Research derived from the Netherlands: founder effect is irrelevant to general prevalence rates.

In SEC filed documents, Sandford D. Smith (CEO) and Gregory D. Perry (CFO) cite an Aegerion funded research paper to promote an extreme prevalence rate for the US and world.[1] This paper references a study of the Netherlands’ population, which has already been documented to suffer from “founder effect” –a genetic anomaly which results in high concentrations of a given genetic trait within a specific population. As such, the data derived from the Netherlands is wholly irrelevant to the HoFH population in the USA. By definition, an unusual situation cannot represent a usual situation. Aegerion thus misrepresents its addressable market when using this report to promote its prospects.

The lead author of this 2014 EAS paper is Marina Cuchel, who was also deeply involved with Aegerion’s clinical trials. She declared that HoFH had a prevalence of 1:1,000,000 – which would be about 300 patients in the USA.  (The Aegerion CEO’s prevalence claim was 1,000% higher.) Her latest paper cites a different prevalence based on the Netherlands’ population.[2]  It should be noted that Aegerion has paid her, and others, “honoraria for lectures/advisory boards, consultancy, travel support and/or research grants.”

The relevant passage from the 2014 EAS paper follows.

This study of HoFH in the Netherlands is far from representative of general prevalence.

Footnote #4 in the above actually refers to a specific study of whites of Danish descent — even though it is portrayed here and in the footnotes as a study of the general population. We will deal with this obfuscation later. Our focus at this point is on the other prevalence estimate, cited in footnote #5. It is the study of FH in the Netherlands:[3]   

  • Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome Barbara Sjouke, D. Meeike Kusters, Joep C. Defesche … et al.

This study of HoFH in the Netherlands is far from representative of general prevalence. As it turns out two of the very scientists just cited above also did previous work demonstrating the existence of founder effect in the Netherlands. Here is a brief explanation of founder effect from a comprehensive study, “A HuGE Prevalance Review”:

As shown in table 4, the frequency of heterozygous FH is considerably higher than 1/500 in some populations, and the elevated frequency is generally attributed to a founder effect. A founder effect occurs when a subpopulation is formed through the immigration of a small number of “founder” subjects, followed by a population expansion. If, by chance, some of the founders had FH, then genetic drift could lead to a high proportion of affected subjects who share specific mutations introduced by the founders. Such founder effects are thought to influence the spectrum of FH mutations in French Canadians; South African Afrikaners, Jews, and Indians; Tunisians; Christian Lebanese; Icelanders; and Finns (for review, see the article by Goldstein et al.). These founder populations have a frequency of FH ranging from 1/411 for North Karelians of Finland to 1/67 (1.5 percent) for Ashkenazi Jews in South Africa.[4]

It is easy to see that data derived from a population influenced by founder effect cannot reasonably be used as a proxy for the “general population.”  For example, it is not reasonable to take the extreme prevalence of 1 in 67 among the Ashkenazi Jews of South Africa and argue that estimates for USA or world prevalence must therefore be adjusted.  But this is exactly what is done with the 2014 EAS report, using the Netherlands for comparison.

Both Joep C. Defesche’s and D. Meeike Kusters’ names appear on the source[5] for the 2014 EAS report.  Yet both had previously published work on the existence of founder effect in the Netherlands. Here is their previous work, titled “Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes.”

Conclusions: Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician’s perception of FH, and understanding the prevalence and distribution of homozygous patients in the Netherlands.[6]

The above section — “Conclusions” — was from the abstract on page 124 of that publication. What follows is from “Discussion” and “Conclusion” at the end of that paper, on pages 132 and 135 respectively.

Discussion

For this study, we determined the geographical distribution of the 12 most common mutations, which represent 64% of all Dutch FH patients. We demonstrated that almost all common mutations showed a clearly marked region of preference, suggesting the existence of a founder effect. This can be explained by the occurrence of a local founder mutation in combination with limited migration, possibly attributable to the geographical isolation in the past, as in West Friesland and the islands of Noord and Zuid Beveland, the two regions with the highest prevalence of mutations per se. The phenomenon of geographical preference of FH causing mutations can have several clinical implications.

….

Conclusion: Although more than 550 different FH mutations are identified in the Netherlands, for most of the 12 most prevalent Dutch mutations a founder effect can be observed, resulting in differences in geographical prevalence across the Netherlands. This can be explained by local founder effects plus limited migration, which is also reflected by the fact that neighbouring countries and countries were the Dutch used to go, share the same mutations. The high prevalence and typical distribution of Dutch homozygous patients can also be understood by these founder effects. Molecular screening can be more efficient if it is tailored to the allele frequency distribution of the Dutch population.

It is clear that a population documented to be influenced by founder effect cannot be used as a proxy for the general population.  By promoting this study as relevant, when in fact responsible players must know that it is irrelevant, Aegerion has misrepresented its addressable market. The source material of this study was re-published by way of Aegerion’s funding the 2014 EAS report and it is promoted by Aegerion in SEC filed documents, which are signed by CEO Sandford Smith.


[1] Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Cuchel, et al.

[2] Authors on the Netherlands’ study received money from Amgen, Regeneron, Aegerion, and others. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome. Barbara Sjouke, et al.

[3] “Autosomal dominant hypercholesterolemia” is another name for “familial hypercholesterolemia.”

[4] Genetic Causes of Monogenic Heterozygous Familial Hypercholesterolemia: A HuGE Prevalence Review; Melissa A. Austin, et al.

[5] Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome. Barbara Sjouke, et al.

[6] Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes, Neth Heart J. 2011 Apr; 19(4): 175–182 : D. Meeike Kusters, et al. http://hdl.handle.net/11245/2.114966 | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058324/