SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women.
Insulin regulates apoB metabolism via activation of PI3K or regulation of MTP via MAPK/ERK signalling. SHP-2 enhances both pathways through increased IRS-1 phosphorylation. We hypothesized that variants in the SHP-2 gene PTPN11 and PI3K p85alpha subunit gene PIK3R1 may influence fasting levels of plasma apoB and/or LDL cholesterol. We tested association of tagging SNPs (tSNPs) in each gene with serum lipids in a large sample of unselected population-based Caucasian female twins (n=2771, mean age 47.4+/-12.5 years) and then tested interaction between tSNPs in determining apoB and LDL levels. PTPN11 tSNP rs11066322 was associated with apoB (P=0.007) and rs11066320 was associated with LDL cholesterol (P=0.016). PIK3R1 tSNP rs251406 was associated with apoB (P=0.0003) and rs706713 was associated with LDL cholesterol (P=0.009). PTPN11 tSNP rs11066322 interacted with PIK3R1 tSNP rs251406 in determining serum apoB levels (P=0.012) and with PIK3R1 tSNP rs40318 in determining LDL cholesterol levels (P=0.009). Association of single tSNPs with both apoB and LDL cholesterol as well as interactions between the two genes suggest that variants influencing SHP-2 activity may modulate the acute pathway by which insulin regulates these lipids.
Jamshidi
Y
Y
Nutrition Food and Health Research Centre, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
Gooljar
S B
SB
Snieder
H
H
Wang
X
X
Ge
D
D
Swaminathan
R
R
Spector
T D
TD
O'Dell
S D
SD
D000328:Adult; D001055:Apolipoproteins B / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D014427:Twins / Q000235:genetics
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D019869:Phosphatidylinositol 3-Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11