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. 1993 Apr;52(4):808–826.

Polymorphic haplotypes and recombination rates at the LDL receptor gene locus in subjects with and without familial hypercholesterolemia who are from different populations.

A R Miserez 1, H Schuster 1, N Chiodetti 1, U Keller 1
PMCID: PMC1682072  PMID: 8096361

Abstract

RFLPs at the low-density lipoprotein (LDL) receptor locus for TaqI, StuI, HincII, AvaII, ApaLI (5' and 3'), PvuII, and NcoI were studied in Swiss and German families with familial hypercholesterolemia (FH). A total of 1,104 LDL receptor alleles were analyzed using Southern blotting and new PCR-based techniques for detection of the TaqI, StuI, HincII, AvaII, NcoI RFLPs. Two hundred fifty-six independent haplotypes from 368 individuals of 61 unrelated Swiss families, as well as 114 independent haplotypes from 184 subjects of 25 unrelated German families, were constructed. In 76 families, clinical diagnosis of FH was confirmed by cosegregation analysis. Of the 43 unique haplotypes consisting of seven RFLPs detected in the Swiss and Germans, only 9 were common in both population samples. Analysis of linkage disequilibrium revealed nonrandom associations between several of the investigated RFLPs. ApaLI (5'), NcoI, PvuII, TaqI, and AvaII or HincII were particularly informative (cumulative informativeness .85). Relative frequencies, heterozygosity indexes, and PICs of the RFLPs from the Swiss and Germans were compared with values calculated from reported haplotype data for Italians, Icelanders, North American Caucasians, South African Caucasians, and Japanese. Pairwise comparisons of population samples by common RFLPs demonstrated unexpected differences even between geographically adjacent populations (e.g., the Swiss and Germans). Furthermore, genetic distances from the Germans to the other Caucasians were larger than to the Japanese. An unexpected lack of correlation between linkage disequilibria and physical distances was detected for the German and Japanese data, possibly because of nonuniform recombination with excessively high rates between exon 13 and intron 15. Hence, the present study revealed a striking variety of polymorphic haplotypes and heterogeneity of RFLP frequencies and recombination rates among the seven population samples.

