Origin, Spread, and Phenotypic Variance of a Common Lithuanian Mutation (G197del LDLR) Causing Familial Hypercholesterolemia in Ashkenazi Jews
Ronen Durst 1, Roberto Colombo 2, Shoshi Shpitzen 1, Liat Ben Avi 1, Yechiel Friedlander 3, Roni Wexler 3, Derick Raal 4, David A Marais 5, Joep Defeshce 6, Michail Y Mandelshtam 7, Marthina J Kotze 8, Eran Leitersdorf 1 and Vardiella Meiner 9
1. Division of Medicine and the Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah University Hospital, 91120 Jerusalem, Israel.
2. Human Biology and Genetics Research Unit, Department of Psychology, Catholic University of the Sacred Heart, Milan, Italy.
3. Department of Social Medicine, School of Public Health, Hebrew University, Jerusalem, Israel.
4. Carbohydrate and Lipid Metabolism Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
5. Internal Medicine Lipid Laboratory, University of Cape Town Medical School, Cape Town, South Africa.
6. Lipid research Group, Academic Medical center, Utrecht, The Netherlands.
7. Institute for Experimental Medicine, Department of Molecular Genetics, St. Petersburg Academy, St. Petersburg, Russia.
8. Division of Human Genetics, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Stellenbosch, Tygerberg , South Africa.
9. Department of Human Genetics Hadassah University Hospital, Jerusalem, Israel.
Address for correspondence: Eran Leitersdorf MD, Tel: 00-972-2-6778029; Fax 00-972-2-6411136; E mail: [email protected]
Running title: G197del LDLR in Ashkenazi Jews
Key Words: Familial hypercholesterolemia, LDL cholesterol, founder effect, genetic
Abstract
G197del is a most prevalent low-density lipoprotein receptor (LDLR) mutation causing familial hypercholesterolemia (FH) in Ashkenazi Jews (AJ) (Meiner et. al. 1991).
The purpose of the current study was to investigate whether G197del is of a single origin, estimate its age and detect possible environmental and genetic effects on the biochemical phenotype.
Index cases from Israel (46), South Africa (24), Russia (7), The Netherlands (1) and the USA (1) were included.
A putative ancestral haplotype (D19S221:104 D19S865:208 D19S413:74) and five related haplotypes were identified in G197del chromosomes from 54 (68%) and 14 index cases (18%), respectively, supporting the possibility of a common founder mutant allele.
The age estimate of G197del was found to be 11.8± 6.4 generations (mean±SD, 95% CI: 6.716.9 generations) using the Risch et al. (1995) algorithm, and 11.3± 6.1 (95% CI: 6.416.2 generations) using the Reich and Goldstein (1999) iterative method. Applying the Luria-Delbrück correction for rapid growing population gives an astimat mutation age of 20.1± 7.1 and 20.1± 6.9 respectively.
The mutation is therefore dated to the 14th century. A trend for an age-dependent increase in TC, TG and HDL among heterozygotes and higher mean HDL-C levels in females was detected.
There was no difference in mean lipid levels among G197del FH patients from different countries. Apolipoprotein E (apo E) and the Scavenger receptor type BI (SR-BI) polymorphisms did not affect the biochemical phenotype.
The lack of a significant environmental and genetic influence on the FH phenotype does not support the possibility of a heterozygote evolutionary advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains as a simple, parsimonious, hypothesis explaining the spread of G197del FH in AJ.
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