Genetic Flaw Linked to Early Heart Disease Association With Osteoporosis Also Found

Tracy Hampton, PhD

JAMA. 2007;297:1643-1644.

A rare mutation in an Iranian family led researchers to potentially important determinants of risks for developing heart disease and osteoporosis. A recent study found that many family members with a single genetic defect had high blood pressure, high low-density lipoprotein (LDL) cholesterol levels, diabetes, and early onset coronary artery disease. Many of them also experienced unexplained hip fractures at young ages (Mani A et al. Science. 2007;315:1278-1282).

The cause of these effects was found within the gene that codes for LDL receptor-related protein 6 (LRP6). While this mutation is not found in most individuals in the population who develop heart disease or osteoporosis, it may provide clues to common abnormalities underlying altered glucose homeostasis, elevated blood pressure, dyslipidemia, and low bone density.

A rare mutation in the LRP6 gene on chromosome 12 causes high blood pressure, elevated low-density lipoprotein cholesterol levels, diabetes, and early onset heart disease.

RARE MUTATION

From a screen of patients and families with coronary artery disease, a collaborative team of scientists in the United States and Iran found that among 58 blood relatives of one patient, 28 were diagnosed with early coronary artery disease, 23 of whom died of the condition by an average age of 52. In obtaining medical records and blood samples from 19 surviving members of the family (7 with early onset coronary artery disease, 5 who were unaffected, and 7 who were too young to assess) and performing a detailed genetic comparison of affected and disease-free individuals, the investigators found that a specific segment of chromosome 12 was the most likely genetic cause of the disease.

It was not until the researchers noted an increased incidence in hip fractures among affected family members that the gene, which lies within this segment of chromosome 12, was implicated. (In addition to the original patient identified, 2 other affected family members had early hip fractures, and 3 affected individuals had low bone density.) Members of the LRP family are known to be important in bone development. For example, inhibition of LRP5 and LRP6 causes osteopenia in mice (Li J et al. Bone. 2006;39:754-766), and in humans, mutations in the LRP5 gene cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome, a disease hallmarked by severe visual impairment and osteoporosis (Gong Y et al. Cell. 2001;107:513-523). Cardiovascular effects have also been noted—for example, loss of expression of LRP5 contributes to elevated cholesterol levels and impaired glucose tolerance in mice (Fujino T et al. Proc Natl Acad Sci U S A. 2003;100:229-234). The mutation found in this study is extremely rare, however; investigators did not find it in 400 unrelated coronary artery disease patients in the United States and Iran.

While a mutation in LRP6 plays a major role in both coronary artery disease and osteoporosis in this particular family, the study's authors doubt that either condition causes or affects the other. "Instead, it's likely that these are independent consequences of an alteration in the same underlying signaling pathway," said principal investigator Richard Lifton, MD, PhD, of the Howard Hughes Medical Institute and Yale University School of Medicine, in New Haven, Conn.

WNT SIGNALING

That underlying signaling pathway, called Wnt, is made up of a complex network of proteins that play a role in embryonic development, cancer, and other processes. "Wnt signaling is one of those pathways that is used for many different functions throughout the body," said Lifton, adding that it plays a role in cell-to-cell interactions, particularly during development.

Experiments initiated by Arya Mani, MD, of Lifton's laboratory, revealed that the LRP6 mutation within the Iranian family causes an amino acid substitution in the encoded protein that compromises its function within the Wnt signaling pathway. LRP6's precise role and how things go awry when it is mutated are not known, however. "It's a classic scientific paradox—we know a genotype and we know a phenotype, but there's a black box in between," said Lifton.

Because of these latest findings, the Wnt signaling pathway will likely become a research target for understanding coronary artery disease and osteoporosis in some individuals. Lifton plans to study whether other mutations in the pathway might contribute to the metabolic syndrome and coronary artery disease. While many other variables influence the manifestation of these conditions, and alterations in the Wnt signaling pathway may come into play in only a minority of cases, the work might have therapeutic implications for some. "Down the road, one can think about whether one might be able to intervene in therapeutically useful ways in the Wnt signaling pathway," said Lifton. Specifically, scientists may be able to disrupt or increase the activity of various components of the pathway.

Lifton also plans to explore the curious link between coronary artery disease and osteoporosis, as others have suggested that the 2 conditions occur together more often than expected by chance (Marcovitz PA et al. Am J Cardiol. 2005;96:1059-1063). "This has not been widely studied at this point but it is a tantalizing observation that dovetails into the current study," said Lifton.