Genetic analysis of familial breast and ovarian cancer indi cates that BRCA1 is a tumor suppressor gene. The BRCA1 gene encodes a 190 kDa protein with Sequence homology and biochemical analogy to the granin family of proteins. Granins are Secreted from endocrine cells via the regulated Secretory pathway and are proteolytically cleaved to yield biologically active peptides. BRCA1 protein localizes to Secretory vesicles, and was demonstrated to be Secreted. Gene transfer of BRCA1 inhibits growth and tumorigenesis of breast and ovarian cancer cells, but not colon or lung cancer cells or fibroblasts, Suggesting that BRCA1 encodes a tissue-specific growth inhibitor. Thus, BRCA1 is a Secreted growth inhibitor and functions by a mechanism not previously described for tumor Suppressor genes. The BRCA2 breast and ovarian cancer gene encodes a protein that also includes a granin region, indicating that the BRCA2 protein is also a Secreted tumor Suppressor. Therapeutic methods using the BRCA1 and BRCA proteins and genes are also described. A method of Screening for the receptors of the BRCA1 protein and BRCA2 proteins is also described.

Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34–37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25–26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34–37, 9q21, 10q25–26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.