Familial Hypercholesterolemia in a Healthy Elderly Population
2020; Wolters Kluwer; Volume: 13; Issue: 4 Linguagem: Inglês
10.1161/circgen.120.002938
ISSN2574-8300
AutoresPaul Lacaze, Robert Sebra, Moeen Riaz, Amanda J. Hooper, Jane Tiller, Andrew Bakshi, Robyn L. Woods, Andrew Tonkin, Christopher M. Reid, Anne M. Murray, Stephen J. Nicholls, Gerald F. Watts, Eric E. Schadt, John J. McNeil,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoHomeCirculation: Genomic and Precision MedicineVol. 13, No. 4Familial Hypercholesterolemia in a Healthy Elderly Population Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBFamilial Hypercholesterolemia in a Healthy Elderly Population Paul Lacaze, PhD, Robert Sebra, PhD, Moeen Riaz, PhD, Amanda J. Hooper, PhD, Jane Tiller, LLB, MSc GenCoun, Andrew Bakshi, MSc, Robyn L. Woods, PhD, Andrew M. Tonkin, PhD, Christopher M. Reid, PhD, Anne M. Murray, MD, MSc, Stephen J. Nicholls, MD, PhD, Gerald F. Watts, PhD, DM, Eric Schadt, PhD and John J. McNeil, MD, PhD Paul LacazePaul Lacaze Correspondence to: Paul Lacaze, PhD, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Level 5, The Alfred Centre, 99 Commercial Rd, Melbourne, VIC 3004, Australia. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0902-6798 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). , Robert SebraRobert Sebra Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY (R.S., E.S.). Sema4, Stamford, CT (R.S., E.S.). , Moeen RiazMoeen Riaz https://orcid.org/0000-0001-5858-3788 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). , Amanda J. HooperAmanda J. Hooper School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth (A.J.H., G.F.W.). Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Australia (A.J.H.). , Jane TillerJane Tiller https://orcid.org/0000-0003-3906-6632 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). , Andrew BakshiAndrew Bakshi https://orcid.org/0000-0001-5650-7036 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). , Robyn L. WoodsRobyn L. Woods https://orcid.org/0000-0003-1249-6149 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). , Andrew M. TonkinAndrew M. Tonkin https://orcid.org/0000-0001-5291-0610 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). , Christopher M. ReidChristopher M. Reid https://orcid.org/0000-0001-9173-3944 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). School of Public Health, Curtin University, Perth, WA, Australia (C.M.R.). , Anne M. MurrayAnne M. Murray https://orcid.org/0000-0002-2787-8433 Berman Center for Outcomes and Clinical Research, Hennepin Healthcare Research Institute, Hennepin Healthcare, Minneapolis, MN (A.M.M.). , Stephen J. NichollsStephen J. Nicholls Monash Cardiovascular Research Centre, Monash University and MonashHeart, Monash Health, Clayton, VIC, Australia (S.J.N.). , Gerald F. WattsGerald F. Watts School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth (A.J.H., G.F.W.). Department of Cardiology, Lipid Disorders Clinic, Royal Perth Hospital, WA, Australia (G.F.W.). , Eric SchadtEric Schadt Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY (R.S., E.S.). Sema4, Stamford, CT (R.S., E.S.). and John J. McNeilJohn J. McNeil https://orcid.org/0000-0002-1049-5129 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.). Originally published10 Jun 2020https://doi.org/10.1161/CIRCGEN.120.002938Circulation: Genomic and Precision Medicine. 2020;13:e002938Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 11, 2020: Ahead of Print Heterozygous familial hypercholesterolemia (FH) is an autosomal codominant genetic condition characterized by elevated LDL (low-density lipoprotein) cholesterol and increased risk of coronary heart disease (CHD). Genetic testing facilitates diagnosis of FH through detection of pathogenic variants in canonical genes (LDLR, APOB, and PCSK9). Pathogenic FH variants, especially in patients with elevated LDL cholesterol or with a family history of coronary disease, increase the risk of premature CHD.1 However, heterozygous FH is not fully phenotypically penetrant, implying that a subset of people who are carriers of a gene variant, and hence are at high genetic risk, may survive to advanced ages without developing CHD.The prevalence of pathogenic FH variants in the general US population is estimated at 1 in 256.2 Prevalence is higher in patients with dyslipidemia and premature CHD. However, the prevalence of pathogenic FH variants in older individuals who remain CHD free is unknown. Measuring FH variant prevalence in CHD-free healthy older populations may help overcome historic clinical ascertainment bias and help understand the survival risk conferred by FH variants during middle years of life. Healthy elderly populations may also provide new insights into