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Abstract

Background:

Familial hypercholesterolemia (FH) is characterized by inherited high levels of LDL-C (low-density lipoprotein cholesterol) and premature coronary heart disease. Over a thousand low-frequency variants in LDLR, APOB, and PCSK9 have been implicated in FH, but few have been examined at the population level. We aim to estimate the phenotypic effects of a subset of FH variants on LDL-C and clinical outcomes among 331 107 multiethnic participants.

Methods:

We examined the individual and collective association between putatively pathogenic FH variants included on the Million Veteran Program biobank array and the maximum LDL-C level over an interval of 15 years (maxLDL). We assessed the collective effect on clinical outcomes by leveraging data from 61.7 million clinical encounters.

Results:

We found 8 out of 16 putatively pathogenic FH variants with ≥30 observed carriers to be significantly associated with elevated maxLDL (9.4–80.2 mg/dL). Phenotypic effects were similar for European Americans and African Americans, despite substantial differences in carrier frequencies. Based on observed effects on maxLDL, we identified a total of 748 carriers (1:443) who had elevated maxLDL (36.5±1.4 mg/dL; P=1.2×10–152), and higher prevalence of clinical diagnoses related to hypercholesterolemia and coronary heart disease in a phenome-wide scan. Adjusted for maxLDL, FH variants collectively associated with higher prevalence of coronary heart disease (odds ratio, 1.59; 95% CI, 1.36–1.86, P=1.1×10–8) but not peripheral artery disease.

Conclusions:

The distribution and phenotypic effects of putatively pathogenic FH variants were heterogeneous within and across variants. More robust evidence of genotype-phenotype associations of FH variants in multiethnic populations is needed to accurately infer at-risk individuals from genetic screening.
Familial hypercholesterolemia (FH) is a common genetic disorder affecting ≈ 1 in 250 adults.1 The condition causes lifelong elevated levels of LDL-C (low-density lipoprotein cholesterol), which substantially increases the risk for developing atherosclerotic cardiovascular disease, including early onset disease. A recent study suggests that carriers of FH variants have an elevated risk for incident coronary heart disease (CHD) that is independent of a single measure of LDL-C.2 Treating FH with statins at younger ages can greatly reduce the risk of atherosclerotic cardiovascular disease–related morbidity.3 Based on the National Institute for Health and Clinical Excellence guideline,4 FH screening is classified as a tier 1 genomic application.5
Many causal mutations for FH have been reported, and >1000 variants have been documented in the LDL receptor (LDLR) gene alone. The functional effect of these variants appears to be highly variable, as estimated by LDLR activities and LDL-C in affected families.6,7 The advancement of genotyping technologies enables accurate and cost-effective genetic screening of FH variants in large population and assessment of their individual effects. Previously, rare FH variants based on functional annotation were typically grouped together to assess their joint phenotypic effects on LDL-C.2,8
The phenotypic effects of most FH variants have been assessed either in pedigrees without proper population controls or in population samples without sufficient sample size to assess phenotypic effects of individual variants. The majority of published genetic studies of FH were conducted in samples of European ancestry (EA). Although the prevalence of FH is higher in samples of African ancestry,1 the knowledge of FH variants in minority populations is limited. To determine LDL-raising effects, and to better understand the distribution of rare FH variants, we examined pathogenic and likely pathogenic (P/LP) FH variants and their associations with LDL cholesterol levels and clinical outcomes among >300 000 multiethnic veterans in the Million Veteran Program (MVP).9

Methods

The individual-level data of veteran participants will not be made available to other researchers without approval from the U.S. Department of Veterans Affairs (VA) Institutional Review Board.
Participants of multiple ethnicities were recruited from ≈50 VA healthcare facilities across the United States.9 Individuals consented to a blood draw and to have their DNA extracted for genomic profiling and linked to their full electronic health record within the VA. Both MVP biobank and this analysis were approved by the VA institutional review boards.
The phenotypic and genotypic measures of the MVP participants were previously described.10 The detailed methods are available in the Data Supplement.

