Fine Mapping of the Insulin-Induced Gene 2 Identifies a Variant Associated With LDL Cholesterol and Total Apolipoprotein B Levels
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abstract
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.
Methods and 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).
Conclusion—
These results suggest that
INSIG2
genetic variants may have a more direct role in lipid and lipoprotein metabolism than in obesity.