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Selected References

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  1. Aalto-Setälä K., Helve E., Kovanen P. T., Kontula K. Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype. J Clin Invest. 1989 Aug;84(2):499–505. doi: 10.1172/JCI114192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Antonarakis S. E., Boehm C. D., Giardina P. J., Kazazian H. H., Jr Nonrandom association of polymorphic restriction sites in the beta-globin gene cluster. Proc Natl Acad Sci U S A. 1982 Jan;79(1):137–141. doi: 10.1073/pnas.79.1.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Antonarakis S. E., Oettgen P., Chakravarti A., Halloran S. L., Hudson R. R., Feisee L., Karathanasis S. K. DNA polymorphism haplotypes of the human apolipoprotein APOA1-APOC3-APOA4 gene cluster. Hum Genet. 1988 Nov;80(3):265–273. doi: 10.1007/BF01790095. [DOI] [PubMed] [Google Scholar]
  4. Barker D., Holm T., White R. A locus on chromosome 11p with multiple restriction site polymorphisms. Am J Hum Genet. 1984 Nov;36(6):1159–1171. [PMC free article] [PubMed] [Google Scholar]
  5. Bech-Hansen N. T., Linsley P. S., Cox D. W. Restriction fragment length polymorphisms associated with immunoglobulin C gamma genes reveal linkage disequilibrium and genomic organization. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6952–6956. doi: 10.1073/pnas.80.22.6952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Botstein D., White R. L., Skolnick M., Davis R. W. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet. 1980 May;32(3):314–331. [PMC free article] [PubMed] [Google Scholar]
  7. Brink P. A., Steyn L. T., Coetzee G. A., Van der Westhuyzen D. R. Familial hypercholesterolemia in South African Afrikaners. PvuII and StuI DNA polymorphisms in the LDL-receptor gene consistent with a predominating founder gene effect. Hum Genet. 1987 Sep;77(1):32–35. doi: 10.1007/BF00284709. [DOI] [PubMed] [Google Scholar]
  8. Chakravarti A., Buetow K. H. A strategy for using multiple linked markers for genetic counseling. Am J Hum Genet. 1985 Sep;37(5):984–997. [PMC free article] [PubMed] [Google Scholar]
  9. Chakravarti A., Buetow K. H., Antonarakis S. E., Waber P. G., Boehm C. D., Kazazian H. H. Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet. 1984 Nov;36(6):1239–1258. [PMC free article] [PubMed] [Google Scholar]
  10. Chakravarti A., Elbein S. C., Permutt M. A. Evidence for increased recombination near the human insulin gene: implication for disease association studies. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1045–1049. doi: 10.1073/pnas.83.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Daga A., Mattioni T., Balestreri R., Coviello D. A., Corte G., Bertolini S. Use of three DNA polymorphisms of the LDL receptor gene in the diagnosis of familial hypercholesterolemia. Hum Genet. 1990 Apr;84(5):412–416. doi: 10.1007/BF00195811. [DOI] [PubMed] [Google Scholar]
  12. Haviland M. B., Kessling A. M., Davignon J., Sing C. F. Estimation of Hardy-Weinberg and pairwise disequilibrium in the apolipoprotein AI-CIII-AIV gene cluster. Am J Hum Genet. 1991 Aug;49(2):350–365. [PMC free article] [PubMed] [Google Scholar]
  13. Hobbs H. H., Brown M. S., Goldstein J. L., Russell D. W. Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia. J Biol Chem. 1986 Oct 5;261(28):13114–13120. [PubMed] [Google Scholar]
  14. Hobbs H. H., Brown M. S., Russell D. W., Davignon J., Goldstein J. L. Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia. N Engl J Med. 1987 Sep 17;317(12):734–737. doi: 10.1056/NEJM198709173171204. [DOI] [PubMed] [Google Scholar]
  15. Hobbs H. H., Esser V., Russell D. W. AvaII polymorphism in the human LDL receptor gene. Nucleic Acids Res. 1987 Jan 12;15(1):379–379. doi: 10.1093/nar/15.1.379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hobbs H. H., Leitersdorf E., Goldstein J. L., Brown M. S., Russell D. W. Multiple crm- mutations in familial hypercholesterolemia. Evidence for 13 alleles, including four deletions. J Clin Invest. 1988 Mar;81(3):909–917. doi: 10.1172/JCI113402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Horsthemke B., Beisiegel U., Dunning A., Havinga J. R., Williamson R., Humphries S. Unequal crossing-over between two alu-repetitive DNA sequences in the low-density-lipoprotein-receptor gene. A possible mechanism for the defect in a patient with familial hypercholesterolaemia. Eur J Biochem. 1987 Apr 1;164(1):77–81. doi: 10.1111/j.1432-1033.1987.tb10995.x. [DOI] [PubMed] [Google Scholar]
