Familial defective apolipoprotein B-100: a mutation emerged in the Mesolithic ancestors of Celtic peoples?
Introduction
As part of the WHO MONICA project, plasma low density lipoprotein cholesterol (LDL-C) concentrations were determined in 3341 randomly selected individuals from Switzerland [1]. Mean LDL-C was 16% higher than in US Caucasians, and 4–60% higher than in other European populations [1], [2], [3]. If the cut-off of the National Cholesterol Education Program (LDL-C >4.14 mmol/l [4]) is applied to US Caucasians, then 12–32% of males and 5–40% of females have elevated LDL-C [2], whereas in the Swiss, 31–56% of males and 14–66% of females have LDL-C above this cut-off [1]. Although this data is based on a relatively small sample, it raises the question as to whether the higher prevalence of hypercholesterolemia in Switzerland compared to other populations is due to genetic differences.
Section snippets
Familial forms of hypercholesterolemia
In 1990, we established a nation-wide registry for familial forms of hypercholesterolemia (FFH) in Basel. In the beginning, restriction fragment length polymorphisms at the LDL receptor (LDLR) locus were used to diagnose familial hypercholesterolemia (FH). The results from our studies in five populations revealed unexpectedly high and nonuniform recombination rates due to recombinational hot spots [5]. This data was in perfect agreement with the large number of insertions and deletions observed
Familial defective apo B-100 (FDB)
Defective binding of LDL particles to the LDLR, due to a structural apolipoprotein (apo) B-100 defect, was identified in patients with moderately increased plasma LDL-C [9], [10], [11], [12] and designated FDB. FDB is caused by a single base substitution (G to A) at nucleotide 10708 in exon 26 of the apo B-100 gene (2p23.24), creating an arginine to glutamine substitution in the codon for amino acid 3500 [12], [13]. Further less intensively studied point mutations (e.g. R3500W, R3531C) are rare
Discussion
Since hypercholesterolemia associated with FDB is often moderate [6], [23], even in individuals homozygous for the mutation [24], and since it is rarely associated with CHD before the age of 50 [25], FDB is very likely not to affect Darwinian fitness. In natural populations, a single gene mutation newly arisen runs a high risk of chance elimination in its immediate descendants. Considering the R3500Q mutation, such an elimination obviously did not occur. Fixation of the mutant allele, at least
Conclusion
Because of the high prevalence in the Swiss, it is reasonable to molecularly test individuals with FFH for the presence of FDB in a first line. The molecular diagnosis facilitates unequivocal identification of affected family members, even if their LDL-C levels are not yet elevated [6], [23]. Furthermore, follow-up of molecularly affected but normocholesterolemic subjects allows the registration of the time point when LDL-C begins to increase and thus, drug treatment has to be started.
References (30)
- et al.
Estimation of the age of the ancestral arginine 3500-glutamine mutation in human Apo B-100
Genomics
(1997) - et al.
Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia
J. Lipid. Res.
(1990) - et al.
Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease
Atherosclerosis
(1992) - et al.
High prevalence of familial defective apolipoprotein B-100 in Switzerland
J. Lipid. Res.
(1994) - et al.
Familial defective apolipoprotein B-100 and myocardial infarction. The ECTIM study (Letter)
Atherosclerosis
(1995) - et al.
Familial defective apolipoprotein B-100: mild hypercholesterolaemia without atherosclerosis in a homozygous patient
Lancet
(1992) - et al.
Familial defective apolipoprotein B-100: clinical characteristics of 54 cases
Atherosclerosis
(1992) - et al.
Absence of familial defective apolipoprotein B-100 in Finnish patients with elevated serum cholesterol
Atherosclerosis
(1990) - et al.
Lipides sanguins dans la population suisse: enquête MONICA 1988–89
Schweiz. Med. Wschr.
(1993) - US Department of Health and Human Services, Lipid Research Clinics Program. Population Studies Data Book. Vol. I, The...