Fine mapping of the insulin-induced gene 2 identifies a variant associated with LDL cholesterol and total apolipoprotein B levels.
BACKGROUND
In a whole-genome scan, a single nucleotide polymorphism (SNP) (rs7566605) upstream of the insulin-induced gene 2 (INSIG2) was shown to influence body mass index and obesity in the Framingham Heart Study, with replication of these results in an additional 4 of 5 studies. However, other studies could not replicate the association. Because INSIG2 plays an important role in cholesterol biosynthesis, we hypothesized that human INSIG2 variants might play a role in the regulation of plasma lipid and lipoprotein levels.


RESULTS
We selected tagging SNPs spanning >100 kb of INSIG2 locus and sequenced 18 434 base pairs to discover novel SNPs. Thirty-two SNPs were genotyped in 645 individuals from the Quebec Family Study. Two SNPs (rs10490626 and rs12464355) were associated with plasma low-density lipoprotein cholesterol (LDL-C) (P<0.0015) and total apolipoprotein B (apoB) levels (P<0.014), whereas no association was found between any SNP and body mass index. We replicated the finding of rs10490626 for both LDL-C and total apoB in additional study samples, including 758 individuals from Saguenay-Lac St. Jean, Quebec (P=0.040 for LDL-C, P=0.044 for apoB), 3247 Europeans (P=0.028 for LDL-C, P=0.030 for apoB), and 1695 South Asians (P=0.0036 for LDL-C, P=0.034 for apoB) from the INTERHEART study (for LDL-C, the combined 2-sided P=6.2×10⁻⁵ and for total apoB, P=0.0011). Furthermore, we identified a variant in the human sorbin and SH(3)-domain-containing-1 gene that was associated with INSIG2 mRNA levels, and this SNP was shown to act in combination with rs10490626 to affect LDL-C (P=0.022) in the Quebec Family Study and in INTERHEART South Asians (P=0.019) and Europeans (P=0.052).


CONCLUSIONS
These results suggest that INSIG2 genetic variants may have a more direct role in lipid and lipoprotein metabolism than in obesity.
Do
Ron
R
Department of Human Genetics, McGill University, Montreal, Canada.
Bailey
Swneke D
SD
Paré
Guillaume
G
Montpetit
Alexandre
A
Desbiens
Katia
K
Hudson
Thomas J
TJ
Yusuf
Salim
S
Bouchard
Claude
C
Gaudet
Daniel
D
Pérusse
Louis
L
Anand
Sonia
S
Vohl
Marie-Claude
MC
Pastinen
Tomi
T
Engert
James C
JC
D000328:Adult; D000818:Animals; D001055:Apolipoproteins B / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D002874:Chromosome Mapping / Q000379:methods*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; C432967:SORBS1 protein, human