  18. Hudson R. R., Kaplan N. L. Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics. 1985 Sep;111(1):147–164. doi: 10.1093/genetics/111.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Humphries S. E., Kessling A. M., Horsthemke B., Donald J. A., Seed M., Jowett N., Holm M., Galton D. J., Wynn V., Williamson R. A common DNA polymorphism of the low-density lipoprotein (LDL) receptor gene and its use in diagnosis. Lancet. 1985 May 4;1(8436):1003–1005. doi: 10.1016/s0140-6736(85)91611-3. [DOI] [PubMed] [Google Scholar]
  20. Kotze M. J., Langenhoven E., Dietzsch E., Retief A. E. A RFLP associated with the low-density lipoprotein receptor gene (LDLR). Nucleic Acids Res. 1987 Jan 12;15(1):376–376. doi: 10.1093/nar/15.1.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kotze M. J., Langenhoven E., Retief A. E., Seftel H. C., Henderson H. E., Weich H. F. Haplotypes identified by 10 DNA restriction fragment length polymorphisms at the human low density lipoprotein receptor gene locus. J Med Genet. 1989 Apr;26(4):255–259. doi: 10.1136/jmg.26.4.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kotze M. J., Langenhoven E., Warnich L., Marx M. P., Retief A. E. Molecular characterisation of a low-frequency mutation in exon 8 of the human low-density lipoprotein receptor gene. S Afr Med J. 1989 Oct 21;76(8):402–405. [PubMed] [Google Scholar]
  23. Kotze M. J., Langenhoven E., Warnich L., du Plessis L., Marx M. P., Oosthuizen C. J., Retief A. E. The identification of two low-density lipoprotein receptor gene mutations in South African familial hypercholesterolaemia. S Afr Med J. 1989 Oct 21;76(8):399–401. [PubMed] [Google Scholar]
  24. Kotze M. J., Retief A. E., Brink P. A., Weich H. F. A DNA polymorphism in the human low-density lipoprotein receptor gene. S Afr Med J. 1986 Jul 19;70(2):77–79. [PubMed] [Google Scholar]
  25. Lehrman M. A., Goldstein J. L., Russell D. W., Brown M. S. Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. Cell. 1987 Mar 13;48(5):827–835. doi: 10.1016/0092-8674(87)90079-1. [DOI] [PubMed] [Google Scholar]
  26. Lehrman M. A., Schneider W. J., Brown M. S., Davis C. G., Elhammer A., Russell D. W., Goldstein J. L. The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. J Biol Chem. 1987 Jan 5;262(1):401–410. [PubMed] [Google Scholar]
  27. Lehrman M. A., Schneider W. J., Südhof T. C., Brown M. S., Goldstein J. L., Russell D. W. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science. 1985 Jan 11;227(4683):140–146. doi: 10.1126/science.3155573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Leitersdorf E., Chakravarti A., Hobbs H. H. Polymorphic DNA haplotypes at the LDL receptor locus. Am J Hum Genet. 1989 Mar;44(3):409–421. [PMC free article] [PubMed] [Google Scholar]
  29. Leitersdorf E., Hobbs H. H. Human LDL receptor gene: two ApaLI RFLPs. Nucleic Acids Res. 1987 Mar 25;15(6):2782–2782. doi: 10.1093/nar/15.6.2782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Leitersdorf E., Van der Westhuyzen D. R., Coetzee G. A., Hobbs H. H. Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners. J Clin Invest. 1989 Sep;84(3):954–961. doi: 10.1172/JCI114258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lewontin R C. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics. 1964 Jan;49(1):49–67. doi: 10.1093/genetics/49.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Litt M., Jorde L. B. Linkage disequilibria between pairs of loci within a highly polymorphic region of chromosome 2Q. Am J Hum Genet. 1986 Aug;39(2):166–178. [PMC free article] [PubMed] [Google Scholar]
  33. Ma Y. H., Bétard C., Roy M., Davignon J., Kessling A. M. Identification of a second "French Canadian" LDL receptor gene deletion and development of a rapid method to detect both deletions. Clin Genet. 1989 Oct;36(4):219–228. doi: 10.1111/j.1399-0004.1989.tb03194.x. [DOI] [PubMed] [Google Scholar]
