Inflating FDB: Earlier studies only counted the R3500Q

R3500Q is also known as p.Arg3527Gln. This is the mutation used in the past when calculating FDB prevalence. There is another controversial APOB mutation often referred to as R3531C; in the Regeneron study, it is referred to as p.Arg3558Cys.  In the lab p.Arg3558Cys (R3531C) shows some interference with cholesterol processing.  However, in living humans, it has been said to be too weak to be included as FDB.   But this controversy does not affect us here. We are in a math exercise, not a scientific effort. We are simply trying to bring two sets of mathematical tables into comparison. Since p.Arg3558Cys (R3531C) was not included in prior prevalence studies, and since it is included in this Regeneron prevalence study we can either take the p.Arg3558Cys (R3531C) out of the Regeneron study or add it into the table provided by Rader, et al.

FDB, Monogenic Heterozygous Familial hypercholesterolemia, p.Arg3558Cys (R3531C)

Let’s give Regeneron’s 2016 report the benefit of the doubt and assume that the heretofore uncounted p.Arg3558Cys should be counted as FDB.  To do so, we add the Regeneron study’s 1 in 1,102.7 into the established estimates as presented by Rader, et al. (We derive the 1 in 1,102.7 by referencing the Regeneron study’s Supplement: 50,726 total / 46 p.Arg3558Cys = 1,102.7.) This will bring the old and new studies into alignment and allow an apples-for-apples comparison.

  1. FH 1,000,000 / 500 = 2,000
  2. FDB 1,000,000 /1,000 = 1,000
  3. FH3 1,000,000 / 2,500 = 400
  4. p.Arg3558Cys 1,000,000 / 1,103 = 907 (Regeneron study.)
  5. Prevalence: 1,000,000 / 4,307 = 1:232.

Now the old and new prevalence estimates are more parallel than they were before.

  Old Prevalence New Prevalence
Prevalence of all mutations 1:232 1:222 ~ 1:256
Prevalence of FH-as-LDLR 1:500 1:518

FH prevalence has not been overthrown. The old and new numbers actually compare well:

  • FH-as-LDLR was originally said by a Nobel Prize winner to have a prevalence of 1:500.
  • The Regeneron study shows a prevalence of the LDLR to be 1:518.

The only thing new here lies with linguistic usage.