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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Mar 15;101(6):1283–1291. doi: 10.1172/JCI1343

Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.

J Wang 1, D J Freeman 1, S M Grundy 1, D M Levine 1, R Guerra 1, J C Cohen 1
PMCID: PMC508682  PMID: 9502769

Abstract

Interindividual differences in plasma low-density lipoprotein cholesterol (LDL-C) levels reflect both environmental variation and genetic polymorphism, but the specific genes involved and their relative contributions to the variance in LDL-C are not known. In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7). Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL-C concentrations. This finding was replicated in an independent sample. DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDL-C concentrations, both in sibling pairs and in unrelated individuals. Taken together, these findings indicate that polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account for little of the heritable variation in plasma LDL-C concentrations in the general population.

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Selected References

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  1. Amos C. I. Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet. 1994 Mar;54(3):535–543. [PMC free article] [PubMed] [Google Scholar]
  2. Amos C. I., Zhu D. K., Boerwinkle E. Assessing genetic linkage and association with robust components of variance approaches. Ann Hum Genet. 1996 Mar;60(Pt 2):143–160. doi: 10.1111/j.1469-1809.1996.tb01184.x. [DOI] [PubMed] [Google Scholar]
  3. Austin M. A., King M. C., Bawol R. D., Hulley S. B., Friedman G. D. Risk factors for coronary heart disease in adult female twins. Genetic heritability and shared environmental influences. Am J Epidemiol. 1987 Feb;125(2):308–318. doi: 10.1093/oxfordjournals.aje.a114531. [DOI] [PubMed] [Google Scholar]
  4. Björkhem I., Reihnér E., Angelin B., Ewerth S., Akerlund J. E., Einarsson K. On the possible use of the serum level of 7 alpha-hydroxycholesterol as a marker for increased activity of the cholesterol 7 alpha-hydroxylase in humans. J Lipid Res. 1987 Aug;28(8):889–894. [PubMed] [Google Scholar]
  5. Boerwinkle E., Sing C. F. The use of measured genotype information in the analysis of quantitative phenotypes in man. III. Simultaneous estimation of the frequencies and effects of the apolipoprotein E polymorphism and residual polygenetic effects on cholesterol, betalipoprotein and triglyceride levels. Ann Hum Genet. 1987 Jul;51(Pt 3):211–226. doi: 10.1111/j.1469-1809.1987.tb00874.x. [DOI] [PubMed] [Google Scholar]
  6. Bucher K. D., Friedlander Y., Kaplan E. B., Namboodiri K. K., Kark J. D., Eisenberg S., Stein Y., Rifkind B. M. Biological and cultural sources of familial resemblance in plasma lipids: a comparison between North America and Israel--the Lipid Research Clinics Program. Genet Epidemiol. 1988;5(1):17–33. doi: 10.1002/gepi.1370050103. [DOI] [PubMed] [Google Scholar]
  7. Friedewald W. T., Levy R. I., Fredrickson D. S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972 Jun;18(6):499–502. [PubMed] [Google Scholar]
  8. Gaffney D., Freeman D. J., Shepherd J., Packard C. J. The ins/del polymorphism in the signal sequence of apolipoprotein B has no effect on lipid parameters. Clin Chim Acta. 1993 Sep 30;218(2):131–138. doi: 10.1016/0009-8981(93)90177-6. [DOI] [PubMed] [Google Scholar]
  9. Gavish D., Brinton E. A., Breslow J. L. Heritable allele-specific differences in amounts of apoB and low-density lipoproteins in plasma. Science. 1989 Apr 7;244(4900):72–76. doi: 10.1126/science.2565046. [DOI] [PubMed] [Google Scholar]
  10. Glueck C. J., Ford S., Jr, Scheel D., Steiner P. Colestipol and cholestyramine resin. Comparative effects in familial type II hyperlipoproteinemia. JAMA. 1972 Nov 6;222(6):676–681. doi: 10.1001/jama.222.6.676. [DOI] [PubMed] [Google Scholar]
  11. Grundy S. M. George Lyman Duff Memorial Lecture. Multifactorial etiology of hypercholesterolemia. Implications for prevention of coronary heart disease. Arterioscler Thromb. 1991 Nov-Dec;11(6):1619–1635. doi: 10.1161/01.atv.11.6.1619. [DOI] [PubMed] [Google Scholar]
  12. Guerra R., Wang J., Grundy S. M., Cohen J. C. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4532–4537. doi: 10.1073/pnas.94.9.4532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hansen P. S., Gerdes L. U., Klausen I. C., Gregersen N., Faergeman O. Polymorphisms in the apolipoprotein B-100 gene contributes to normal variation in plasma lipids in 464 Danish men born in 1948. Hum Genet. 1993 Mar;91(1):45–50. doi: 10.1007/BF00230221. [DOI] [PubMed] [Google Scholar]
  14. Haseman J. K., Elston R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972 Mar;2(1):3–19. doi: 10.1007/BF01066731. [DOI] [PubMed] [Google Scholar]
