Genetic variants in adipose triglyceride lipase influence lipid levels in familial combined hyperlipidemia
Introduction
Familial combined hyperlipidemia (FCHL) is the most prevalent genetic lipid disorder and confers a substantially increased risk of premature coronary artery disease (CAD) [1]. The genetic defect underlying this hyperlipidemia is presently unknown. Three susceptibility loci and numerous genetic variants affecting FCHL lipid expression have been identified [2] although the total number of variants and their relative contributions to the disease susceptibility are not known yet.
Several investigators have proposed that the impaired metabolism of FFA is the common determinant of metabolic disorders associated with FCHL [3], [4], [5]. There are in fact, direct demonstrations that the increased influx of FFA into the liver may cause the VLDL-apoB overproduction which is the typical abnormality of FCHL [4], and that changes in serum FFA levels could explain the impaired glucose metabolism occurring in these patients [6]. Blood FFA concentration is determined primarily by the balance between the lipolytic activity and the rate of triglyceride re-esterification in adipocytes [7]. Therefore, investigations on genetic factors regulating the lipolytic activity may provide useful insights into the genetic background of FCHL.
FFAs are released from lipid storage tissues in fasting or energy-demanding states by lipolytic enzymes. Recent studies have definitively indicated that the adipose triglyceride lipase (also defined as patatin-like phospholipase domain containing-2 or PNPLA2) plays a pivotal role in the mobilization of fat stores by catalyzing the initial step of the breakdown of intracellular triglycerides (TGs) [8], [9], [10], [11]. Consistently with this mechanism, mice lacking PNPLA2 (atgl−/−) as well as patients with defective PNPLA2 activity showed impaired degradation of cytoplasmic TGs [9], [12], [13]. In addition, atgl−/− mice exhibited reduced plasma FFA concentrations in both the fed and the fasted state [12].
In searching whether genetic variations in the PNPLA2 gene might influence fatty acid metabolism, Schoenborn et al. [14] reported several single nucleotide polymorphisms (SNPs) associated with lower FFA and plasma TGs concentrations. Although these Authors did not provide direct evidence of the functional impact of these SNPs, their data clearly suggest that these sequence variations may be markers of a lower activity of PNPLA2.
The possibility that a disorder could be explained, at least in part, by either enrichment of predisposing genetic variations or depletion of protective ones [15] led to our interest in examining the later in FCHL. Therefore, we performed a case–control study to evaluate whether there was a significant depletion in allelic, genotypic or haplotype frequencies of four SNPs in PNPLA2, previously identified to be associated with lower FFA and TG levels [14]. It was a secondary goal to elucidate the impact of these genetic variants on the lipid phenotypic expression of FCHL to establish a possible role of PNPLA2 as a modifier gene for FCHL.
Section snippets
Study subjects
Eighty-three Italian families with FCHL were enrolled in the study. They were identified through probands (>20 years old) (n = 83) diagnosed based on the presence of untreated TC and/or TG levels above the age- and sex-specific 90th percentile for the Italian population, and/or isolated elevation of plasma apoB concentrations (>130 mg/dl corresponding to the 90th Italian population percentile) and at least one first degree relative with hyperlipidemia (TC and/or TG > 90th percentile). Hyperlipidemic
Experimental results
MAFs of the four analyzed SNPs in our control population in comparison with those reported in other populations [14] and in the NCBI database are shown in Supplementary Table 2. Based on genotypes data, we found that all four SNPs were highly correlated (Lewontin's D′ ≥ 0.73), with the rs7925131 and rs1138693 being particularly close (D′ > 0.89) (Fig. 1). The genotypes frequencies did not show a significant deviation from the Hardy–Weinberg equilibrium. In addition, no effect of age, sex or BMI on
Discussion
In the present study, we have evaluated whether the PNPLA2 variants rs7925131, rs7942159, rs66460720 as well as the nonsynonymous P481L, previously associated with lower FFA and plasma TG levels, influence the susceptibility to FCHL and its lipid-related phenotypes in 83 Italian FCHL families.
Although none of SNPs was individually related to the FCHL phenotype, we found that two haplotypes (CCC+ and TTT−) were associated to significantly lower susceptibility to FCHL phenotype. More importantly,
Sources of funding
This study was supported by grants COFIN 2002058281-003 from the Ministero dell’Università, Ricerca Scientifica e Tecnologica (MURST) and grants from La Sapienza University of Rome (Progetto Ateneo 2004 and 2006) to M.A.
Disclosures
None.
Acknowledgements
We thank FCHL family members for their participation in this study. We thank Bruno Mazzarella and Mr. Renzo Cantini for their excellent technical support. F.Q. and I.M. were recipient of the PhD Fellowships in Tecnologie Biomediche in Medicina Clinica and Genetica Medica, at Sapienza University of Rome, respectively.
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2012, Nature Reviews Endocrinology