Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from
David H McDermott1, Alan M Fong, Qiong Yang
1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases/NIH, Building 10, 9000 Rockville Pike, Bethesda, MD 20892-1886, USA.
The Journal of Clinical Investigation
|April 17, 2003
Summary
The CX3CR1-M280 variant of the fractalkine receptor CX3CR1 is linked to reduced cardiovascular disease (CVD) risk. This genetic variant impairs leukocyte adhesion and migration, potentially explaining its protective effect against atherosclerosis.
Area of Science:
- Immunology
- Cardiovascular Science
- Genetics
Background:
- The chemokine receptor CX3CR1 (fractalkine receptor) plays a role in inflammation.
- Previous studies suggest a CX3CR1 variant (CX3CR1-M280) is associated with lower atherosclerosis prevalence.
- The functional significance and mechanism of CX3CR1-M280 in cardiovascular disease (CVD) remain undefined.
Purpose of the Study:
- To investigate the functional significance of the CX3CR1-M280 variant.
- To determine the mechanism by which CX3CR1-M280 influences CVD pathogenesis.
- To assess the association of CX3CR1-M280 with CVD risk in a prospective cohort.
Main Methods:
- Assessed fractalkine (FKN)-dependent cell-cell adhesion under physiologic shear in cells expressing CX3CR1-M280.
- Measured FKN binding kinetics and FKN-induced chemotaxis of leukocytes from CX3CR1-M280 homozygous donors.
- Analyzed the association of CX3CR1-M280 with CVD risk in the Framingham Heart Study Offspring Cohort.
Main Results:
- CX3CR1-M280 significantly reduced FKN-dependent cell-cell adhesion under shear conditions.
- Reduced FKN binding kinetics and impaired FKN-induced leukocyte chemotaxis were observed in CX3CR1-M280 homozygous individuals.
- CX3CR1-M280 was independently associated with a lower risk of CVD (OR, 0.60; P = 0.008) in the Framingham Heart Study.
Conclusions:
- These findings provide mechanism-based and epidemiological evidence linking CX3CR1 to CVD pathogenesis.
- The CX3CR1-M280 variant may protect against CVD by reducing leukocyte recruitment into the arterial wall.
- CX3CR1-M280 represents a potential genetic risk factor for cardiovascular disease in humans.
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