Exam 3 Main Points Flashcards
First successful GWA study
Age-related macular degeneration
Other successful GWA study
Chron’s disease
GWA and inflammatory bowel diseases
GWA only showed a small part of genetic variance in inflammatory bowel disease.
SLCO1B1
A variant of a chromosome associated with statin-induced myopathy.
Problems with GWAs
Etiology of genes questionable
Difficulty of finding relevant gene
Low penetrate
Identified region far away from actual gene.
Changes in _ rather than changes in _ underlie most GWA associations.
Changes in gene regulation rather than changes in proteins underlie most GWA associations.
CDRV
GWAs will not identify rare variants in most cases.
T1D and HLA - what form is the highest risk
D3/DR4. At least 1 allele present in 95% of patients with TD
T1D and VNTR (INS)
Short (26 - 63 repeats) predispose to T1D
Long (140 - 210 repeats) are protective of B cells.
Concordance of T1D
Concordance of 50% of monozygotic twins, environmental factors are important.
T2D and concordance
70%
Best predictor for T2D
Insulin resistance
TCF7L2
First important gene identified in T2D. Associated with impaired beta cell function, but not with insulin resistance.
T allele of rs7903146
Enhances expression of TCF7L2 -> impairs insulin secretion.
SLC30A8 (zinc transporter)
Confers T2D risk in addition to TCF7L2 gene.
T2D: most of the genes identified by GWAs apppear to be involved in
Beta cell dysfunction than insulin resistance.
T2D: 80-90% SNPs are
Intergenic/intrionic
T2D: common variants contribute more than
Rare variants
Features of MODY
Early onset No autoimmune disorder/antibodies No insulin resistance Low insulin Absence of obesity
Major classes of cancer genes
Oncogenes Tumor suppressor (TS) genes
Tumor suppressor (TS) genes
Gatekeepers
Caretakers
Number of mutations needed in TS genes to show phenotype
Mutations are recessive; function of both alleles must be lost to be cancerous.
Function of TS cells
Block uncontrolled cell growth
Cell adhesion molecules
Negative regulators of cell cycle
Repair of mutations in DNA
RB1 (cancer)
Controls cell proliferation and binds E2F (required for cell cycle progression).
Hyper phosphorylated RB1 (cancer)
Inhibits transition from G1 to S. Increased phosphorylation -> E2F released -> cell can go into S phase.
In the absence of RB1
E2F not repressed -> cells undergo more cell divisions
Caretaker TS genes encode
Proteins to detect and repair DNA
Proteins involved in normal chromosome disjunction
Programmed cell death machinery
Examples of caretaker TS genes
BRCA1 & 2 - involved in cellular response to dsDNA breaks.
Tp53 gatekeeper
“Guardian of the genome”
Activates DNA repair proteins
Holds cell at G1/S cell cycle checkpoint
Can initiate apoptosis
Mutation of Tp53 gatekeeper genes
DNA not repaired, cell cycle not arrested.
EAOD inheritance
Autosomal dominant.
WES and EOAD
Sorting protein related receptor gene SORL1.
Number of genes associated with LOAD
20 genes, including TREM2
APOE4
Strongest genetic risk factor for AD; also decreases age of onset.
APOE4 amino acids
Arginine, arginine
APOE3 amino acids
Cysteine, arginine
APOE4 is not sufficient to
Predict disease status. Not all APOE4 homogzygotes develop AD.
