Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: The NHLBI family heart study

Steven C. Hunt, Florian Kronenberg, John H. Eckfeldt, Paul N. Hopkins, Richard H. Myers, Gerardo Heiss

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


Decreased serum bilirubin levels have been associated with coronary heart disease (CHD). It is believed that bilirubin acts as an antioxidant, preventing formation of oxidized LDL and subsequent atherosclerosis. Serum bilirubin also segregates as a major gene, with the rarer genotype associated with elevated bilirubin levels and occurring in about 12% of the population. Using a large population-based study of random and CHD high risk families, this analysis was designed to replicate the association of lower serum bilirubin levels with early CHD (onset by age 55 for males and 65 for females) using 328 case/control samples and the major gene segregation of bilirubin levels in 555 families. There were significant differences in plasma bilirubin levels between 188 males (12.5 μmol/l) and 140 females (9.3 μmol/l, P < 0.0001). Higher serum albumin and lower HDL-C significantly correlated with higher plasma bilirubin levels in females but not males. In sex-specific logistic regression models of early CHD (148 cases and 180 controls), lower plasma bilirubin was associated with increased prevalence of CHD in males with borderline significance (odds ratio = 0.93 for a 1 μmol/l increase in bilirubin, P = 0.056) but not in females. Bilirubin was found to segregate as a major gene using all 555 families consisting of 1292 individuals, with estimates replicating those in the previously published study. The most parsimonious model was a recessive model for high bilirubin levels that occurred in about 23% of the population. The means were separated by 1.7 standard deviations and there was a significant polygenic effect (h2 = 0.33, P = 0.0009). We conclude that decreased bilirubin is mildly related to CHD in males but not in females. Because of an inverse correlation between HDL-C and bilirubin, the protective high HDL-C levels may have counteracted the CHD risk associated with lower bilirubin levels in females. The inferred major gene for bilirubin may protect against CHD, since elevated levels, rather than lower levels, were associated with this inferred gene.

Original languageEnglish (US)
Pages (from-to)747-754
Number of pages8
Issue number3
StatePublished - Feb 15 2001

Bibliographical note

Funding Information:
This study was supported by cooperative agreements from NHLBI: UO1-HL-56563, -56564, -56565, -56566, -56567, -56568, and -56569. F. Kronenberg is supported by the ‘Austrian Programme for Advanced Research and Technology’ (APART) of the Austrian Academy of Science.


  • Antioxidants
  • Atherosclerosis
  • Bilirubin
  • Coronary heart disease
  • Epidemiology
  • Genetics
  • Lipids
  • Segregation analysis


Dive into the research topics of 'Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: The NHLBI family heart study'. Together they form a unique fingerprint.

Cite this