The risk of tendon xanthomas in familial hypercholesterolaemia is influenced by variation in genes of the reverse cholesterol transport pathway and the low-density lipoprotein oxidation pathway.
OBJECTIVE
The presence of tendon xanthomas is a marker of high risk of cardiovascular disease (CVD) among patients with familial hypercholesterolaemia (FH). Therefore, xanthomas and atherosclerosis may result from the same pathophysiological mechanisms. Reverse cholesterol transport (RCT) and low-density lipoprotein (LDL) oxidation are pathophysiological pathways of atherosclerosis, and it is well established that genetic variation in these pathways influences CVD risk. We therefore determined whether genetic variation in these pathways is also associated with the occurrence of tendon xanthomas in FH patients.


RESULTS
Four genetic variants in each pathway were genotyped in 1208 FH patients. We constructed a gene-load score for both pathways. The odds of xanthomas increased with the number of the risk alleles in the RCT pathway (OR 1.21, 95% CI 1.08-1.36, P(trend) = 0.0014). Similarly, higher numbers of risk alleles in the LDL oxidation pathway were associated with the presence of xanthomas (OR 1.24, 95% CI 1.08-1.41, P(trend) = 0.0015).


CONCLUSIONS
The presence of tendon xanthomas in FH patients is associated with genetic variation in the RCT and LDL oxidation pathways. These results support the hypothesis that xanthomas and atherosclerosis share pathophysiological mechanisms.
Oosterveer
Daniëlla M
DM
Department of Internal Medicine - D435, Erasmus University Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
Versmissen
Jorie
J
Yazdanpanah
Mojgan
M
Defesche
Joep C
JC
Kastelein
John J P
JJ
Sijbrands
Eric J G
EJ
D000328:Adult; D002784:Cholesterol / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000235:genetics* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D052256:Tendinopathy / Q000235:genetics*; D014973:Xanthomatosis / Q000235:genetics*
D008077:Lipoproteins, LDL; D026901:Membrane Transport Proteins; C099252:oxidized low density lipoprotein; D002784:Cholesterol