Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09–2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0–1st percentile) and 21% (screening 0–20th percentile) of all variants were not identified; among these were variants previously associated with amyloidosis. Population-based resequencing of APOA1 identified a majority of rare NS variants associated with reduced apoA-1 and HDL cholesterol levels and/or predisposing to amyloidosis. In addition, NS variants associated with increased risk of MI.
Vyšlo v časopise: Population-Based Resequencing of in 10,330 Individuals: Spectrum of Genetic Variation, Phenotype, and Comparison with Extreme Phenotype Approach. PLoS Genet 8(11): e32767. doi:10.1371/journal.pgen.1003063 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003063
1. ManolioTA, CollinsFS, CoxNJ, GoldsteinDB, HindorffLA, et al. (2009) Finding the missing heritability of complex diseases. Nature 461 : 747–753.
2. CirulliET, GoldsteinDB (2010) Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11 : 415–425.
3. Tall AR, Breslow JL, Rubin EM (2001) Genetic disorders affecting plasma high-density lipoproteins. In: Schriver C, Beaudet A, Sly W, Valle D, editors. The metabolic and molecular bases of inherited diseases. New York, NY: McGraw-Hill. pp. 2915–2936
4. BoesE, CoassinS, KolleritsB, HeidIM, KronenbergF (2009) Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: A systematic in-depth review. Exp Gerontol 44 : 136–160.
5. Sorci-ThomasMG, ThomasMJ (2002) The effects of altered apolipoprotein A-I structure on plasma HDL concentration. Trends Cardiovasc Med 12 : 121–128.
6. ZannisVI, ChroniA, KriegerM (2006) Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. J Mol Med 84 : 276–294.
7. BensonMD (2005) Ostertag revisited: the inherited systemic amyloidoses without neuropathy. Amyloid 12 : 75–87.
8. ObiciL, PalladiniG, GiorgettiS, BellottiV, GregoriniG, et al. (2004) Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families. Gastroenterology 126 : 1416–1422.
9. de SousaMM, VitalC, OstlerD, FernandesR, Pouget-AbadieJ, et al. (2000) Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis. Am J Pathol 156 : 1911–1917.
10. PerseyMR, BoothDR, BoothSE, Zyl-SmitR, AdamsBK, et al. (1998) Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I. Kidney Int 53 : 276–281.
11. RallSCJr, WeisgraberKH, MahleyRW, OgawaY, FieldingCJ, et al. (1984) Abnormal lecithin:cholesterol acyltransferase activation by a human apolipoprotein A-I variant in which a single lysine residue is deleted. J Biol Chem 259 : 10063–10070.
12. HaaseCL, Tybjærg-HansenA, GrandeP, Frikke-SchmidtR (2010) Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Clin Endocrinol Metab 95: E500–E510.
13. HaaseCL, Frikke-SchmidtR, NordestgaardBG, KateifidesAK, KardassisD, et al. (2011) Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels. J Int Med 270 : 136–146.
14. Frikke-SchmidtR, NordestgaardBG, JensenGB, Tybjærg-HansenA (2004) Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population. J Clin Invest 114 : 1343–1353.
15. CohenJC, KissRS, PertsemlidisA, MarcelYL, McPhersonR, et al. (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305 : 869–872.
16. CohenJC, PertsemlidisA, FahmiS, EsmailS, VegaGL, et al. (2006) Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc Natl Acad Sci USA 103 : 1810–1815.
17. SchnohrP, JensenJS, ScharlingH, NordestgaardBG (2002) Coronary heart disease risk factors ranked by importance for the individual and community. A 21 year follow-up of 12000 men and women from The Copenhagen City Heart Study. Eur Heart J 23 : 620–626.
18. Frikke-SchmidtR, NordestgaardBG, SteneMCA, SethiAA, RemaleyAT, et al. (2008) Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 299 : 2524–2532.
19. ZachoJ, Tybjærg-HansenA, JensenJS, GrandeP, SillesenH, et al. (2008) Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 359 : 1897–1908.
20. ThygesenK, AlpertJS, WhiteHD, JaffeAS, AppleFS, et al. (2007) Universal definition of myocardial infarction. Eur Heart J 28 : 2525–2538.
21. The Joint European Society of Cardiology/American College of Cardiology Committee (2000) Myocardial infarction redefined - A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 21 : 1502–1513.
22. FriedewaldWT, LevyRI, FriedricksonDS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18 : 499–502.
23. Tybjærg-HansenA, SteffensenR, MeinertzH, SchnohrP, NordestgaardBG (1998) Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med 338 : 1577–1584.
