Keywords >>> Genes, Aging, Obesity, Myocardial Infarct

1. Genes related to Aging, Obesity
and Myocardial Infarction
Thet Su Win
MTMT/D 5736940

2. Outline
 Genes related to Aging
 Genes related to Obesity
 Genes related to Myocardial Infarction
 Update article

3. 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)

4. 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/

5. Examples of genes identified to influence lifespan
in model organisms
Kuningas M. et al. Neurobiology of Aging. 2007; doi:10.1016/j.neurobiolaging.2007

6. Aging regulation in model animals

7. DAF2 mutations double the worm’s lifespan
Kenyon C.J. (2010) Nature; 464(25), 504-

8. Kuningas M. et al. Neurobiology of Aging. 2007; doi:10.1016/j.neurobiolaging.2007

9. LMNA, WRN, ERCC8
http://genomics.senescence.info/genes/

10. 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)

11. 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

12. 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

13. 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

14. Obesity
 Excessive amount of body
fat

15. Causes of obesity

16. 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.

17. OB gene and leptin

18. Genes in Melanocortin Pathway
 Melanocortin-4 receptor (MC4R) polymorphism
 Proopiomelanocortin (POMC) deficiency

19. FTO (fat mass and obesity associated) gene
 FTO protein
 α-ketoglutarate-dependent dioxygenase FTO
 Enzyme enconded by FTO gene
 Located on
chromosome 16

20. genes that may be implicated in mediating
the pathological consequences of obesity

21. Myocardial infarction

22. Causes of Myocardial Infarction
Myocardial
Infarction
Life style
Genetic
Others
Diseases
Smoking
Lack of exercise
Job stress
Dietary saturated fat
Diabetes
mellitus
Hypertension
LDL↑
HDL ↓
TG ↑
obesity

23. 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

24. ApoE and ApoB100
ApoE mutation
Structure defect of
ApoE
Hypercholesterolemia
High levels of ApoB
ApoB100 mutation

25. 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-

26. Update Article

27. Obesity

29. Objective of the study
 Association of candidate genes in pathways related
to food intake and energy expenditure with BMI

30. Materials and Methods
 reanalysed 355 common genetic variants of 30
candidate genes in 7 molecular pathways related to
obesity

31. Candidategenes
Chung et al, Hum Hered. 2009;67:193-

32. 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

33. Gene wide association study (GWA)

34. GWA

35. Results
SNPs significantly associated with BMI

36. Genes significantly associated with BMI

37. 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

38. 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.

39. 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

40. 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.

41. 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.

42. References
1. 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