Faculty Bibliography

Family history is a major risk factor for myocardial infarction (MI). However, known gene variants associated with MI cannot fully explain the genetic component of MI risk. We hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. We studied 11,053 single-nucleotide polymorphisms (SNPs) in 6,891 genes, focusing on SNPs that could influence gene function to increase the likelihood of identifying disease-causing gene variants. To minimize false-positive associations generated by multiple testing, two studies were used to identify a limited number of nominally associated SNPs; a third study tested the hypotheses that these SNPs are associated with MI. In the initial study (of 340 cases and 346 controls), 637 SNPs were associated with MI (P<.05); these were evaluated in a second study (of 445 cases and 606 controls), and 31 of the 637 SNPs were associated with MI (P<.05) and had the same risk allele as in the first study. For each of these 31 SNPs, we tested the hypothesis that it is associated with MI, using a third study (of 560 cases and 891 controls). We found that four of these gene variants were associated with MI (P<.05; false-discovery rate <10%) and had the same risk allele as in the first two studies. These gene variants encode the cytoskeletal protein palladin (KIAA0992 [odds ratio (OR) 1.40]), a tyrosine kinase (ROS1 [OR 1.75]), and two G protein-coupled receptors (TAS2R50 [OR 1.58] and OR13G1 [OR 1.40]); all ORs are for carriers of two versus zero risk alleles. These findings could lead to a better understanding of MI pathophysiology and improved patient risk assessment.

PURPOSE/OBJECTIVES: To describe knowledge of hereditary, familial, and sporadic breast cancer risk factors among women in the community and to identify characteristics associated with this knowledge. DESIGN: Descriptive, cross-sectional. SETTING: Community settings in the San Francisco Bay Area. SAMPLE: 184 women who had never been diagnosed with cancer, were 30-85 years old (mean = 47 + 12), and agreed to complete a questionnaire in English. Participants were from diverse racial and cultural backgrounds (i.e., 43% European descent, 27% African descent, 16% Asian descent, and 14% Hispanic descent). Many (49%) were college graduates, and 24% had a median annual family income of $30,000-$50,000. METHODS: Survey. MAIN RESEARCH VARIABLES: Knowledge of hereditary, familial, and sporadic breast cancer risk factors and characteristics associated with this knowledge. FINDINGS: Although most women recognized heredity as a risk factor, some did not understand the impact of paternal family history on risk. Some women did not recognize the relationship between breast and ovarian cancer, risk factors associated with the Gail model, and that aging increases risk. Education level was the most important characteristic associated with knowledge of risk factors. CONCLUSIONS: Although age and family history are independent predictors of sporadic, hereditary, and familial breast cancer risk, women in the community could not distinguish between the three forms of the disease. Although the sample included a large number of educated women, their knowledge of breast cancer risk factors appeared incomplete. IMPLICATIONS FOR NURSING: Advanced practice nurses should provide individualized risk assessment and education regarding breast cancer risk factors.

More than 24,000 women in the United States are diagnosed with ovarian cancer every year, and half of these women die from their disease. Stage 1 ovarian cancer is curable in 95% of cases; however, due to inadequate screening tools and lack of symptoms in early disease, ovarian cancer is generally at Stage 3 or 4 when finally diagnosed. CA125 is a tumor antigen used to monitor the progression and regression of epithelial ovarian cancer. When its levels are elevated postsurgery (hysterectomy/salpingo-oophorectomy with or without peritoneal washings and lymph node biopsy) and postchemotherapy, it is suggestive of recurrent disease. Due to its similarly elevated levels in some nonmalignant conditions, however, it is not specific enough to be used for population screening. The CA125 molecule is considered a very large glycoprotein because of its molecular weight, and it has three domains: the carboxy terminal domain, the extracellular domain, and the amino terminal domain. MUC16 is the gene that encodes the peptide moiety of the CA125 molecule. MUC16 domains provide novel opportunities to develop new assays and refine current tools to improve the sensitivity and specificity of CA125 for population-based screening guidelines.

Apolipoprotein E (APOE) polymorphism plays an important role in lipid metabolism. Preliminary evidence suggests that APOE genotype appears to be a risk factor for not only cardiovascular disease, but also Alzheimer's disease and cancer. We screened the APOE genotype in 290 breast cancer patients and 232 non-cancer controls and determined the relationship between APOE gene polymorphism and breast cancer in Taiwan. We found risk for breast cancer was associated with the APOE genotype (xi(2) = 8.652, p = 0.013). Carriers of the epsilon4 allele were more common in breast cancer cases than carriers of epsilon3 allele (p = 0.004, OR = 1.786, 95% CI: 1.197-2.664). In addition, the epsilon4 allele is also associated with HER2/neu negative status in breast cancer patients (p = 0.006, OR = 0.277, 95% CI: 0.111-0.693). No significant associations between APOE genotype and tumor grade, TN classification, progesterone receptor, estrogen receptor, lymphatic invasion, or recurrence of breast cancer were in evidence. These results suggest that the APOE epsilon4 allele may be a risk factor for breast cancer and correlates with HER2/neu negative status.

HM74 (GPR109B) and the highly homologous gene, HM74A (GPR109A) code for Gi-G protein-coupled orphan receptors that recently have been discovered to be involved in the metabolic effects of niacin. The B vitamin niacin is an important agent used in the treatment of dyslipidemias, but its use is limited by side effects. The novel role of the adjacent HM74 and HM74A genes in the metabolism of niacin may provide new targets for drug development. Human genetic variations in HM74 and HM74A have been reported but have not been studied in detail. These variations may play a role in the response to agents targeting receptors coded by these genes. Here we show that many of the nonsynonymous SNPs listed in public databases for HM74 and HM74A are artifacts resulting from extensive homology between these two genes. This may be representative of a neglected phenomenon in reporting sequences of highly homologous genes. We provide primer sequences that permit selective amplification of the complete coding regions of HM74 and HM74A. Using these primers, we show that subsequent sequencing of HM74 and HM74A reveals a novel and unique variation in the HM74A gene. Haplotype analysis suggests four SNPs can define the five major haplotypes that lie within a single haplotype block encompassing these two genes.

Thoracic aortic aneurysm and dissection (TAAD) is associated with high mortality and medical expense. These poor outcomes are preventable by surgical repair; however, identifying at-risk individuals is difficult. Researchers are actively surveying the human genome (the repository of human genes) to characterize the genetic determinants of TAAD by identifying chromosomal regions likely to harbor such predisposing genes. In previous studies, investigators identified genetic markers shared by a subset of families who were ascertained to have the disease, which clustered into 2 chromosomal regions: 5q13-q15 (TAAD1) and 11q23.2-q24 (familial aortic aneurysm [FAA1]). In a subsequent study, a third chromosomal region at 3p24-25 (TAAD2) was found to contribute to TAAD in a 4-generation, 52-member family that displayed little evidence of sharing either the TAAD1 or FAA1 regions. Although additional regions of the genome may contribute to TAAD, investigators are focusing their efforts on identifying the actual genes and the specific mutations that participate in the disease process. The goal of these endeavors is to develop screening tests to identify individuals at risk for familial TAAD. This genetic discovery has significant clinical implications because high-risk individuals and families can be closely monitored and can benefit from preventative surgical repairs.