the role polygenic risk and protective alleles play in modifying FH penetrance.To measure the prevalence of pathogenic FH variants in healthy older individuals without CHD, we sequenced 13 131 participants from the ASPREE study (Aspirin in Reducing Events in the Elderly).3 Consistent with the exclusion criteria of the ASPREE trial, participants had no current symptoms or history of cardiovascular events to age ≥70 years (mean age, 75 years), including myocardial infarction, heart failure, stroke, transient ischemic attack, atrial fibrillation, or high blood pressure. Participants also had no dementia diagnosis, physical disability, or illness likely to cause death within 5 years at enrollment.4We sequenced the DNA of 13 131 participants using the Thermo Fisher Scientific S5TM XL system following standard protocols (average 200× depth, alignment to GRCh37). Single-nucleotide variants and small insertions/deletions with pathogenic or likely pathogenic annotation or high confidence predicted loss of function were curated following the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.5 Variants of uncertain significance or conflicting interpretations of pathogenicity were excluded. FH variant prevalence was compared with 50 726 unselected individuals from the Geisinger Health System for LDLR, APOB, and PCSK9 genes combined.2 We assessed blood lipid levels and statin medication use at enrollment and cardiovascular end points during mean 4.5 years of follow-up.3 We generated polygenic risk scores (PRSs) for coronary artery disease using 50 single-nucleotide polymorphisms6 measured on the Axiom Precision Medicine Diversity Array (Thermo Fisher). The study was approved by the Alfred Hospital Human Research Ethics Committee, and data are available from the corresponding author upon request.Sequenced participants from the ASPREE trial were mostly white/Caucasian (99% self-reported), female (54%), with low rates of obesity (28%, body mass index ≥30 kg/m2), and current smoking (4%). Among 13 131 participants, we detected 13 individuals harboring pathogenic FH variants. We detected 11 different pathogenic FH variants passing clinical variant curation (Table).Table 1. Characteristics of Carriers of a Pathogenic Gene Variant Causative of Familial Hypercholesterolemia in ASPREEGeneVariantrsIDConsequenceSexAge, yBMILDL, mg/dL*HDL, mg/dL*Tg, mg/dL*TC, mg/dL*Statin Use*CVD End Point†CAD PRS Quintile‡Start*End†LDLR11213381C>T (p.Arg78Cys)rs370860696MissenseF828726.1259.165.7203.7367.4……Q4LDLR11216083C>A (p.Cys167Ter)rs752596535Stop gainedM798440.9112.154.1203.7208.8Atorvastatin…Q5LDLR11216084G>A (p.Asp168Asn)rs200727689MissenseM717744.092.834.870.9143.1Atorvastatin…Q4LDLR11218138C>A (p.Cys296Ter)rs879254708MissenseF707730.1162.446.4168.3243.6Atorvastatin…Q1LDLR11221336G>A (p.Glu317Lys)rs746834464Stop gainedF727630.1150.858.0115.1232……Q2LDLR11221336G>A (p.Glu317Lys)rs746834464Stop gainedF788127.5154.758.0168.3247.5AtorvastatinNonfatal MINALDLR11221414G>A (p.Gly343Ser)rs730882096MissenseM717623.8135.3104.497.4259.1Simvastatin…Q4LDLR11221435C>T (p.Arg350Ter)rs769737896Stop gainedM717425.4100.542.562.0154.7Simvastatin…Q1LDLR11224005C>T (p.Thr413Met)rs368562025MissenseF788130.2139.273.5159.4243.6Atorvastatin…NALDLR11227685C>Grs370245937Intron variantM717526.7150.850.379.7216.6Atorvastatin…Q5LDLR11240330G>A (p.Gly844Asp)rs121908037MissenseF717433.2119.938.7230.3204.9……NAAPOB21229160C>T (p.Arg3527Gln)rs5742904MissenseF737823.1143.154.197.4212.7Atorvastatin…Q4APOB21229160C>T (p.Arg3527Gln)rs5742904MissenseM808526.2112.150.344.3174Atorvastatin…NAMean747929.814156.2130.8223.710 of 13……BMI=weight in kilograms/height in meter squared. ASPREE indicates Aspirin in Reducing Events in the Elderly; BMI, body mass index; CAD PRS, Coronary Artery Disease Polygenic Risk Score; CVD, cardiovascular disease; F, female; HDL, high-density lipoprotein; LDL, low-density lipoprotein; M, male; MI, myocardial infarction; NA, not available; rsID, reference SNP cluster ID; TC, total cholesterol; and Tg, triglycerides.* At ASPREE study enrollment (time of randomization to aspirin).† At the end of ASPREE trial (time of last secondary end point screen).