Segregation analysis of HDL cholesterol in the NHLBI family heart study and in Utah pedigrees

Florian Kronenberg, Hilary Coon, R. Curtis Ellison, Ingrid Borecki, Donna K. Arnett, Michael A. Province, John H. Eckfeldt, Paul N. Hopkins, Steven C. Hunt

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


We investigated the genetic determination of high-density-lipoprotein cholesterol (HDL-C) levels in the NHLBI Family Heart Study by segregation analysis. Included was a total of 3755 subjects from 560 randomly selected nuclear families and 522 families selected due to a high family risk of coronary heart disease (CHD). In the whole dataset, there was no evidence for an allele at a major gene locus responsible for HDL-C levels lower than the population mean or even for significant bimodality for low levels of HDL-C. However, we observed evidence for a recessive allele that was associated with higher HDL-C levels than average. This evidence for a recessive major gene was independent of triglyceride concentrations and was most strongly observed in families recruited for CHD. The environmental model was rejected (P=0.0027) while the codominant and recessive models were not rejected (P=0.085 and P=0.133, respectively). The dominant model was also rejected (P<0.0001). In the recessive segregation model, the means of those inferred to be homozygous for the high HDL-C allele and those without the high HDL-C allele were separated by about 25 mg/dl HDL-C (73.9 ± 1.99 vs 48.2 ± 0.36 mg/dl). Because these results were unexpected, segregation was tested in a separate sample of 2013 individuals in 85 large pedigrees ascertained for early heart disease deaths, early stroke deaths, and early hypertension in Utah. Similar evidence for an allele at a major gene locus for high HDL-C was found. In summary, we did not find evidence for an allele at a major gene locus associated with low HDL-C levels segregating in pedigrees recruited for the NHLBI Family Heart Study, or in pedigrees ascertained in Utah for early CHD or related phenotypes. Instead we found some evidence for the segregation of an allele associated with high HDL-C.

Original languageEnglish
Pages (from-to)367-374
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number6
StatePublished - 2002

Bibliographical note

Funding Information:
F Kronenberg is supported by the ‘Austrian Programme for Advanced Research and Technology’ (APART) of the Austrian Academy of Science and by the Austrian Science Fund (P14717-GEN). This study was supported by cooperative agreements from NHLBI: UO1-HL-56563, -56564, -56565, -56566, -56567, -56568, and -56569; two grants from NHLBI: R01HL21088 and R01HL24855; and a grant from NIA: AG18734. This paper is presented on behalf of the investigators of the NHLBI Family Heart Study. Participating institutions and principal staff of the study are as follows: Forsyth County/University of North Carolina/Wake Forest University: Gerar-do Heiss, Stephen Rich, Greg Evans; James Pankow; HA Tyroler, Jeannette T Bensen, Catherine Paton, Delilah Posey and Amy Haire; University of Minnesota Field Center: Donna K Arnett, Aaron R Folsom, Larry Atwood, James Peacock, and Greg Feitl; Boston University/Framingham Field Center: R Curtis Ellison, Richard H Myers, Yuqing Zhang, Andrew G Bostom, Luc Djoussé, Jemma B Wilk and Greta Lee Splansky; University of Utah Field Center: Steven C Hunt, Roger R Williams (deceased), Paul N Hopkins, Hilary Coon and Jan Skuppin; Coordinating Center, Washington University, St. Louis: Michael A Province, DC Rao, Ingrid B Borecki, Yuling Hong, Mary Feitosa, Jeanne Cashman, and Avril Adelman; Central Biochemistry Laboratory, University of Minnesota: John H Eckfeldt, Catherine Leiendecker-Foster, Michael Y Tsai, and Greg Rynders; Central Molecular Laboratory, University of Utah: Mark F. Leppert, Jean-Marc Lalouel, Tena Varvil, Lisa Baird; National Heart, Lung, & Blood Institute – Project Office: Phyliss Sholinsky, Millicent Higgins (retired), Jacob Keller (retired), Sarah Knox, and Lorraine Silsbee.


  • Atherosclerosis
  • Family heart study
  • Genetics
  • HDL cholesterol
  • Segregation analysis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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