Fine mapping of the insulin-induced gene 2 identifies a variant associated with LDL cholesterol and total apolipoprotein B levels

Ron Do, Swneke D. Bailey, Guillaume Pare, Alexandre Montpetit, Katia Desbiens, Thomas J. Hudson, Salim Yusuf, Claude Bouchard, Daniel Gaudet, Louis Pérusse, Sonia Anand, Marie Claude Vohl, Tomi Pastinen, James C. Engert

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 SH3-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.

Original languageEnglish
Pages (from-to)454-461
Number of pages8
JournalCirculation: Cardiovascular Genetics
Volume3
Issue number5
DOIs
StatePublished - Oct 2010
Externally publishedYes

Keywords

  • Cholesterol
  • INSIG2
  • LDL cholesterol
  • Single nucleotide polymorphism
  • Total apoB

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