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Feitosa MF, Wojczynski MK, Straka R, et al. Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol. Front Genet. 2014;5:159doi: 10.3389/fgene.2014.00159.
Feitosa, M. F., Wojczynski, M. K., Straka, R., Kammerer, C. M., Lee, J. H., Kraja, A. T., Christensen, K., Newman, A. B., Province, M. A., & Borecki, I. B. (2014). Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol. Frontiers in genetics, 5159. https://doi.org/10.3389/fgene.2014.00159
Feitosa, Mary F, et al. "Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol." Frontiers in genetics vol. 5 (2014): 159. doi: https://doi.org/10.3389/fgene.2014.00159
Feitosa MF, Wojczynski MK, Straka R, Kammerer CM, Lee JH, Kraja AT, Christensen K, Newman AB, Province MA, Borecki IB. Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol. Front Genet. 2014 Jun 03;5:159. doi: 10.3389/fgene.2014.00159. eCollection 2014. PMID: 24917880; PMCID: PMC4042684.
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Front Genet. 2014 Jun 03;5:159. doi: 10.3389/fgene.2014.00159. eCollection 2014.

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

Frontiers in genetics

Mary F Feitosa, Mary K Wojczynski, Robert Straka, Candace M Kammerer, Joseph H Lee, Aldi T Kraja, Kaare Christensen, Anne B Newman, Michael A Province, Ingrid B Borecki

Affiliations

  1. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine St. Louis, MO, USA.
  2. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota Minneapolis, MN, USA.
  3. Departments of Epidemiology and of Human Genetics, Center for Aging and Population Health University of Pittsburgh Pittsburgh, PA, USA.
  4. Sergievsky Center and Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA.
  5. The Danish Aging Research Center, Epidemiology, University of Southern Denmark Odense, Denmark ; Departments of Clinical Genetics and Clinical Biochemistry and Pharmacology, Odense University Hospital Odense, Denmark.
  6. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health Pittsburgh, PA, USA.

PMID: 24917880 PMCID: PMC4042684 DOI: 10.3389/fgene.2014.00159

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.

Keywords: NALP1; aging; familial longevity; family-based study; genomewide association study; lipids

References

  1. Ann Rheum Dis. 2011 Apr;70(4):668-74 - PubMed
  2. J Gerontol A Biol Sci Med Sci. 2008 Nov;63(11):1235-40 - PubMed
  3. Nature. 2010 Aug 5;466(7307):707-13 - PubMed
  4. Science. 2009 Jun 26;324(5935):1720-3 - PubMed
  5. Cardiovasc Res. 2002 Aug 15;55(3):506-19 - PubMed
  6. Aging (Albany NY). 2011 Jan;3(1):63-76 - PubMed
  7. Circ Res. 2014 Jan 3;114(1):205-13 - PubMed
  8. Biochem J. 2004 Dec 1;384(Pt 2):281-6 - PubMed
  9. Cancer Res. 2009 Jan 15;69(2):709-17 - PubMed
  10. Hum Immunol. 2010 May;71(5):530-4 - PubMed
  11. Acta Derm Venereol. 2011 Sep;91(5):541-4 - PubMed
  12. JAMA. 2010 Jan 13;303(2):150-8 - PubMed
  13. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10 - PubMed
  14. Arthritis Rheum. 2006 Aug;54(8):2541-9 - PubMed
  15. Atherosclerosis. 2011 Dec;219(2):737-42 - PubMed
  16. Alzheimer Dis Assoc Disord. 2012 Jul-Sep;26(3):277-81 - PubMed
  17. PLoS Comput Biol. 2007 Aug;3(8):e170 - PubMed
  18. N Engl J Med. 2007 Mar 22;356(12):1216-25 - PubMed
  19. Bioinformatics. 2001 Aug;17(8):742-3 - PubMed
  20. Neurology. 2006 Dec 26;67(12):2170-5 - PubMed
  21. Am J Hum Genet. 1997 Sep;61(3):748-60 - PubMed
  22. Cell Metab. 2011 May 4;13(5):540-9 - PubMed
  23. Am J Cardiovasc Dis. 2011;1(3):244-54 - PubMed
  24. Am J Epidemiol. 2009 Dec 15;170(12):1555-62 - PubMed
  25. Genome Res. 2012 Sep;22(9):1790-7 - PubMed
  26. Am J Cardiol. 2011 Apr 15;107(8):1173-7 - PubMed
  27. Clin Immunol. 2010 Oct;137(1):147-56 - PubMed
  28. Nature. 2011 May 5;473(7345):43-9 - PubMed
  29. Genes Immun. 2009 Mar;10(2):120-4 - PubMed
  30. J Biol Chem. 2001 Mar 23;276(12):9230-8 - PubMed
  31. Nat Genet. 2006 Aug;38(8):904-9 - PubMed
  32. Bioinformatics. 2010 Sep 15;26(18):2336-7 - PubMed
  33. Dan Med Bull. 2006 Nov;53(4):441-9 - PubMed
  34. Cell Cycle. 2009 Dec;8(23):3925-42 - PubMed
  35. Mutat Res. 2010 Dec 10;694(1-2):13-9 - PubMed
  36. Am J Hum Genet. 2012 Jul 13;91(1):27-37 - PubMed
  37. Mol Cell Biochem. 2014 Apr;389(1-2):197-207 - PubMed
  38. J Clin Lipidol. 2013 Sep-Oct;7(5):484-525 - PubMed

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