FCH is a disease with a complex phenotype that is not completely understood, and remains difficult to diagnose. This dyslipemic syndrome is associated with disturbances in all lipoprotein fractions. The key underlying abnormality of this condition is elevation of VLDL due to overproduction or defective catabolism . Small and dense LDL is the final expression of this catabolism. These particles are more easily oxidized and display a higher affinity for the extracellular matrix and a higher degree of retention in arterial wall than their larger, normal-sized counterparts . Small and dense LDL has been accepted as an emergent cardiovascular risk factor by the National Cholesterol Education Programme (Adult Treatment Panel III) , as many studies have demonstrated that the predominance of these particles is associated with an increase in cardiovascular risk more than classic lipid variables [23, 24]. FCH patients with phenotype B of LDL show a clearly atherogenic lipid profile. There is evidence that hypolipidemic treatment can modify the distribution of LDL subclasses . Very high risk patients, including those with this atherogenic lipoprotein profile, may benefit from more potent lipid-lowering therapies .
It has been suggested that FCH is a heterogeneous and oligogenic disease . One of the genes likely to exert an influence in this disease is the lipoprotein lipase gene. Many codon polymorphisms of the LPL gene have been described, some of them associated with alterations of the metabolism of triglyceride-rich lipoproteins . One of the most frequent polymorphisms is located in exon 6 (rs268, c. 1128 A>G; N291S) . The prevalence of this mutation in our FCH patients was 9.7%, which is similar to the 9.3% described for Dutch FCH patients  but considerably higher than the 2–5% described for other Caucasian populations . No polymorphism was detected in the sample from the general population, which reflects findings in other populations  in which no carriers were found, suggesting that the N291S mutation is more frequent among FCH patients. The mutation is likely to affect postprandial lipemia by altering its enzymatic activity , resulting in an increase of VLDL particles and high concentrations of apo B100 and leading to the appearance of a greater number of small and dense LDL particles as the final and most important expression of the catabolism of triglyceride-rich lipoprotein particles . In this way, the FCH phenotype of patients with the polymorphism is negatively affected, with altered postprandial responses to fat-rich meals being described, even in patients that were initially normolipemic .
These previously published data coincide with our results; polymorphism-carrier patients have been reported to present a smaller LDL diameter, suggesting a clearly atherogenic alteration of the metabolism of triglyceride-rich particles . In fact, in some studies regarding FCH, this polymorphism has been related to patients who had previously presented an ischemic cardiopathy .
In our study, patients with the N291S polymorphism showed a smaller average LDL diameter, corresponding with pattern B and constituting the final expression of the alteration of the metabolism of triglyceride-rich particles. This represents a higher cardiovascular risk among such patients. On the other hand, most patients without this polymorphism had pattern A, constituting a clear difference between both groups. We are aware of the limitations of this study in relation to the number of patients with the polymorphism. Unfortunately, its low prevalence among the general population makes it difficult to conduct a genetic study with a large number of patients that would permit us to draw more solid conclusions. That said, our data show important differences between the two patterns.
In conclusion, FCH patients with pattern B of LDL show a clearly atherogenic lipid profile. The relationship between small and dense LDL and the presence of the allele encoding for N291S mutation of the LPL gene, present in a high percentage of our FCH patients, could disrupt the phenotype of the disease by altering the clearance of triglyceride-rich lipoproteins. Such phenotype expression is the basis for a more atherogenic profile. Therefore, based on our results in FCH patients in the Autonomous Community of Valencia, the cardiovascular risk of those with pattern B of LDL who carry this polymorphism could be considerably reduced through rigorous treatment of Hyperlipemia.