KELOMPOK II

Pendahuluan
Terjadinya peningkatan
resiko CAD (Coronary
Artery Disease)

Suatu varian DNA pada Kromosom

1p13peningkatan resikonya mencapai 29% per
alel
Kromosom 1p13
Gen pada kromosom 1p13 CAD
dikaitkan dengan peningkatan kadar LDL
dan VLDL (kolesterol)

Bagaimana mekanisme nya???

Basic research carried out
by Musunuru et al
Kromosom 1p13

Modulasi berbagai gen oleh alel yang

mengalami kerusakan pada kromosom 1p13
diperkirakan mempengaruhi Regulator
Element VLDL dan LDL tinggi
CAD
Kromosom 1p13
SNP (Single Nucleotide Polymorphism)
SNP Perubahan satu nukleotida pada
varian sekuen DNA
Terjadi mutasi pada
mikrosatelitMenyebar disepanjang 23
pasang kromosom manusia frekuensinya
kira-kira > 1%
Kombinasi SNP di sepanjang
kromosomHaplotype
Map of 1p13 SNPs genotyped in ~20,000 individuals of
European descent relative to CELSR2 and PSRC1 genes.
The six SNPs with strongest association with LDL
(indicated with boxes),
Musunuru, et al. (2010):
determined that a noncoding polymorphism SNP rs12740374 in 1p13 impacts
a transcription factor binding site that alters hepatic expression of SORT1.
The risk allele G in rs12740374 disrupts the C/EBP transcription factor
binding site and is significantly associated hepatic expression of SORT1
C/EBP (CAAT Enhancer Binding Protein

The PPARg and C/EBP

family of transcription
factors are
considered as the master
regulators of
adipogenesis
(Experimental Biology
and Medicine)
 the G (risk) allele of rs12740374
disrupts a binding site for the
transcription factor
CCAAT/enhancer binding
protein (C/EBP).
This in turn leads to reduced
expression of sortilin 1 (SORT1)
and less sortilin 1 protein.
Sortilin 1 is an intracellular
protein localized in the in the
Golgi apparatus, where it is
involved in the processing of
particles containing
apolipoprotein
Sortilin 1 Receptor decreased
leads to increased levels VLDL
and LDL cholesterol in the
blood and increased risk of
coronary disease.
Mechanism of Sortilin 1 :new player in lipoprotein
metabolism
Sort 1 interacts with APO-B in the Golgi and facilitates the formation and
hepatic export of VLDL lipoproteinsthereby regulating plasma LDL
concentration
Kjolby et
Sort 1 overexpression stimulated hepatic release of lipoproteins and
al increased plasma LDL

Inverse relationship between Sort1 1 expression and circulating LDL

cholesterol.
Musunuru Sort 1 in mice decreased serum LDL cholesterol whereas knockdownhad
et al. opposite effect

Sort 1 enhanced LDL endocytosis

Linsel-
Nitschke
Mechanism of Sortilin 1 :new player in lipoprotein
metabolism
SEKIAN & TERIMA
KASIH
MATUR NUUN