genes related to aging, obesity and myocardial infarction
TRANSCRIPT
Genes related to Aging, Obesity and Myocardial Infarction
Thet Su WinMTMT/D 5736940
Outline
Genes related to Aging
Genes related to Obesity
Genes related to Myocardial Infarction
Update article
Aging (becoming older) A process of physical, psychological and
social change Aging and longevity is differing in different
animal species (even in the different individuals)
Aging related genes
genes related to longevity and/or ageing in model organisms (yeast, worms, flies, mice, etc.)
ageing-related human genes
http://genomics.senescence.info/genes/
Examples of genes identified to influence lifespan in model organisms
Kuningas M. et al. Neurobiology of Aging. 2007; doi:10.1016/j.neurobiolaging.2007.07.001
Aging regulation in model animals
DAF2 mutations double the worm’s lifespan
Kenyon C.J. (2010) Nature; 464(25), 504-512
Kuningas M. et al. Neurobiology of Aging. 2007; doi:10.1016/j.neurobiolaging.2007.07.001
LMNA, WRN, ERCC8
http://genomics.senescence.info/genes/
LMNA LMNA is a gene encoded for structural protein
prelamin A. If mutation occurs, it will result in the
production of abnormal protein called progerin, which play a role in normal human aging.
Leads to premature aging like “progeria”.
Autosomal recessive disorders
(rapid aging disease)
WRN WRN lies on chromosome 8 in humans, which
encodes the WRNp. WRN protein has an important role in
responding to replication malfunctions, particularly double-stranded breaks.
More than 20 mutaions in WRN
WRN (continued) Mutations in WRN gene resulted in an abnormally
shortened WRNp protein. Cannot perform the tasks of replication and repair. Mutations in WRN gene cause Werner Syndrome.
Werner syndrome (WS), also known as "adult progeria”
is a rare, autosomal recessive progeroid syndrome (PS)
is characterized by the appearance of premature aging
ERCC8 ERCC8 is the DNA excision repair protein. encoded by ERCC8 gene. Mutations in this gene have been found in patients
with “Cockayne syndrome (CS)”.
Autosomal recessive congenital disorder growth failure impaired development
of nervous system abnormal
photosensitivity premature aging
Obesity Excessive amount of
body fat
Causes of obesity
Genes related to obesity
There are many genes related with obesity. The genes related to obesity are mainly
involved with the brain’s regulation of appetite.
OB gene and leptin
Genes in Melanocortin Pathway Melanocortin-4 receptor (MC4R) polymorphism Proopiomelanocortin (POMC) deficiency
FTO (fat mass and obesity associated) gene FTO protein α-ketoglutarate-dependent dioxygenase FTO Enzyme enconded by FTO gene Located on chromosome 16
genes that may be implicated in mediatingthe pathological consequences of obesity
Myocardial infarction
Causes of Myocardial Infarction
Myocardial
Infarction
Life style
Genetic
Others
Diseases
SmokingLack of exerciseJob stressDietary saturated fatDiabetes
mellitusHypertensionLDL↑HDL ↓TG ↑obesity
PCSK9 and LDLR LDLR is responsible for
removal of LDL from circulation
Mutation in LDLR gene stop the binding of LDL to the receptor and leads the accumulation of LDL in circulation.
PCSK9 degrade the LDLR . Gene silencing of PCSK9
increases expression of LDLR and decrease circulating cholesterol level.
ApoE and ApoB100
ApoE mutation
Structure defect of ApoE
Hypercholesterolemia
High levels of ApoB
ApoB100 mutation
MAI3 and other genes related to MI melanoma inhibitory activity 3 (MAI3) on chromosome 1 were identified to be associated
with coronary artery disease and myocardial infarction (MI).
the role of common variation at the MIA3 locus has not yet been investigated.