24. RowczenioD, DoganA, TheisJD, VranaJA, LachmannHJ, et al. (2011) Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. Am J Pathol 179 : 1978–1987.
25. RomeoS, PennacchioLA, FuY, BoerwinkleE, Tybjærg-HansenA, et al. (2007) Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 39 : 513–516.
26. CoventryA, Bull-OttersonLM, LiuX, ClarkAG, MaxwellTJ, et al. (2010) Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nat Commun 1 : 131.
27. ArakiK, SasakiJ, MatsunagaA, TakadaY, MoriyamaK, et al. (1994) Characterization of two new human apolipoprotein A-I variants: apolipoprotein A-I Tsushima (Trp-108→Arg) and A-I Hita (Ala-95→Asp). Biochim Biophys Acta 1214 : 272–278.
28. von EckardsteinA, FunkeH, WalterM, AltlandK, BenninghovenA, et al. (1990) Structural analysis of human apolipoprotein A-I variants. Amino acid substitutions are nonrandomly distributed throughout the apolipoprotein A-I primary structure. J Biol Chem 265 : 8610–8617.
29. TeslovichTM, MusunuruK, SmithAV, EdmondsonAC, StylianouIM, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 : 707–713.
30. ZannisVI, KoukosG, DrosatosK, VezeridisA, ZanniEE, et al. (2008) Discrete roles of apoA-I and apoE in the biogenesis of HDL species: Lessons learned from gene transfer studies in different mouse models. Ann Med 40 Suppl 1 : 14–28.
31. MenzelHJ, AssmannG, RallSCJr, WeisgraberKH, MahleyRW (1984) Human apolipoprotein A-I polymorphism. Identification of amino acid substitutions in three electrophoretic variants of the Münster-3 type. J Biol Chem 259 : 3070–3076.
32. von EckardsteinA, FunkeH, HenkeA, AltlandK, BenninghovenA, et al. (1989) Apolipoprotein A-I variants. Naturally occurring substitutions of proline residues affect plasma concentration of apolipoprotein A-I. J Clin Invest 84 : 1722–1730.
33. MiccoliR, BertolottoA, NavalesiR, OdoguardiL, BoniA, et al. (1996) Compound heterozygosity for a structural apolipoprotein A-I variant, apo A-I(L141R)Pisa, and an apolipoprotein A-I null allele in patients with absence of HDL cholesterol, corneal opacifications, and coronary heart disease. Circulation 94 : 1622–1628.
34. KissRS, KavaslarN, OkuhiraKi, FreemanMW, WalterS, et al. (2007) Genetic etiology of isolated low HDL syndrome: Incidence and heterogeneity of efflux defects. Arterioscler Thromb Vasc Biol 27 : 1139–1145.
35. MatsunagaT, HiasaY, YanagiH, MaedaT, HattoriN, et al. (1991) Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. Proc Natl Acad Sci USA 88 : 2793–2797.
36. FullertonM, BuchananV, SonparA, TaylorL, SmithD, et al. (2004) The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster. Hum Genet V115 : 36–56.
37. UtermannG, FeussnerG, FranceschiniG, HaasJ, SteinmetzA (1982) Genetic variants of group A apolipoproteins. Rapid methods for screening and characterization without ultracentrifugation. J Biol Chem 257 : 501–507.
38. AmarzguiouiM, MucchianoG, HäggqvistB, WestermarkP, KavlieA, et al. (1998) Extensive intimal apolipoprotein A1-derived amyloid deposits in a patient with an apolipoprotein A1 mutation. Biochem Biophys Res Commun 242 : 534–539.
39. Tilly-KiesiM, PackardCJ, KahriJ, EhnholmC, ShepherdJ, et al. (1997) In vivo metabolism of apo A-I and apo A-II in subjects with apo A-I(Lys107→0) associated with reduced HDL cholesterol and Lp(AI w AII) deficiency. Atherosclerosis 128 : 213–222.
40. Tilly-KiesiM, QiupingZ, EhnholmS, KahriJ, LahdenperaS, et al. (1995) ApoA-IHelsinki (Lys107→0) associated with reduced HDL cholesterol and LpA-I:A-II deficiency. Arterioscler Thromb Vasc Biol 15 : 1294–1306.
41. RecaldeD, Velez-CarrascoW, CiveiraF, CenarroA, Gomez-CoronadoD, et al. (2001) Enhanced fractional catabolic rate of apo A-I and apo A-II in heterozygous subjects for apoA-IZaragoza (L144R). Atherosclerosis 154 : 613–623.
42. FalkRH, DubreySW (2010) Amyloid heart disease. Prog Cardiovasc Dis 52 : 347–361.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
