Hemorheologic profile in systemic sclerosis: role of NOS3 -786T > C and 894G >T polymorphisms in modulating both the hemorheologic parameters and the susceptibility to the disease.
OBJECTIVE
Microvascular disorders are relevant in systemic sclerosis (SSc). Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of microcirculatory disorders. An impaired availability of nitric oxide, related to polymorphisms in NOS3, the gene for endothelial cell nitric oxide synthase, might influence erythrocyte deformability. We undertook this study to investigate the hemorheologic profile in SSc and the role of NOS3 polymorphisms in modulating the hemorheologic status of SSc patients.


METHODS
We studied 113 consecutive SSc patients (75 with limited cutaneous SSc [lcSSc] and 38 with diffuse cutaneous SSc [dcSSc]) and 113 healthy controls. The hemorheologic profile was obtained by assessing whole blood viscosity (WBV; at shear rates of 0.512 and 94.5 seconds(-1)), plasma viscosity (PLV; at a shear rate of 94.5 seconds(-1)), and erythrocyte deformability index (DI). We determined NOS3 polymorphisms by molecular analysis.


RESULTS
A marked alteration of hemorheologic parameters was found both in patients with lcSSc and in those with dcSSc compared with controls (P < 0.0001). In multivariate analysis, rheologic variables were significantly associated with the disease (for WBV at a shear rate of 94.5 seconds(-1), odds ratio [OR] 5.4, 95% confidence interval [95% CI] 1.4-19.9, P = 0.01; for PLV, OR 2.8, 95% CI 1.2-6.5, P = 0.01; for DI, OR 3.9, 95% CI 1.4-10.8, P = 0.007), and NOS3 -786C and 894T alleles significantly affected the DI (for -786C allele, OR 2.3, 95% CI 1.01-5.4, P = 0.04; for 894T allele, OR 2.2, 95% CI 1.01-4.8, P = 0.04). The simultaneous presence of the -786C and 894T alleles represented a susceptibility factor for SSc (OR 2.8, 95% CI 1.4-5.7, P = 0.004).


CONCLUSIONS
Our findings document an altered rheologic profile in SSc and demonstrate a relationship between this alteration and NOS3 polymorphisms, thus shedding light on a potential novel mechanism influencing the microcirculation in this disease.
Fatini
Cinzia
C
Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. cinziafatini@hotmail.com
Mannini
Lucia
L
Sticchi
Elena
E
Rogai
Veronica
V
Guiducci
Serena
S
Conforti
Maria Letizia
ML
Cinelli
Marina
M
Pignone
Alberto Moggi
AM
Bolli
Paola
P
Abbate
Rosanna
R
Cerinic
Marco Matucci
MM
D000368:Aged; D000483:Alleles; D001775:Blood Circulation / Q000235:genetics / Q000502:physiology*; D001783:Blood Flow Velocity / Q000235:genetics / Q000502:physiology; D001809:Blood Viscosity / Q000235:genetics / Q000502:physiology; D004247:DNA / Q000032:analysis; D004907:Erythrocyte Deformability / Q000235:genetics / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000503:physiopathology; D008875:Middle Aged; D015999:Multivariate Analysis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*
D004247:DNA; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III