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Abstract
The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.
Highlights
Epidemiologic studies have shown that high plasma levels of highdensity lipoprotein cholesterol (HDL) have protective effects on atherosclerosis and cardiovascular disease (CVD) across multiple populations (Toth et al, 2013; Feig et al, 2014)
The variants rs12450571, rs8080616, and rs2215496 were suggested to have a role in binding motif (SEF-1, Foxj1, Foxa, Foxk1, Foxo, Foxp1, HDZC2, HMG, Irf, Nanog, Sox, p300, and/or Pou2f2; Matys et al, 2006; Badis et al, 2009; Scharer et al, 2009), and in DISCUSSION Our current study, focusing on genome-wide association (GWA), demonstrated evidence of genes associated with fasting plasma levels of HDL cholesterol, which have been linked to inflammation, apoptosis and/or longevity (Barzilai et al, 2006; Bergman et al, 2007; Jin et al, 2007; Magitta et al, 2009; Sanders et al, 2010; Zurawek et al, 2010; Dieudé et al, 2011)
The variants in CEPT and APOC3 genes have been connected with healthy aging, in addition to associations with HDL levels
Summary
Epidemiologic studies have shown that high plasma levels of highdensity lipoprotein cholesterol (HDL) have protective effects on atherosclerosis and cardiovascular disease (CVD) across multiple populations (Toth et al, 2013; Feig et al, 2014). There is evidence that HDL levels are associated with longevity (Bergman et al, 2007; Koropatnick et al, 2008; Newman et al, 2011; Rahilly-Tierney et al, 2011). A previous study from the Long Life Family Study (LLFS), which selected families characterized as healthy and having a strong history of longevity, showed that probands and offspring had higher HDL levels and lower cardiovascular risk factors as compared to similar aged individuals in the Cardiovascular Health Study (Newman et al, 2011). Prospective studies have found that HDL levels in subjects who had survived to exceptional age were www.frontiersin.org
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