Pathogenesis Review Lecture Review September 15, 2014 Mariel Arvizu, MD Doctoral Student Harvard School Public Health

Examples of Genes and Disease Breast Cancer : BRACA1 and BRACA2 – approximately 10% of cases Mutations: Sickle cell anemia Diabetes type 1 and Diabetes NOTE: genes load the gun, lifestyle pull the trigger…a genetic mutation alone rarely causes cancer.

Sickle Cell Anemia: one gente mutation causes disease

Genes influence breast cancer risk but other factors are also involved

Type of Cancer General Population That Will Develop Disease Women With BRCA1 or BRCA2 Mutation Who Will Develop Disease Breast13.2%36-85% Ovarian1.7% 16-60% Source: National Cancer Institute ( BRCA2 is also associated with increased risk of prostate cancer, male breast cancer, and pancreatic cancer. BRCA genes and increased cancer risk

Long-term Changes in Gene Expression: Epigenetics Altered expression of genes based on environment during critical periods of development. Can explain discrepancy between genotype (what genes you have) and phenotype (what characteristics you express). Can be persist for generations May also explain why adult lifestyle and genetic background alone fail to predict who is at greatest risk of heart disease and other conditions.

DNA Methylation One mechanism of epigenetic change

Studies of people who were in early gestation during the Dutch Famine showed a –higher risk of obesity –higher levels of lipids in the bloodstream –3-fold higher risk of cardiovascular disease than people who were not exposed to the famine. Also: higher risk of schizophrenia and addictions.

Some ethnic differences (eg: the tendency of Asians to have higher body fat content at a given BMI), probably result from a mix of genetic and epigenetic factors. YudkinYajnik

What do we mean by malnutrition? A diet deficient in essential nutrients. A diet too low or too high in calories.

Malnutrition weakens defenses against many kinds of diseases.

Injury and Toxicity Significance depends on tissue involved. Eg: liver vs. neural tissue Significance also depends on “safety factor” of organ involved.

Biological Safety Factors (ratio of capacity to load) Human Pancreas (enzyme secretion) –About 10 Human Kidney (plasma filtration) –About 4 Human Mammary Gland (milk production) –About 3 Mammalian Lungs (aerobic capacity) –About From: Jared Diamond “Quantitative Evolutionary Design’ J. Physiol 2002, 542:

Inflammation

Increased blood flow to affected area Increased capillary permeability Movement of phagocytic cells into site of injury

Necrosis vs Apoptosis

Example of Apoptosis: Ischemic Stroke