Results

Among the multiethnic MVP cohort (summarized in Table 1), 331 107 veterans (mean age of 58.8 years old; 91.6% male) have both cleaned genotype and phenotype data. The MVP participants represented major continental ancestries of African, European, Asian, and Native American (Figure 1). The self-reported Hispanics had heterogeneous genetic background from all major ancestries indicated by the first 2 principal components (Figure 1), and because of this and the low number of pathogenic variants in this group, Hispanics were not included in the current analyses.
Table 1. Characteristics of the MVP Samples Stratified by non-Hispanic European Americans and African Americans
 Non-Hispanic European Americans (N=231 481)Non-Hispanic African Americans (N=64 929)
Age at enrollment, y, mean±SD64.5±13.158.3±11.9
Sex, n (%)215 240 (93.0)56 752 (87.4)
BMI, kg/m2, mean±SD30.11±5.8830.25±6.15
Obesity, n (%)95 963 (41.5)28 604 (44.1)
Never smoker, n (%)62 716 (27.1)19 265 (29.7)
Former smoker, n (%)126 183 (54.5)28 272 (43.5)
maxLDL-C, mg/dL, mean±SD139.2±38.1142.0±40.3
minHDL-C, mg/dL, mean±SD36.1±11.538.9±12.8
maxTG, mg/dL, median±IQR214±181180±154
maxTC, mg/dL, mean±SD219.2±47.1220.9±46.8
Statin use before maxLDL-C, n (%)9864 (4.3)2650 (4.1)
CHD,* n (%)57 782 (25.0)9764 (15.0)
PAD,* n (%)17 305 (7.5)3956 (6.1)
Hypertension,* n (%)149 634 (64.6)45 642 (70.3)
BMI indicates body mass index; CHD, coronary heart disease; CPT, Current Procedural Terminology; EHR, electronic health record; HDL-C, high-density lipoprotein cholesterol; ICD-9, International Classification of Diseases-Ninth Revision; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; maxLDL, maximum LDL-C level over an interval of 15 y; MVP, Million Veteran Program; PAD, peripheral artery disease; TC, total cholesterol; and TG, triglycerides.
*
Defined using inpatient and outpatient ICD-9 and CPT codes available in EHR data by August 25th, 2017.
Figure 1. Principal component (PC) plot of the 331 107 Million Veteran Program multiethnic participants included in the analysis of FH variants. AA indicates African ancestry; and EA, European ancestry.
We identified 58 FH variants classified as P/LP in ClinVar on the MVP biobank array, of which 57 FH variants were not monomorphic (Table I in the Data Supplement). Although all of these FH variants had at least 1 submission annotated as P/LP, they were classified into 4 clinical significance categories in ClinVar, 4 as pathogenic, 16 as P/LP, 10 as LP, and 27 as conflicting interpretations of pathogenicity. We observed at least 30 carriers for 16 variants (12 variants in LDLR, 2 in APOB, and 2 in PCSK9) which were individually assessed for association with LDL-C (Table 2). The number of carriers observed for the remaining 41 FH variants ranged from 1 to 27.
Table 2. Individual FH Variants (≥30 carriers) Associated With Elevated maxLDL-C Among 331 107 Multiethnic Veterans
SNP IDChr: Basepair PositionGeneEffective AlleleAmino Acid SubstitutionNo.of CarriersBeta±SEP ValuemaxLDL≥190 (%)
rs1415020021:55524222PCSK9TArg469Trp11479.4±1.13.71×10–1717.9
rs127135592:21229068APOBAArg3558Cys3669.9±2.06.32×10–715.3
rs57429042:21229160APOBTArg3527Gln25643.5±2.43.40×10–7542.2
rs76856300019:11217264LDLRAGlu240Ter3420.3±6.51.8×10–326.5
rs15120712219:11218157LDLRTArg303Trp4936.2±5.42.16×10–1136.7
rs12190803019:11218160LDLRAAsp304Tyr3080.2±6.94.67×10–3166.7
rs20157386319:11231154LDLRTPro699Leu5144.0±5.31.03×10–1651.0
rs13785396419:11240278LDLRAVal827Ile32812.6±2.11.67×10–918.0
chr indicates chromosome; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; maxLDL-C, maximum LDL-C level over an interval of 15 y; and SNP, single nucleotide polymorphism.
