Genetic Variance in the Adiponutrin Gene Family and Childhood Obesity

AIM: The adiponutrin gene family consists of five genes (PNPLA1-5) coding for proteins with both lipolytic and lipogenic properties. PNPLA3 has previously been associated with adult obesity. Here we investigated the possible association between genetic variants in these genes and childhood and adolescent obesity. METHODS/RESULTS: Polymorphisms in the five genes of the adiponutrin gene family were selected and genotyped using the Sequenom platform in a childhood and adolescent obesity case-control study. Six variants in PNPLA1 showed association with obesity (rs9380559, rs12212459, rs1467912, rs4713951, rs10947600, and rs12199580, p0.05). When analyzing these SNPs in relation to phenotypes, two SNPs in the PNPLA3 gene showed association with insulin sensitivity (rs12483959: beta = -0.053, p = 0.016, and rs2072907: beta = -0.049, p = 0.024). No associations were seen for PNPLA2, PNPLA4, and PNPLA5. CONCLUSIONS: Genetic variation in the adiponutrin gene family does not seem to contribute strongly to obesity in children and adolescents. PNPLA1 exhibited a modest effect on obesity and PNPLA3 on insulin sensitivity. These data, however, require confirmation in other cohorts and ethnic groups

Genetic variants associated with fasting blood lipids in the U.S. population: Third National Health and Nutrition Examination Survey

<p>Abstract</p> <p>Background</p> <p>The identification of genetic variants related to blood lipid levels within a large, population-based and nationally representative study might lead to a better understanding of the genetic contribution to serum lipid levels in the major race/ethnic groups in the U.S. population.</p> <p>Methods</p> <p>Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), we examined associations between 22 polymorphisms in 13 candidate genes and four serum lipids: high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG). Univariate and multivariable linear regression and within-gene haplotype trend regression were used to test for genetic associations assuming an additive mode of inheritance for each of the three major race/ethnic groups in the United States (non-Hispanic white, non-Hispanic black, and Mexican American).</p> <p>Results</p> <p>Variants within <it>APOE </it>(rs7412, rs429358), <it>PON1 </it>(rs854560), <it>ITGB3 </it>(rs5918), and <it>NOS3 </it>(rs2070744) were found to be associated with one or more blood lipids in at least one race/ethnic group in crude and adjusted analyses. In non-Hispanic whites, no individual polymorphisms were associated with any lipid trait. However, the <it>PON1 </it>A-G haplotype was significantly associated with LDL-C and TC. In non-Hispanic blacks, <it>APOE </it>variant rs7412 and haplotype T-T were strongly associated with LDL-C and TC; whereas, rs5918 of <it>ITGB3 </it>was significantly associated with TG. Several variants and haplotypes of three genes were significantly related to lipids in Mexican Americans: <it>PON1 </it>in relation to HDL-C; <it>APOE </it>and <it>NOS3 </it>in relation to LDL-C; and <it>APOE </it>in relation to TC.</p> <p>Conclusions</p> <p>We report the significant associations of blood lipids with variants and haplotypes in <it>APOE</it>, <it>ITGB3, NOS3</it>, and <it>PON1 </it>in the three main race/ethnic groups in the U.S. population using a large, nationally representative and population-based sample survey. Results from our study contribute to a growing body of literature identifying key determinants of plasma lipoprotein concentrations and could provide insight into the biological mechanisms underlying serum lipid and cholesterol concentrations.</p

Pharmacological Properties and Biological Functions of the GPR17 Receptor, a Potential Target for Neuro-Regenerative Medicine

In 2006, cells heterologously expressing the "orphan" receptor GPR17 were shown to acquire responses to both uracil nucleotides and cysteinyl-leukotrienes, two families of signaling molecules accumulating in brain or heart as a result of hypoxic/traumatic injuries. In subsequent years, evidence of GPR17 key role in oligodendrogenesis and myelination has highlighted it as a "model receptor" for new therapies in demyelinating and neurodegenerative diseases. The apparently contrasting evidence in the literature about the role of GPR17 in promoting or inhibiting myelination can be due to its transient expression in the intermediate stages of differentiation, exerting a pro-differentiating function in early oligodendrocyte precursor cells (OPCs), and an inhibitory role in late stage maturing cells. Meanwhile, several papers extended the initial data on GPR17 pharmacology, highlighting a "promiscuous" behavior of this receptor; indeed, GPR17 is able to respond to other emergency signals like oxysterols or the pro-inflammatory cytokine SDF-1, underlying GPR17 ability to adapt its responses to changes of the surrounding extracellular milieu, including damage conditions. Here, we analyze the available literature on GPR17, in an attempt to summarize its emerging biological roles and pharmacological properties

Complex haplotypes derived from noncoding polymorphisms of the intronless α(2A)-adrenergic gene diversify receptor expression

α(2A)-adrenergic receptors (α(2A)AR) regulate multiple central nervous system, cardiovascular, and metabolic processes including neurotransmitter release, platelet aggregation, blood pressure, insulin secretion, and lipolysis. Complex diseases associated with α(2A)AR dysfunction display familial clustering, phenotypic heterogeneity, and interindividual variability in response to therapy targeted to α(2A)ARs, suggesting common, functional polymorphisms. In a multiethnic discovery cohort we identified 16 single-nucleotide polymorphisms (SNPs) in the α(2A)AR gene organized into 17 haplotypes of two major phylogenetic clades. In contrast to other adrenergic genes, variability of the α(2A)AR was primarily due to SNPs in the promoter, 5′ UTR and 3′ UTR, as opposed to the coding block. Marked ethnic variability in the frequency of SNPs and haplotypes was observed: one haplotype represented 70% of Caucasians, whereas Africans and Asians had a wide distribution of less common haplotypes, with the highest haplotype frequencies being 16% and 35%, respectively. Despite the compact nature of this intronless gene, local linkage disequilibrium between a number of SNPs was low and ethnic-dependent. Whole-gene transfections into BE(2)-C human neuronal cells using vectors containing the entire ≈5.3-kb gene without exogenous promoters were used to ascertain the effects of haplotypes on α(2A)AR expression. Substantial differences (P < 0.001) in transcript and cell-surface protein expression, by as much as ≈5-fold, was observed between haplotypes, including those with common frequencies. Thus, signaling by this virtually ubiquitous receptor is under major genetic influence, which may be the basis for highly divergent phenotypes in complex diseases such as systemic and pulmonary hypertension, heart failure, diabetes, and obesity