Recent Origin and Spread of a Common Lithuanian Mutation, G197del LDLR, Causing Familial Hypercholesterolemia: Positive Selection Is Not Always Necessary to Account for Disease Incidence among Ashkenazi Jews

G197del is the most prevalent LDL receptor (LDLR) mutation causing familial hypercholesterolemia (FH) in Ashkenazi Jew (AJ) individuals. The purpose of this study was to determine the origin, age, and population distribution of G197del, as well as to explore environmental and genetic effects on dise...

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Published in:	American journal of human genetics Vol. 68; no. 5; pp. 1172 - 1188
Main Authors:	Durst, Ronen, Colombo, Roberto, Shpitzen, Shoshi, Avi, Liat Ben, Friedlander, Yechiel, Wexler, Roni, Raal, Frederick J., Marais, David A., Defesche, Joep C., Mandelshtam, Michail Y., Kotze, Maritha J., Leitersdorf, Eran, Meiner, Vardiella
Format:	Journal Article
Language:	English
Published:	Chicago, IL Elsevier Inc 01-05-2001 University of Chicago Press The American Society of Human Genetics
Subjects:	Adolescent Adult Aged Apolipoproteins E - genetics Biological and medical sciences CD36 Antigens - genetics Child Chromosomes, Human, Pair 19 - genetics Disorders of blood lipids. Hyperlipoproteinemia Female Founder Effect Gene Frequency - genetics Genetic Heterogeneity Haplotypes Humans Hyperlipoproteinemia Type II - epidemiology Hyperlipoproteinemia Type II - genetics Incidence Jews - genetics Linkage Disequilibrium - genetics Lithuania - ethnology Male Medical sciences Membrane Proteins Metabolic diseases Middle Aged Models, Genetic Penetrance Polymorphism, Genetic - genetics Receptors, Immunologic Receptors, LDL - genetics Receptors, Lipoprotein Receptors, Scavenger Scavenger Receptors, Class B Sequence Deletion - genetics Lithuania Human Linkage Family study Pathogenesis Metabolic diseases Lipids Hyperlipoproteinemia Founder effect Linkage equilibrium Genetic determinism Genetic disease Lipoprotein LDL Hypercholesterolemia Gene Mutation Dyslipemia Haplotype Biological receptor
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Summary:	G197del is the most prevalent LDL receptor (LDLR) mutation causing familial hypercholesterolemia (FH) in Ashkenazi Jew (AJ) individuals. The purpose of this study was to determine the origin, age, and population distribution of G197del, as well as to explore environmental and genetic effects on disease expression. Index cases from Israel ( n=46), South Africa ( n=24), Russia ( n=7), The Netherlands ( n=1), and the United States ( n=1) were enlisted. All trace their ancestry to Lithuania. A highly conserved haplotype (D19S221:104-D19S865:208-D19S413:74) was identified in G197del chromosomes, suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 ± 7 generations (the 95% confidence interval is 15–26 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 a.d.), as well as with the great demographic expansion of AJ individuals in eastern Europe, which followed this settlement. The penetrance of mutation-linked severe hypercholesterolemia is high (94% of heterozygotes have a baseline concentration of LDL cholesterol (LDL-C) that is >160 mg/dl), and no significant differences in the mean baseline lipid level of G197del carriers from different countries were found. Polymorphisms of apolipoprotein E and of scavenger-receptor class B type I were observed to have minor effects on the plasma lipid profile. With respect to determinative genetic influences on the biochemical phenotype, there is no evidence that could support the possibility of a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of G197del-LDLR–linked FH in AJ individuals.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0002-9297 1537-6605
DOI:	10.1086/320123