Limits...
Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol.

Feitosa MF, Wojczynski MK, Straka R, Kammerer CM, Lee JH, Kraja AT, Christensen K, Newman AB, Province MA, Borecki IB - Front Genet (2014)

Bottom Line: 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.NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.

View Article: PubMed Central - PubMed

Affiliation: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine St. Louis, MO, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Regional plots represent the associations between plasma levels of HDL and NLRP1 (A), ZNF259 (B), and CEPT (C) gene regions. The −log10 (p-value) for HDL is represented in the ordinate axis, while the chromosome position in Megabase (Mb) using build 37.3 is represented in the abscissa axis. The bottom panels give the relative positions of genes in the locus. Purple diamond indicates the effect of the top significant SNP with HDL cholesterol. Each circle indicates a SNP with the color of the circle representing the correlation (r2) between that SNP and the top significant SNP. Blue line indicates estimated recombination hotspots.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4042684&req=5

Figure 1: Regional plots represent the associations between plasma levels of HDL and NLRP1 (A), ZNF259 (B), and CEPT (C) gene regions. The −log10 (p-value) for HDL is represented in the ordinate axis, while the chromosome position in Megabase (Mb) using build 37.3 is represented in the abscissa axis. The bottom panels give the relative positions of genes in the locus. Purple diamond indicates the effect of the top significant SNP with HDL cholesterol. Each circle indicates a SNP with the color of the circle representing the correlation (r2) between that SNP and the top significant SNP. Blue line indicates estimated recombination hotspots.

Mentions: On chromosome 17p13, we found statistical evidence for a novel variant near-NLRP1 (rs12450571: p = 1.82E-08, β = 0.13, minor allele frequency (maf) of G allele=0.47) influencing fasting plasma levels of HDL. In addition, we detected association of variants in ZNF259-APOA5-A4-C3-A1 [11q23.3, rs3741298: p = 2.04E-08, β = −0.16, maf(C) = 0.21] and HERPUD1-CEPT (16q21, rs72786786: p = 3.64E-26, β = −0.28, maf (A) = 0.32] with HDL, which were previously reported in the literature (e.g., Teslovich et al., 2010; Brautbar et al., 2011). The regional plots show the LD and block structures for SNPs on 17p13 (Figure 1A), on 11q23.3 (Figure 1B) and on 16q21 (Figure 1C). Table 2 shows the SNPs with the strongest associations with HDL levels in each chromosome region, while the Supplementary Table 1 lists all associated SNPs.


Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol.

Feitosa MF, Wojczynski MK, Straka R, Kammerer CM, Lee JH, Kraja AT, Christensen K, Newman AB, Province MA, Borecki IB - Front Genet (2014)

Regional plots represent the associations between plasma levels of HDL and NLRP1 (A), ZNF259 (B), and CEPT (C) gene regions. The −log10 (p-value) for HDL is represented in the ordinate axis, while the chromosome position in Megabase (Mb) using build 37.3 is represented in the abscissa axis. The bottom panels give the relative positions of genes in the locus. Purple diamond indicates the effect of the top significant SNP with HDL cholesterol. Each circle indicates a SNP with the color of the circle representing the correlation (r2) between that SNP and the top significant SNP. Blue line indicates estimated recombination hotspots.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042684&req=5

Figure 1: Regional plots represent the associations between plasma levels of HDL and NLRP1 (A), ZNF259 (B), and CEPT (C) gene regions. The −log10 (p-value) for HDL is represented in the ordinate axis, while the chromosome position in Megabase (Mb) using build 37.3 is represented in the abscissa axis. The bottom panels give the relative positions of genes in the locus. Purple diamond indicates the effect of the top significant SNP with HDL cholesterol. Each circle indicates a SNP with the color of the circle representing the correlation (r2) between that SNP and the top significant SNP. Blue line indicates estimated recombination hotspots.
Mentions: On chromosome 17p13, we found statistical evidence for a novel variant near-NLRP1 (rs12450571: p = 1.82E-08, β = 0.13, minor allele frequency (maf) of G allele=0.47) influencing fasting plasma levels of HDL. In addition, we detected association of variants in ZNF259-APOA5-A4-C3-A1 [11q23.3, rs3741298: p = 2.04E-08, β = −0.16, maf(C) = 0.21] and HERPUD1-CEPT (16q21, rs72786786: p = 3.64E-26, β = −0.28, maf (A) = 0.32] with HDL, which were previously reported in the literature (e.g., Teslovich et al., 2010; Brautbar et al., 2011). The regional plots show the LD and block structures for SNPs on 17p13 (Figure 1A), on 11q23.3 (Figure 1B) and on 16q21 (Figure 1C). Table 2 shows the SNPs with the strongest associations with HDL levels in each chromosome region, while the Supplementary Table 1 lists all associated SNPs.

Bottom Line: 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.NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.

View Article: PubMed Central - PubMed

Affiliation: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine St. Louis, MO, USA.

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.

No MeSH data available.


Related in: MedlinePlus