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.