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 o f this study was to determine the origin, age, and population distribution of G197del, as well as to explore environmental and genetic effects on dise ase expression. Index cases from Israel (n = 46), South Africa (n = 24), Ru ssia (n = 7), The Netherlands (n = 1), and the United States (n = 1) were e nlisted. All trace their ancestry to Lithuania. A highly conserved haplotyp e (D19S221:104-D19S865:208-D19S413: 74) was identified in G197del chromosom es, suggesting the occurrence of a common founder. When two methods were us ed for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over ti me, 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 Lit huania (1338 A.D.), as well as with the great demographic expansion of AJ i ndividuals in eastern Europe, which followed this settlement. The penetranc e of mutation-linked severe hypercholesterolemia is high (94% of heterozygo tes have a baseline concentration of LDL cholesterol (LDL-C) that is >160 m g/dl), and no significant differences in the mean baseline lipid level of G 197del carriers from different countries were found. Polymorphisms of apoli poprotein E and of scavenger-receptor class B type I were observed to have minor effects on the plasma lipid profile. With respect to determinative ge netic influences on the biochemical phenotype, there is no evidence that co uld support the possibility of a selective evolutionary metabolic advantage . Therefore, the founder effect in a rapidly expanding population from a li mited number of families remains a simple, parsimonious hypothesis explaini ng the spread of G197del-LDLR- linked FH in AJ individuals.