The following genes have an association with MI: SORT1, WDR12, MRAS, PHACTR1, LPA, TCF21, MTHFDSL, ZC3HC1, CDKN2A, 2B, ABO, PDGF0, APOA5, MNF1ASM283, COL4A1, HHIPC1, SMAD3, ADAMTS7, RAS1, SMG6, SNF8, SLC5A3, MRPS6, KCNE2
Erdmann et al. Dtsch Arztebl Int. 2010;107(40): 694-9
Update Article
Obesity
Objective of the study
Association of candidate genes in pathways related to food intake and energy expenditure with BMI
Materials and Methods
reanalysed 355 common genetic variants of 30 candidate genes in 7 molecular pathways related to obesity
Cand
idat
e ge
nes
Chung et al, Hum Hered. 2009;67:193- 205
Molecular Pathway Genes involved
Leptin Pathway LEP, LEPR, JAK2, SOCS3, STAT3
Melanocortin Pathway AGRP, MC4R, POMC, CPE
Ghrelin Pathway GHRL, GHSR
Glucagon-like peptide 1 Pathway GCG, GLP1R
Neuropeptide Y Pathway NPY1R, NPY5R
Serotonin Pathway HTR2A, HTR2C
Bardet-Biedl Group BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8
Gene wide association study (GWA)
GWA
Results
SNPs significantly associated with BMI
Genes significantly associated with BMI
Discussion - 1 GHRL is an endogenous peptide that stimulates
growth hormone secretion and enhances appetite. Polymorphisms in GHRL have previously been
reported to be associated with obesity in different both rs35682 and rs35683 were found to be
significantly associated with BMI on the basis of the individual SNP tests.
Because these two SNPs are closely located (within 600 base pairs) in intron 2 and intron 3
they are highly correlated
Discussion - 2 AGRP is an endogenous antagonist of
melanocortin signalling therefore stimulates appetite. The SNP rs5030980, causing the Thr67Ala
mutant, was shown to have a significant association with BMI.
Discussion - 3 CPE is an enzyme that functions in the production
and activation of many neuropeptides and peptide hormones.
Two SNPs (rs1946816 and rs4481204) were found to be associated with BMI in the European American population.
In fact, some previous studies have shown that a single-point mutation in the CPE gene is sufficient to cause multiple disorders in animals, including obesity.
In addition, other studies have reported an association of the CPE gene with human obesity and diabetes
Discussion - 4 Neuropeptide Y and neuropeptide Y receptor
(NPY1R and NPY5R) have a key role in the physiological control of energy homeostasis.
It has been reported that polymorphisms in NPY5R are associated with obesity in a European American population.
The effects of individual variants in NPY1R also shows a significant gene effect.
Conclusion AGRP, CPE, GHRL and NPY1R are directly
associated with increased BMI. SNPs in AGRP, CPE, GHRL, NPY5R, GLP1R,
HTR2A, SOCS3 and STAT3 are also significantly associated with BMI
New obesity related genes are found out from this study.
Underlying mechanism of these association requires further investigation.
References1. Kenyon CJ. The genetics of ageing. Nature.
2010;464(25):504-512.2. Kuningas M, Mooijaart SP, Jolles J, Slagboom PE, Westendorp
RGJ, Heemst DV. VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiology of Aging. 2007; doi:10.1016/j.neurobiolaging.2007.07.001
3. Erdmann J, Linsel-Nitschke P, Schunkert H. Genetic Causes of Myocardial Infarction. Dtsch Arztebl Int. 2010;107(40):694-699.
4. Chung W.K, Patki A. Matsuoka N, Boyer BB, Liu N, Musani SK, Goropashnaya AV, Tan PL, Katsanis N, Johnson SB, Gregersen PK. Allison DB, Leibel RL, Tiwari HK. Analysis of 30 Genes (355 SNPS) Related to Energy Homeostasis for Association with Adiposity in European-American and Yup’ik Eskimo Populations. Hum Hered 2009;67:193–205.