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Familial Hypercholesterolemia in a Healthy Elderly Population

Originally publishedhttps://doi.org/10.1161/CIRCGEN.120.002938Circulation: Genomic and Precision Medicine. 2020;13:e002938

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.4

We 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 ASPREE

GeneVariantrsIDConsequenceSexAge, yBMILDL, mg/dL*HDL, mg/dL*Tg, mg/dL*TC, mg/dL*Statin Use*CVD End PointCAD PRS Quintile
Start*End
LDLR11213381C>T (p.Arg78Cys)rs370860696MissenseF828726.1259.165.7203.7367.4Q4
LDLR11216083C>A (p.Cys167Ter)rs752596535Stop gainedM798440.9112.154.1203.7208.8AtorvastatinQ5
LDLR11216084G>A (p.Asp168Asn)rs200727689MissenseM717744.092.834.870.9143.1AtorvastatinQ4
LDLR11218138C>A (p.Cys296Ter)rs879254708MissenseF707730.1162.446.4168.3243.6AtorvastatinQ1
LDLR11221336G>A (p.Glu317Lys)rs746834464Stop gainedF727630.1150.858.0115.1232Q2
LDLR11221336G>A (p.Glu317Lys)rs746834464Stop gainedF788127.5154.758.0168.3247.5AtorvastatinNonfatal MINA
LDLR11221414G>A (p.Gly343Ser)rs730882096MissenseM717623.8135.3104.497.4259.1SimvastatinQ4
LDLR11221435C>T (p.Arg350Ter)rs769737896Stop gainedM717425.4100.542.562.0154.7SimvastatinQ1
LDLR11224005C>T (p.Thr413Met)rs368562025MissenseF788130.2139.273.5159.4243.6AtorvastatinNA
LDLR11227685C>Grs370245937Intron variantM717526.7150.850.379.7216.6AtorvastatinQ5
LDLR11240330G>A (p.Gly844Asp)rs121908037MissenseF717433.2119.938.7230.3204.9NA
APOB21229160C>T (p.Arg3527Gln)rs5742904MissenseF737823.1143.154.197.4212.7AtorvastatinQ4
APOB21229160C>T (p.Arg3527Gln)rs5742904MissenseM808526.2112.150.344.3174AtorvastatinNA
Mean747929.814156.2130.8223.710 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 Acronyms

ASPREE

Aspirin in Reducing Events in the Elderly

CHD

coronary heart disease

FH

familial hypercholesterolemia

LDL

low-density lipoprotein

PRS

polygenic risk score

Acknowledgments

We 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.

Footnotes

For 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

References

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