/O genotype), and 7 were homozygous (O/O genotype).

During 9.1 years of follow-up, arterial thrombosis (cerebral or

myocardial infarction [MI] or leg embolus) developed in 6 of the 7

homozygous patients as compared with 18 of the 84 patients in the other

2 groups (hazard ratio 5.8) After correcting for other known risk

factors, the hazard ratio was 7.0.

" The increased thrombotic risk was specific for the arterial side of the

circulation, " the researchers explain, " since there was no significant

association between mannose-binding-lectin deficiency and venous

thrombosis. "

They add: " The increased risk of thrombosis was particular pronounced

for myocardial infarction. This finding is in line with previous

findings among patients with severe atherosclerotic coronary disease,

who were 4 times as likely as control subjects to have the O/O

genotype. " There was no significant association between the risk of

thrombosis and heterozygosity for mannose-binding-lectin variant alleles

(A/O genotype).

Garred told rheumawire that mannose-binding-lectin deficiency is

relatively common in the general population, affecting around 5% of

whites. But unless people have an accompanying disease, such as lupus,

the defect is " unlikely to be particularly dangerous, except during the

vulnerable period of infancy when the immune system is immature. "

Garred and his colleagues estimate that mannose-binding-lectin

deficiency is present in about 8% to 9% of lupus patients.

The researchers believe the mechanism behind the effects of

mannose-binding-lectin deficiency involves inflammation in blood-vessel

walls, but they say more work is required to confirm this.

Source

Ohlenschlaeger T, Garred P, Madsen HO, et al.

Mannose-binding lectin variant alleles and the risk of arterial

thrombosis in systemic lupus erythematosus. N Eng J Med 2004;

351:260-267.

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Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org