  34. Mantel N. The detection of disease clustering and a generalized regression approach. Cancer Res. 1967 Feb;27(2):209–220. [PubMed] [Google Scholar]
  35. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ohta T., Kimura M. Linkage disequilibrium at steady state determined by random genetic drift and recurrent mutation. Genetics. 1969 Sep;63(1):229–238. doi: 10.1093/genetics/63.1.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Renwick J. H. The mapping of human chromosomes. Annu Rev Genet. 1971;5:81–120. doi: 10.1146/annurev.ge.05.120171.000501. [DOI] [PubMed] [Google Scholar]
  38. Schuster H., Rauh G., Müller S., Keller C., Wolfram G., Zöllner N. Allele-specific and asymmetric polymerase chain reaction amplification in combination: a one step polymerase chain reaction protocol for rapid diagnosis of familial defective apolipoprotein B-100. Anal Biochem. 1992 Jul;204(1):22–25. doi: 10.1016/0003-2697(92)90133-r. [DOI] [PubMed] [Google Scholar]
  39. Schuster H., Stiefenhofer B., Wolfram G., Keller C., Humphries S., Huber A., Zöllner N. Four DNA polymorphisms in the LDL-receptor gene and their use in diagnosis of familial hypercholesterolemia. Hum Genet. 1989 Apr;82(1):69–72. doi: 10.1007/BF00288276. [DOI] [PubMed] [Google Scholar]
  40. Soria L. F., Ludwig E. H., Clarke H. R., Vega G. L., Grundy S. M., McCarthy B. J. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci U S A. 1989 Jan;86(2):587–591. doi: 10.1073/pnas.86.2.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Spengel F. A., Harders-Spengel K. M., Keller C. F., Wieczorek A., Wolfram G., Zöllner N. Use of fibroblast culture to diagnose and genotype familial hypercholesterolaemia. Ann Nutr Metab. 1982;26(4):240–247. doi: 10.1159/000176569. [DOI] [PubMed] [Google Scholar]
  42. Sved J. A. Linkage disequilibrium and homozygosity of chromosome segments in finite populations. Theor Popul Biol. 1971 Jun;2(2):125–141. doi: 10.1016/0040-5809(71)90011-6. [DOI] [PubMed] [Google Scholar]
  43. Südhof T. C., Goldstein J. L., Brown M. S., Russell D. W. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985 May 17;228(4701):815–822. doi: 10.1126/science.2988123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Taylor R., Bryant J., Gudnason V., Sigurdsson G., Humphries S. A study of familial hypercholesterolaemia in Iceland using RFLPs. J Med Genet. 1989 Aug;26(8):494–498. doi: 10.1136/jmg.26.8.494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Treco D., Thomas B., Arnheim N. Recombination hot spot in the human beta-globin gene cluster: meiotic recombination of human DNA fragments in Saccharomyces cerevisiae. Mol Cell Biol. 1985 Aug;5(8):2029–2038. doi: 10.1128/mcb.5.8.2029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Weir B. S., Hill W. G. Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet. 1986 May;38(5):776–781. [PMC free article] [PubMed] [Google Scholar]
  47. Yamakawa K., Okafuji T., Iwamura Y., Russell D. W., Hamaguchi H. TaqI polymorphism in the human LDL receptor gene. Nucleic Acids Res. 1987 Sep 25;15(18):7659–7659. doi: 10.1093/nar/15.18.7659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yamakawa K., Yanagi H., Saku K., Sasaki J., Okafuji T., Shimakura Y., Kawai K., Tsuchiya S., Takada K., Naito S. Family studies of the LDL receptor gene of relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas. Hum Genet. 1991 Mar;86(5):445–449. doi: 10.1007/BF00194631. [DOI] [PubMed] [Google Scholar]
  49. Yamamoto T., Davis C. G., Brown M. S., Schneider W. J., Casey M. L., Goldstein J. L., Russell D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. doi: 10.1016/0092-8674(84)90188-0. [DOI] [PubMed] [Google Scholar]
  50. Zerba K. E., Kessling A. M., Davignon J., Sing C. F. Genetic structure and the search for genotype-phenotype relationships: an example from disequilibrium in the Apo B gene region. Genetics. 1991 Oct;129(2):525–533. doi: 10.1093/genetics/129.2.525. [DOI] [PMC free article] [PubMed] [Google Scholar]

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