A total of 8 of these 16 P/LP variants, including 5 in LDLR, 2 in APOB, and 1 in PCSK9, were significantly associated with elevated level of maximum LDL-C level over an interval of 15 years (maxLDL) compared with noncarriers after correction for multiple testing (P<0.05/16; Table 2). Among these 8 variants, we observed a wide range of effects on the mean maxLDL (+9.4 to +80.2 mg/dL) and a wide range of proportion of individuals with a maxLDL >190 mg/dL (15%–67%; Table 2). These effects of individual FH variants were highly heterogeneous (I2=97.8%; 95% CI, 97.1%–98.3%; P<0.001). The distribution of maxLDL among carriers of each FH variant was also highly variable (Figure 2), with some carriers having maxLDL levels <100 mg/dL. We also observed that variants with the largest effect sizes (eg, rs121908030, rs5742904, rs201573863, and rs151207122) were relatively less common (Table 2). Carriers of the remaining less common variants (<30 carriers for each) collectively demonstrated a mean maxLDL that was increased by 27.3±2.1 mg/dL compared with noncarriers (P=2.8×10–39).
Figure 2. Distribution of maximum LDL-C (low-density lipoprotein cholesterol) level over an interval of 15 years (maxLDL) levels of LDL-raising variants among the Million Veteran Program participants. Red horizontal line (190 mg/dL) indicates the threshold for severe hypercholesterolemia; blue horizontal line (140 mg/dL) represents the mean maxLDL of 331 107 multiethnic participants.
We examined the phenotypic effects and distribution of individual P/LP variants among 214 455 MVP participants of EA and 57 850 MVP participants of African ancestry (AA; Table 3). Because no single pathogenic variant had sufficient number of carriers (allele count of ≥30) in the MVP Hispanic Americans to assess the genetic effects, we did not include Hispanic Americans in ethnicity-specific analysis. All except one (rs12713559) of the P/LP variants associated with maxLDL had carrier frequencies that were >3-fold difference in prevalence between EA and AA (Table 3). One variant in PCSK9 (rs141502002) and 2 variants in LDLR (rs121908030 and rs151207122) were predominantly observed among AA participants, with a frequency >70× greater than that in EA participants. For example, rs121908030 (LDLR), which had the largest effect on maxLDL among all tested P/LP variants, was observed only once among EAs and was 85× more frequent among AA participants than for EA participants.
Table 3. Ethnicity-Specific Effects and Frequencies of FH Variants Associated With Elevated maxLDL
SNP IDGeneA1Amino Acid SubstitutionEA N=214 455AA N=57 850Carrier Freq Ratio (AA/EA)
CarriersBeta±SEP ValueCarriersBeta±SEP Value
rs141502002PCSK9TArg469Trp233.1±7.80.6993210.3±1.33.79×10–15150
rs12713559APOBAArg3558Cys24811.0±2.43.20×10–65210.2±5.66.61×10–20.78
rs5742904APOBTArg3527Gln21244.5±2.61.07×10–671550.7±10.39.66×10–70.26
rs768563000LDLRAGlu240Ter3026.6±6.89.01×10–52NANA0.25
rs151207122LDLRTArg303Trp2NANA4237.3±6.21.62×10–978
rs121908030LDLRAAsp304Tyr1NANA2387.7±8.38.44×10–2685
rs201573863LDLRTPro699Leu11NANA2938.8±7.41.86×10–79.8
rs137853964LDLRAVal827Ile24313.9±2.45.75×10–95NANA0.08
AA indicates African ancestry; EA, European ancestry; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; maxLDL, maximum LDL-C level over an interval of 15 y; NA, not applicable; and SNP, single nucleotide polymorphism.
Including all variants associated with elevated maxLDL (9.4–80.2 mg/dL), we identified 2594 carriers (1 in 128). However, the phenotypic effects of 3 variants, rs141502002 (PCSK9), rs12713559 (APOB), and rs137853964 (LDLR), were moderate (increased maxLDL 9.4–12.6 mg/dL) and not considered as pathogenic for FH in follow-up analyses. Of the remaining variants that increase maxLDL by >20 mg/dL, there were 748 veterans carrying these more deleterious FH variants among 331 107 participants (1 in 443). The 10 most frequent variants accounted for 71.0% of genotyped pathogenic FH variant carriers. The carrier rates of these pathogenic FH variants were 1:462 among 214 455 participants of EA, and 1:362 among 57 850 participants of AA. Among 32 174 individuals with maxLDL above 190 mg/dL, 1 in 117 carried one of pathogenic FH variants.