  15. Hopper J. L., Mathews J. D. Extensions to multivariate normal models for pedigree analysis. Ann Hum Genet. 1982 Oct;46(Pt 4):373–383. doi: 10.1111/j.1469-1809.1982.tb01588.x. [DOI] [PubMed] [Google Scholar]
  16. Humphries S., Coviello D. A., Masturzo P., Balestreri R., Orecchini G., Bertolini S. Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy. Arterioscler Thromb. 1991 May-Jun;11(3):509–516. doi: 10.1161/01.atv.11.3.509. [DOI] [PubMed] [Google Scholar]
  17. Jones R. J., Dobrilovic L. Lipoprotein lipid alterations with cholestyramine administration. J Lab Clin Med. 1970 Jun;75(6):953–966. [PubMed] [Google Scholar]
  18. Klausen I. C., Hansen P. S., Gerdes L. U., Rüdiger N., Gregersen N., Faergeman O. A PvuII polymorphism of the low density lipoprotein receptor gene is not associated with plasma concentrations of low density lipoproteins including LP(a). Hum Genet. 1993 Mar;91(2):193–195. doi: 10.1007/BF00222725. [DOI] [PubMed] [Google Scholar]
  19. Linton M. F., Farese R. V., Jr, Young S. G. Familial hypobetalipoproteinemia. J Lipid Res. 1993 Apr;34(4):521–541. [PubMed] [Google Scholar]
  20. Ludwig E. H., Hopkins P. N., Allen A., Wu L. L., Williams R. R., Anderson J. L., Ward R. H., Lalouel J. M., Innerarity T. L. Association of genetic variations in apolipoprotein B with hypercholesterolemia, coronary artery disease, and receptor binding of low density lipoproteins. J Lipid Res. 1997 Jul;38(7):1361–1373. [PubMed] [Google Scholar]
  21. Machleder D., Ivandic B., Welch C., Castellani L., Reue K., Lusis A. J. Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism. J Clin Invest. 1997 Mar 15;99(6):1406–1419. doi: 10.1172/JCI119300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Marcovina S. M., Albers J. J., Kennedy H., Mei J. V., Henderson L. O., Hannon W. H. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of International Reference Material. Clin Chem. 1994 Apr;40(4):586–592. [PubMed] [Google Scholar]
  23. McGowan M. W., Artiss J. D., Strandbergh D. R., Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem. 1983 Mar;29(3):538–542. [PubMed] [Google Scholar]
  24. Miller N. E., Clifton-Bligh P., Nestel P. J. Effects of colestipol, a new bile-acid-sequestering resin, on cholesterol metabolism in man. J Lab Clin Med. 1973 Dec;82(6):876–890. [PubMed] [Google Scholar]
  25. Myant N. B. Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis. 1993 Dec;104(1-2):1–18. doi: 10.1016/0021-9150(93)90171-p. [DOI] [PubMed] [Google Scholar]
  26. Pérusse L., Després J. P., Tremblay A., Leblanc C., Talbot J., Allard C., Bouchard C. Genetic and environmental determinants of serum lipids and lipoproteins in French Canadian families. Arteriosclerosis. 1989 May-Jun;9(3):308–318. doi: 10.1161/01.atv.9.3.308. [DOI] [PubMed] [Google Scholar]
  27. Reihnér E., Björkhem I., Angelin B., Ewerth S., Einarsson K. Bile acid synthesis in humans: regulation of hepatic microsomal cholesterol 7 alpha-hydroxylase activity. Gastroenterology. 1989 Dec;97(6):1498–1505. doi: 10.1016/0016-5085(89)90395-8. [DOI] [PubMed] [Google Scholar]
  28. Rice T., Vogler G. P., Perry T. S., Laskarzewski P. M., Rao D. C. Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study. Hum Hered. 1991;41(2):107–121. doi: 10.1159/000153987. [DOI] [PubMed] [Google Scholar]
  29. Sandkamp M., Tambyrajah B., Schriewer H., Assmann G. Simplified turbidimetric determination of apolipoproteins A-I, A-II and B using a microtitre method. J Clin Chem Clin Biochem. 1988 Nov;26(11):685–688. doi: 10.1515/cclm.1988.26.11.685. [DOI] [PubMed] [Google Scholar]
  30. Stoesz M. R., Cohen J. C., Mooser V., Marcovina S., Guerra R. Extension of the Haseman-Elston method to multiple alleles and multiple loci: theory and practice for candidate genes. Ann Hum Genet. 1997 May;61(Pt 3):263–274. doi: 10.1046/j.1469-1809.1997.6130263.x. [DOI] [PubMed] [Google Scholar]
  31. Superko H. R., Greenland P., Manchester R. A., Andreadis N. A., Schectman G., West N. H., Hunninghake D., Haskell W. L., Probstfield J. L. Effectiveness of low-dose colestipol therapy in patients with moderate hypercholesterolemia. Am J Cardiol. 1992 Jul 15;70(2):135–140. doi: 10.1016/0002-9149(92)91264-5. [DOI] [PubMed] [Google Scholar]
  32. Vessby B., Kostner G., Lithell H., Thomis J. Diverging effects of cholestyramine on apolipoprotein B and lipoprotein Lp(a). A dose-response study of the effects of cholestyramine in hypercholesterolaemia. Atherosclerosis. 1982 Jul;44(1):61–71. doi: 10.1016/0021-9150(82)90053-3. [DOI] [PubMed] [Google Scholar]
  33. Wan Y., Cohen J., Guerra R. A permutation test for the robust sib-pair linkage method. Ann Hum Genet. 1997 Jan;61(Pt 1):79–87. doi: 10.1046/j.1469-1809.1997.6110077.x. [DOI] [PubMed] [Google Scholar]
  34. de Knijff P., van den Maagdenberg A. M., Frants R. R., Havekes L. M. Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels. Hum Mutat. 1994;4(3):178–194. doi: 10.1002/humu.1380040303. [DOI] [PubMed] [Google Scholar]

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