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  • There is a large interindividual difference in


    There is a large interindividual difference in intestinal cholesterol Kobe0065 of cholesterol that is mainly due to genetic variation [15], [19]. Single nucleotide variation (SNV) in NPC1L1 and, ABCG5 and ABCG8 key modulators of cholesterol influx and efflux into intestinal mucosal cells, respectively, have been associated with the LDL cholesterol concentration in several populations including subjects with hypercholesterolemia [20], [21]; may explain interindividual variations in LDL cholesterol level in response to ezetimibe treatment [22], [23], and several rare genotype variations in NPC1L1 are associated with mild reductions in sterol absorption, circulatory LDL cholesterol concentrations and cardiovascular disease [24]. In contrast, obligate heterozygous subjects with severe mutations in ABCG5 or ABCG8 causing sitosterolemia, show normal LDL cholesterol levels [25]; and extensive sequencing analysis of these genes in subjects with ADH has not detected causative mutations [11]. All together indicate that the genetic interindividual variation in cholesterol absorption is not monogenic, but complex and probably polygenic, resulting from the effects of multiples SNVs common in the population, rather than the effects of rare mutation with substantial impact on cholesterol absorption [20]. According with this concept, cholesterol hyperabsorption is a common phenomenon among family members from a hyperabsorber proband, both in subjects with high and with normal LDL cholesterol; and hyperabsorption is more common in affected subjects with high LDL cholesterol than in normolipemic individuals independently of the proband. Consequently, increased intestinal cholesterol absorption is a risk factor for the development of primary hypercholesterolemia but can not discriminate between affected and non-affected individuals. The genetic basis of non-FH is a relevant and controversial issue. In two different whole exome sequencing in ADH patients negative for LDLR/APOB/PCSK9 mutations [26] and individuals selected for extreme LDL cholesterol (>98th percentile) [27] no major novel locus for FH was detected. A new locus at Kobe0065 4p13 associated with ADH was found in a family from The Netherlands, and the study of 400 additional unrelated ADH probands detected 4 missense variants in the STAP1 gene, encoding the protein signal transducing adapter family member 1, a new candidate gene for ADH, but in any case being responsible for a small proportion of non-FH ADH [28]. A recent study in patients with non-FH ADH from two different countries has found that high LDL cholesterol concentrations in some of these subjects might have a polygenic cause, which would difficult a precise diagnosis and the efficiency of cascade testing in family members [9]. Some non-hyperabsorber family members showed high TG what suggests the existing of overlapping between non-FH ADH and FCH. Furthermore, patients with a detected causal mutation in the candidate genes have a substantial polygenic contribution that might contribute to the variable penetrance of the disease and to the large overlap in LDL cholesterol concentrations in mutation-carrier and non-carrier relatives [9]. Our study supports the concept that what we had previously considered ADH, in most cases, are in fact complex metabolic diseases in which different mechanism are involved, one of them being hyperabsorption, and probably with a polygenic contribution, and with environmental interactions. Affected subjects with hyperabsorption show lower BMI than affected non-hyperabsorber subjects in our study (TableĀ 3). This relationship between plasma phytosterols and BMI has been already established, and leaner individuals have increased phytosterols plasma levels than subjects with obesity or metabolic syndrome (MetS) [29]. The mechanism of this association has not been fully established. The weak correlation between LDL cholesterol and intestinal cholesterol markers would support the complex and probably polygenic background of the association. Furthermore, the diagnosis of ADH should be redefined because with the present diagnostic criteria [1], [2] many subjects could be diagnosed of FH, suggesting an inexistent monogenic disorder.