Genetic variants in adipose triglyceride lipase influence lipid levels in familial combined hyperlipidemia

Atherosclerosis. 2010 Nov;213(1):206-11. doi: 10.1016/j.atherosclerosis.2010.08.055. Epub 2010 Aug 19.


Objective: Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Methods: Four SNPs within the PNPLA2 gene (rs7925131, rs7942159, rs66460720 and the nonsynonymous P481L) were selected based on previous association with decreased plasma levels of free fatty acids (FFA) and total triglycerides (TG) and their high frequency (MAF>0.25). These SNPs were genotyped in 214 FCHL individuals from 83 families and in 103 controls and the corresponding haplotypes were reconstructed.

Results: No association between individual SNPs and the FCHL trait was observed. However, two PNPLA2 haplotypes were associated with lower risk of FCHL (P<0.004 after Bonferroni's correction). Compared to the others, these haplotypes were related to lower TG (118.9 ± 66.8 vs. 197.1 ± 114.7 mg/dl; P=0.001) and higher HDL-C (62.3 ± 15.8 vs. 51.0 ± 15.0 mg/dl; P<0.005). In a subgroup of studied subjects (n=63) protective haplotypes were also associated with lower FFA levels (0.33 ± 0.11 vs. 0.46 ± 0.18 mEq/L; P<0.05). These effects were independent from age, BMI and HOMA(IR).

Conclusion: These data demonstrate that variants within PNPLA2 may modulate the TG component of FCHL trait, thus implicating PNPLA2 as modifier gene in this lipid disorder. They also suggest a potential role of PNPLA2 in the metabolism of TG-rich lipoproteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cohort Studies
  • Family Health
  • Fatty Acids / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Haplotypes
  • Humans
  • Hyperlipidemia, Familial Combined / blood*
  • Hyperlipidemia, Familial Combined / genetics*
  • Lipase / genetics*
  • Liver / metabolism
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk


  • Fatty Acids
  • Lipase
  • PNPLA2 protein, human