‡ CAD PRS (Khera et al6): Q1, low; Q2/3/4, mid; Q5, high.The carrier rate for heterozygous FH in the ASPREE population was 1 in 1010, markedly lower than the 1 in 256 reported in the general US population (odds ratio, 0.25 [0.14–0.47]; P<0.001). Among the 13 heterozygous FH variant carriers detected, mean LDL cholesterol at enrollment was 141 mg/dL (minimum, 92.8; maximum, 259), with 10 of 13 taking statin medication (Table). All 13 FH variant carriers survived a mean 4.5 years of follow-up, with only 1 developing a cardiovascular event (nonfatal myocardial infarction). The remaining 12 FH variant carriers (6 male and 6 female) survived CHD event free to mean age of 79 years (minimum, 74; maximum, 87) at completion of the ASPREE trial.The low prevalence of FH observed in ASPREE suggests a selective depletion of FH carriers at enrollment, due to the strict cardiovascular exclusion criteria.4 FH carriers, being more prone to premature CHD, were less likely to be enrolled, consistent with their survival disadvantage to age 70 years. Despite this, we identified 12 surviving FH variant carriers who met the study criteria and completed the trial to mean age 79 years (some to over 85 years) without developing CHD.We hypothesized that these CHD-free FH carriers may be enriched with protective genetic modifiers or low polygenic risk, modifying FH penetrance. Among the 12 CHD-free FH carriers detected, PRS data passing quality control were available on 9 individuals. A low PRS (in the bottom quintile or lowest 20% of the ASPREE population) was only observed for 2 of 9 (Table). This suggests PRS alone did not explain reduced penetrance. Another 2 of 9 had high PRS (in the top quintile or highest 20%), and the remaining 4 had average PRS (in quintile 2/3/4). The fact that PRS alone did not explain reduced penetrance suggests that environmental factors, adherence to a healthy lifestyle, long-term statin use, or yet undiscovered rare protective alleles may also have played a role.Older FH variant carriers who survive CHD free are typically not the focus of large genetic research studies. We suggest that with larger sample sizes and whole-genome analysis, elderly unaffected FH carriers may provide important clues toward understanding polygenic risk and the role protective variants may play. Further genomic evaluation of FH carriers that remain unaffected by CHD to advances in ages may also provide a new opportunity for novel target discovery for preventive therapies.Nonstandard Abbreviations and AcronymsASPREEAspirin in Reducing Events in the ElderlyCHDcoronary heart diseaseFHfamilial hypercholesterolemiaLDLlow-density lipoproteinPRSpolygenic risk scoreAcknowledgmentsWe thank the trial staff in Australia and the United States, the participants who volunteered for this trial, and the general practitioners and staff of the medical clinics who cared for the participants.Sources of FundingThe ASPREE (Aspirin in Reducing Events in the Elderly) Healthy Ageing Biobank is supported by a Flagship cluster grant (including the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne) and grants (U01AG029824) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency. P.L. is supported by a National Heart Foundation Future Leader Fellowship (102604).DisclosuresDr Watts has received honoraria and research grants from Arrowhead, AstraZeneca, Kowa, Regeneron, Sanofi, Amgen, and Novartis. Dr Nicholls has received research support and honoraria for Amgen, AstraZeneca, Eli Lilly, Esperion, Novartis, Merck, Pfizer, Iowa and Sanofi-Regeneron. Dr Sebra serves as Vice President of Technology Development at Sema4. Dr Schadt serves as Chief Executive Officer at Sema4. The other authors report no conflicts.FootnotesFor Sources of Funding and Disclosures, see page 339.Correspondence to: Paul Lacaze, PhD, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Level 5, The Alfred Centre, 99 Commercial Rd, Melbourne, VIC 3004, Australia. Email paul.[email protected]eduReferences1. Onorato A, Sturm AC. 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Coutinho E, Miname M, Rocha V, Bittencourt M, Jannes C, Tada M, Lima I, Filho W, Chacra A, Pereira A, Krieger J and Santos R (2021) Familial hypercholesterolemia and cardiovascular disease in older individuals, Atherosclerosis, 10.1016/j.atherosclerosis.2020.12.012, 318, (32-37), Online publication date: 1-Feb-2021. Lacaze P, Riaz M, Sebra R, Hooper A, Pang J, Tiller J, Polekhina G, Tonkin A, Reid C, Zoungas S, Murray A, Nicholls S, Watts G, Schadt E and McNeil J (2021) Protective lipid-lowering variants in healthy older individuals without coronary heart disease, Open Heart, 10.1136/openhrt-2021-001710, 8:2, (e001710), Online publication date: 1-Jul-2021. Santos R and Coutinho E (2021) Resilience of individuals with familial hypercholesterolaemia to develop atherosclerotic cardiovascular disease: lessons learned from the elderly, European Journal of Preventive Cardiology, 10.1093/eurjpc/zwab196 August 2020Vol 13, Issue 4 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.120.002938PMID: 32522009 Originally publishedJune 10, 2020 Keywordsgenetic testingallelesgeneticsfamilial hypercholesterolemiahumansPDF download Advertisement SubjectsAgingCardiovascular DiseaseCoronary Artery DiseaseGeneticsPrecision Medicine
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