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High Prevalence of FDB3500Q mutation in the Swiss population

2000; Elsevier BV; Volume: 153; Issue: 2 Linguagem: Inglês

10.1016/s0021-9150(00)00618-3

1879-1484

Edward A. Fisher, Werner Groß, Winfried März,

Folate and B Vitamins Research

In this year's second issue of Atherosclerosis, a newsletter appeared by Miserez and Muller [ [1] Miserez A.R. Muller P.Y. Familial defective apolipoprotein B-100: a mutation emerged in the Mesolithic ancestors of Celtic peoples?. Atherosclerosis. 2000; 148: 433-436 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar ], who discussed the high prevalence of the FDB3500Q mutation in the Swiss population. Miserez et al. assumed that the FDB3500Q mutation was already present in the ancestors of the Celtic Swiss population (Helvetii) originally living in the area between the Rhein and Main in central Germany. The authors did not mention two articles presenting high prevalence of FDB3500Q outside Switzerland. These two prevalence studies concern Belgium and the Rhein-Main area of Germany [ 2 Kotze M.J. Peeters A.V. Langenhoven E. Wauters J.G. van Gaal L.F. Phenotypic expression and frequency of familial defective apolipoprotein B-100 in Belgian hypercholesterolemics. Atherosclerosis. 1994; 111: 217-225 Abstract Full Text PDF PubMed Scopus (31) Google Scholar , 3 Fisher E. Scharnagl H. Hoffmann M.M. et al. Mutations in the Apolipoprotein (apo) B-100 receptor-binding region: detection of apo B-100 (Arg3500→Trp) associated with two new haplotypes and evidence that apo B-100 (Glu3405→Gln) diminishes receptor-mediated uptake of LDL. Clin. Chem. 1999; 45: 1026-1038 PubMed Google Scholar ]. In both the studies, an extremely high frequency of FDB3500Q-heterozygotes in the random population was delineated from the screening of patients with hyperlipoproteinemia (Fig. 1). The Belgian study comprised 62 people with type IIa hypercholesterolemia (LDL-cholesterol>4.66 mmol/l), of which five subjects (8%) were found to be heterozygous for the mutation. We screened 297 hypercholesterolemic patients of Caucasian descent (LDL-cholesterol>4.00 mmol/l) and found that 7.1% were carriers of the mutation, all having the same apolipoprotein B haplotype 194 described by [ [4] Ludwig E.H. McCarthy B.J. Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B100. Am. J. Hum. Genet. 1990; 47: 712-720 PubMed Google Scholar ]. Assuming a prevalence of LDL-cholesterol>4.0 mmol/l in the general German population aged between 40 and 65 years (PROCAM Münster heart study) to be 25% [ [5] Assmann G. Cullen P. Schulte H. The Münster heart study (PROCAM). Results of follow-up at 8 years. Eur. Heart J. 1998; 19: A2-A11 PubMed Google Scholar ], the FDB3500Q mutation would occur with a frequency of 1:72 in the Rhein-Main area, whereas in Northwest-Switzerland the prevalence estimation was 1:114. It is thus not surprising that the first patient homozygous for FDB was identified in the Rhein-Main area [ [6] März W. Ruzicka V. Pohl T. Usadel K.H. Groß W. Familial defective apo B-100: mild hypercholesterolemia without evidence of atherosclerosis in a homozygous patient. Lancet. 1992; 340: 1362 Abstract Full Text PDF PubMed Scopus (22) Google Scholar ]. On the basis of the high prevalence of FDB3500Q subjects in our area, all of ethnic German background, one can indeed assume that the ancestor of the FDB3500Q mutation carriers originated in central Germany. In Bavaria (Munich), for example, the mutation was less frequent. Rauh et al. [ [7] Rauh G. Keller C. Schuster H. Wolfram G. Zöllner N. Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia. Clin. Invest. 1992; 70: 77-84 Crossref PubMed Scopus (33) Google Scholar ] screened 415 hypercholesterolemic subjects and found 11 carriers (2.7%) of FDB3500Q. The high prevalence found in Belgium and Germany supports recent theories as to when and where FDB3500Q first arose in the history of mankind. Myant et al. [ [8] Myant N.B. Forbes S.A. Day I.N.M. Gallagher J. Estimation of the age of the ancestral Arginine3500→Glutamine mutation in human apo B-100. Genomics. 1997; 45: 78-87 Crossref PubMed Scopus (36) Google Scholar ] traced back the R3500Q mutation by the recombination rates between the apo B gene and three distant microsatellite markers to about 270 generations .The ancient progenitor of today's FDB3500Q subjects would have lived about 6750 years ago, assuming a generation-split of 25 years. In the Early-Neolithic period (8000–7000 years ago), Europe was populated by presumably 200 000–700 000 individuals, with higher population densities in the southern regions than in the northern ones. With the transition to agriculture due to the spread of farming people from the near-east, population densities rose to 1–5 inhabitants per km2 in central Europe [ [9] Cavalli-Sforza L.L. Menozzi P. Piazza A. The History and Geography of Human Genes. Princeton University Press, New Jersey, USA1994 Google Scholar ]. An estimation from the Aldenhoven Plate (Cologne/Rhein) in Germany at the time of early ‘Bandkeramik’ (5000 B.C.) suggests a population density of about 17 inhabitants per km2 [ [10] Lüning J. Studien zur neolithischen Besiedlung der Aldenhovener platte und ihrer Ungebung. Beitrag zur neolithischen besiedlung aldenhovener platte VI. Rhein. Ausgr. 43, Köln, 1997. Google Scholar ]. So, by the time the FDB3500Q ancestors lived, there was already a relatively high population density in the Rhein-Main area. Over a period of 1000 years (4500–3500 BC) neolithic farmers extended their agricultural settlements from the fertile river valleys into the central European mountains, south to the lands bordering the Alps and north as far as Denmark. Archaeological records of this period indicate a cultural unity (‘Michelsberger Kultur’) among the populations of that region including the Rhein-Main area and Belgium (Fig. 2). Trading and the beginning of mining (flintstones) supported the mobility of man in these early societies [ [11] Lüning J, Central Europe during the Neolithic In: De Laet SJ, (Ed.), History of Humanity, Vol. I. Prehistory and the Beginnings of Civilisation, Paris, 1994, pp. 540–556. Google Scholar ]. It is quite conceivable that the early spreading of FDB3500Q had taken place by that time.