1MCB140, 17-01-07 1MCB 140 – GeneticsMCB140, 17-01-07 2And quite soon, young women will come home from the hospital with their newborn babies in countries with good health systems with little gene cards that will say, ‘Here are your child’s strengths and weaknesses, and if you do the following ten things your baby has a life expectancy of 93 years.’ This is going to happen in the lifetimes, and in the childbearing lifetimes of those young people in this audience.”President Clinton Comes to Cal (Jan. 29, 2002)“I was honored to be president at the time when the International Consortium of Scientists finished the sequencing of the human genome, something which has already yielded the two major variances that are high predictors of breast cancer, something that is leading us very close to unlocking the genetic strains that cause Parkinson’s and Alzheimer’s.MCB140, 17-01-07 3www.genelex.com – listed solely for reference purposes, and does not imply an endorsement of any sort.MCB140, 17-01-07 4Insulin SensitivityPPAR2Heart Health; Insulin SensitivityACEInflammation; Bone HealthTNFaHeart Health; Inflammation; Bone HealthIL-6Bone HealthCOL1A1Bone HealthVDRHeart Health; Antioxidant Activity SOD3Heart Health; Antioxidant ActivityMnSODDetoxification; Antioxidant ActivityGSTP1Detoxification; Antioxidant ActivityGSTT1Detoxification; Antioxidant ActivityGSTM1Heart Health; Vitamin B UseCBSHeart Health; Vitamin B Use MS-MTRRHeart Health; Vitamin B Use MTRHeart Health; Vitamin B UseMTHFRHeart HealtheNOSHeart HealthLPLHeart HealthCETPHeart HealthAPOC3Area of ActivityGene Namewww.genelex.com – listed solely for reference purposes, and does not imply an endorsement of any sort.“Apolipoprotein C-III gene (APOC3)APOC3 plays an important role in lipid metabolism. It inhibits the break down of triacylglycerol, a lipid, by the enzyme lipoprotein lipase; leading to higher triglyceride levels (hypertriglyceridemia). The polymorphism 3175G is associated with a four-fold risk of hypertriglyceridemia and is linked to an increased risk of heart attack, atherosclerosis and cardiovascular disease.” (emphasis mine – fdu)MCB140, 17-01-07 5The complexity of the truth(stay tuned for Prof. Brem’s lecture, #35)1. SNP2. Haplotype3. Linkage disequlibrium4. “Tags informative for multiple proxies”! the very significant scientific problem all of this – put together –creates for using linkage data as a tool for generating “nutrigenomics” guidelines based on a particular individual’sgenotype at a particular SNP.For now, read:1. Naukkarinen et al, Curr. Opin. Lipidol. 17(3), p 285–290 (not required); 2. Haga and Willard Nature Reviews Cancer 206 – requiredPubMedMCB140, 17-01-07 6A fact, and a problemFact: what we do is a function of what we know (and many other things, of course).Problem: our knowledge comes in shades of gray, but actions tend to be black-and-white.2MCB140, 17-01-07 7Five percent of 178,700 “Germline mutations in BRCA1 confer a 56%-80% lifetime risk for breast cancer and a 15%-60% lifetime risk for ovarian cancer in women.”Dapic V, Monteiro AN. Crit Rev Eukaryot Gene Expr. 2006;16(3):233- 52.MCB140, 17-01-07 8Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%.Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.King et al. Science. 2003 Oct 24;302(5645):643-6 MCB140, 17-01-07 9The complexity of the truth, part II(stay tuned for Prof. Brem’s lecture, #31)1. QTL2. Epistasis3. Environmental vs. genetic variance4. Norm of reaction 5. Narrow- sense v. broad- sense heritability! the very significant scientific problem all of this creates for generating treatment guidelines based on a particular individual’s genotype for a “cancer susceptibility locus.”MCB140, 17-01-07 10www.myriadgenetics.com – listed solely for reference purposes, and does not imply an endorsement of any sort.MCB140, 17-01-07 11 MCB140, 17-01-07 123MCB140, 17-01-07 13Forward PCR primer: AAATTATTGAGCCTCATTTATTTTCReverse PCR primer: AAACAAAAGCTAATAATGGAGCNote: the SNP shown is not 185delAG. MCB140, 17-01-07 14A proper description of how this is done:http://www.myriadtests.com/provider/doc/BRACAnalysis-Technical-Specifications.pdfMCB140, 17-01-07 15Prophylactic bilateral mastectomy (and/or oopherectomy) for BRCA1/2 mutation carriers“A study of 139 women with deleterious BRCA1 or BRCA2 mutations who were followed at the Rotterdam Family Cancer Clinic. To reduce their risk of breast cancer, 76 of these women chose to undergo prophylactic bilateral mastectomy, whereas the remaining 63 were followed according to a surveillance protocol consisting of a monthly breast self-examination, a semiannual breast examination by a health care professional, and annual mammography. … No breast cancers were observed in the 76 women who underwent prophylactic bilateral mastectomy, whereas eight were detected in the surveillance group. This study … supports the report by Hartmann et al. that prophylactic bilateral mastectomy has an efficacy of at least 90 percent in women classified as at high risk on the basis of a family history of breast cancer. Together [these studies] suggest that of the strategies to reduce the risk of breast cancer in high-risk women, prophylactic bilateral mastectomy is the most effective.Two decades of research have convincingly shown that most women with breast cancer can safely be treated with breast-conserving surgery instead of mastectomy. Thus, it is difficult to accept that prevention should be more extreme than the cure. In this era of molecular medicine, we strive for cancer-prevention options that are more targeted and less invasive than surgical extirpation. Chemoprevention for breast cancer that is as effective and safe as prophylactic bilateral mastectomy is a hope for the future.”Andrea Eisen and Barbara Weber (2001) NEJM 345: 208MCB140, 17-01-07 16People with insufficient education in genetics AND statistics and not enough time to look at the primary data1. Policymakers.2. Health insurance company officials.3. Health care providers (i.e., physicians).4. Journalists who write about science and medicine for major newspapers.5. The patients themselves.Policy:Data:MCB140, 17-01-07 17A complicated truthMCB140, 17-01-07 18Living With Our GenesD. Hamer and P. Copeland
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