Dolores Corella

Association Between the PPARA L162V Polymorphism and Plasma Lipid Levels: The Framingham Offspring Study

Peroxisome proliferator activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily that regulates key proteins involved in fatty acid oxidation, extracellular lipid metabolism, hemostasis, and inflammation. A L162V polymorphism at the PPARA locus has been associated with alterations in lipid and apolipoprotein concentrations. We studied the association among lipids, lipoproteins, and apolipoproteins and the presence of the L162V polymorphism in 2373 participants (1128 men and 1244 women) in the Framingham Offspring Study. The frequency of the less common allele (V162) was 0.069. The V162 allele was associated with increased serum concentrations of total and LDL cholesterol in men (P =0.0012 and P =0.0004, respectively) and apolipoprotein B in men (P =0.009) and women (P =0.03 after adjustment for age, body mass index, smoking, and use of &bgr;-blockers, diuretics or estrogens). Apolipoprotein (apo) C-III concentrations were higher in carriers of the V162 allele. The association of the L162V polymorphism on LDL cholesterol concentration was greatest in those who also carried the E2 allele at the APOE locus and the G allele at the APOC3 3238C>G polymorphism. This suggests that alterations in triglyceride-rich lipoprotein metabolism may be involved in the generation of the increase LDL cholesterol observed with the L162V PPARA polymorphism.

Genetic variation at the perilipin (PLIN) locus is associated with obesity‐related phenotypes in White women

Perilipin coats intracellular lipid droplets and modulates adipocyte lipolysis. We have evaluated the association between several polymorphisms at the perilipin (PLIN) locus (PLIN1 : 6209T > C, PLIN4 : 11482G > A, PLIN5 : 13041A > G, and PLIN6 : 14995A > T) with obesity‐related phenotypes in 1589 White subjects randomly selected from a general Spanish population. In women (n = 801), the less common alleles of PLIN1 and PLIN4, in strong linkage disequilibrium (D′ : 0.96), were significantly associated with lower body mass index. Carriers of the allele 2 (6209C) at the PLIN1 locus weighed significantly less (−2.2 kg; p = 0.007) than women homozygotes for the wild‐type genotype. The same was true for 11482A carriers at PLIN4 (p = 0.01). Moreover, the PLIN4 variant was associated with significantly lower waist‐to‐hip ratio, plasma glucose, and triacylglycerol concentrations. No significant associations with these obesity‐related phenotypes were found in men. In agreement with these results, statistically significant gene–gender interactions were obtained when the risk of obesity was estimated (281 subjects were obese and 1308 non‐obese). Only in women, PLIN1 and PLIN4 variant alleles (6209C and 11482A) were associated with a lower obesity risk [Odds ratio (OR) = 0.58, 95% confidence interval (CI): 0.38–0.93 and OR = 0.56, 95% CI: 0.36–0.89, respectively]. In summary, our data suggest that common alleles at the PLIN locus modulate body weight and metabolic variables in humans.

Metabolic syndrome pathophysiology: the role of adipose tissue

The metabolic syndrome comprises a set of metabolic and physiological risk factors associated with elevated cardiovascular disease risk. The expression of each one of its major factors (hypertriglyceridemia, low high-density lipoprotein cholesterol levels, hypertension, abdominal obesity, and insulin resistance) has been found to be the result of complex interactions between genetic and environmental factors. Moreover, one of them, obesity, may play a major role in triggering the metabolic syndrome by interacting with genetic variants at candidate genes for dyslipidemia, hypertension, and insulin resistance. In support of this hypothesis, several studies at several candidate genes, mainly adipokines and perilipin, have already demonstrated the significance of these interactions; however, the information and its solidity are still very limited and in many cases, replication studies are still lacking in the literature. Therefore, more studies with better epidemiological design and standardized adiposity measures are needed to estimate the contribution of body weight and fat distribution to the genetic predisposition to the metabolic syndrome, the most common CVD risk factor in industrialized societies.