(From report to report the APOB relevant to this analysis has many synonyms. What concerns us here is that the Regeneron-associated authors’ p.Arg3558Cys is used by other authors as Arg3531Cys and R3531C. Click here and here for references to these synonyms.)
“ASSOCIATION OF MUTATIONS IN THE APOLIPOPROTEIN B GENE WITH HYPERCHOLESTEROLEMIA AND THE RISK OF ISCHEMIC HEART DISEASE,” ANNE TYBJÆRG-HANSEN, et al.
The Arg3531Cys mutation has previously been identified in eight subjects,8,14,15 six of whom had hypercholesterolemia. However, all eight carriers were identified among either patients with hyperlipidemia who were attending lipid clinics8,15 or patients with coronary artery disease14; therefore, the presence of hyperlipidemia could be a consequence of the study design.”
The one patient in our study who had ischemic heart disease and the Arg3531Cys mutation, a 77-year-old man, was the only one of eight carriers who also had hypercholesterolemia. He did not have a family history of either hypercholesterolemia or premature ischemic heart disease. It therefore seems likely that this patient may have had another cause of hypercholesterolemia. Taken together, the absence of simple cosegregation in families, the absence of a family history in our patient with coronary artery disease, and the complete absence of hypercholesterolemia in any carriers in the general population in our study suggest that this mutation is not sufficient to cause hypercholesterolemia.
Although a previous study suggested a borderline overrepresentation of the Arg3531Cys mutation in patients with coronary artery disease as compared with healthy controls, 15 our results suggest that this mutation, in keeping with the absence of an association with hypercholesterolemia, is also not associated with an increased risk of ischemic heart disease.
[In the following, only Arg3500Gln, AKA R3500Q, is FDB, and not Arg3531Cys, AKA p.Arg3558Cys.]
In conclusion, our results suggest that the Arg3500Gln mutation is at present the only known APOB mutation worth screening for in white patients with hypercholesterolemia or ischemic heart disease and their relatives.
“R3531C mutation in the apolipoprotein B gene is not sufficient to cause hypercholesterolemia.” Rabes JP, et al. Arterioscler Thromb Vasc Biol. 2000;20:E76-82.
“APOB-R3531C proband screening suffered from ascertainment bias attributable to patient status.” ….
There is no doubt that the R3531C mutation causes reduced binding of LDL to the LDL receptor in vitro. However, our results additionally support that this reduction is not sufficient to cause hypercholesterolemia in vivo in heterozygotes. The evidence that the R3531C mutation alone does not cause hypercholesterolemia stems from functional, epidemiological, and linkage analysis. ….
In conclusion, the APOB-R3531C substitution, in view of its in vitro effects and our family study, is possibly a susceptibility mutation that, when present with other factors (genetic or environmental), slightly increases cholesterolemia. However, it is not sufficient in itself to cause hypercholesterolemia and should not be considered as an allelic variant leading to FDB.”
“Major Apolipoprotein B-100 Mutations in Lipoprotein,” Metabolism and Atherosclerosis, M. VRABLÕK, et al.
“These are mutations leading to amino acid substitution at positions 3500 (R3500Q and R3500W) and 3531 (R3531C) that have been shown to decrease the binding affinity of apoB-100 in vitro. However, only the former mutations have been unequivocally demonstrated to cause hyperlipidemia in vivo.” ….
“The incidence of the disorder in patients is similar as in the general population which is in accordance with the notion that R3531C does not cause hypercholesterolemia.”
“Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease, Consensus Statement of the European Atherosclerosis Society”; Børge G. Nordestgaard, et al.
This is the same Nordestgaard in the TYBJÆRG-HANSEN study mentioned above, where it was declared “that the Arg3500Gln mutation is at present the only known APOB mutation worth screening for in white patients ….”
Now here is Nordestgaard again in the Authoritative report, declaring that there is only one relevant APOB mutation, and it is not Arg3558Cys. (Again, synonyms are present: p.Arg3527Gln = R3500Q = Arg3500Gln. Click here.)
“Currently, >1200 mutations have been documented worldwide in LDLR; these affect all functional domains of the LDL receptor protein and include single-nucleotide mutations, copy number variations, and splicing mutations throughout the LDLR gene. A single mutation, Arg3500Gln, is the only common FH-related mutation in APOB, while >20 different mutations have been detected in PCSK9. Heterozygous LDLR, APOB, and PCSK9 mutations are found in >90, ~5, and ~1%, respectively, of heterozygous FH subjects with a causative mutation.