We further examined the combined effect of pathogenic FH variants that substantially increase maxLDL (mean increase >20 mg/dL) within each of the 3 FH genes. Carriers of FH variants within LDLR, APOB, and PCSK9 were associated with an increase (>30 mg/dL) of maxLDL (Table 4). We found the highest mean effect on maxLDL in carriers of APOB FH variants. Carriers of any of these FH variants had a maxLDL that was 36.5±1.4 mg/dL greater than noncarriers (P=1.2×10–152). Ethnicity-specific association analysis revealed that the gene-specific and join effects of P/LP variants were similar for individuals of EA and AA (Table 4).
Table 4. Collective Associations of Pathogenic FH Variants With maxLDL Levels Among the Multiethnic, EA and AA Participants
 All N=331,107EA, N=214 455AA, N=57 850
CarriersBeta±SEP ValueCarriersBeta±SEP ValueCarriersBeta±SEP Value
APOB27542.3±2.32.10×10–7622543.8±2.59.79×10–701646.5±10.03.37×10–6
LDLR45132.0±1.82.44×10–7622628.3±2.53.95×10–3014241.7±3.42.28×10–35
PCSK92233.9±8.12.66×10–51335.2±10.36.64×10–42105.2±28.32.04×10–4
ALL74836.5±1.41.22×10–15246436.1±1.71.97×10–9616043.0±3.25.00×10–42
AA indicates African ancestry; EA, European ancestry; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; and maxLDL, maximum LDL-C level over an interval of 15 y.
Overall there were 748 carriers of deleterious FH variants. These individuals had a mean age of 58.5 years old, and 91.7% were male. We determined the collective impact of these deleterious FH variants on a wide range of clinical outcomes through PheWAS (phenome-wide association study) by leveraging data from 61.7 million clinical encounters across 3 million patient-years of health data. Among >200 000 participants with EA, we examined 1171 diagnoses within 17 categories of disease based on International Classification of Diseases-Ninth Revision codes. Compared with noncarriers, carriers of FH variants had a statistically significantly (P<0.05/1171 or 4.3×10–5) higher prevalence of clinical diagnoses related to hypercholesterolemia and CHD-related diagnoses including ischemic heart disease, coronary atherosclerosis, and angina pectoris (Figure 3). We further examined the associations between collective FH variants and the prevalence of CHD and peripheral artery disease as determined by a more refined definition of these outcomes leveraging elements of the electronic health record. Adjusted for age, sex, and the top 10 principal components for population structure, FH variants remained collectively associated with a greater prevalence of CHD (odds ratio of 1.68; 95% CI, 1.43–1.97; P=1.65×10-10), but not peripheral artery disease (odds ratio of 1.09; 95% CI, 0.86–1.39; P=0.45). With additional adjustment for maxLDL, the odds ratio for CHD decreased slightly but remained significant (odds ratio of 1.59; 95% CI, 1.36–1.86; P=1.12×10–8).
Figure 3. The genetic associations between pathogenic familial hypercholesterolemia variants and clinical outcomes in a PheWAS (phenome-wide association study) analysis. Red horizontal line represents Bonferroni corrected P of 0.05. Positive association denoted by triangle pointing up (▴) and negative association by triangle pointing down (▾).
A majority (603 or 80.6%) of the 748 carriers of pathogenic FH variants had been prescribed a statin at least once within the VA healthcare system at any time before or on the day of their enrollment into MVP. Overall the participants who had ever been prescribed statin had mean maxLDL of 186.2 (SD of 56.3) mg/dL, 49.9 mg/dL higher than those without any record of statin prescription. Only 51 (6.8%) had a record of statin use within 90 days before the date of maxLDL measures. A total of 468 FH variant carriers (62.6%) on current therapy (prescription within 3 months of enrollment) had an average treated LDL-C level of 124.2 (SD of 46.7) mg/dL, 64.2 mg/dL lower than their maxLDL. The remaining 145 (19.4%) carriers, who had no record of statin use, had lower level of maxLDL (136.3 [SD of 39.4] mg/dL, P<2.2×10–16).
To explore the phenotypic effects of other rare variants potentially related to FH, we examined 102 additional variants in APOB, LDLR, and PCSK9 with minor allele frequency <0.01 and minor allele count >30 in the MVP. After correction for multiple testing, we identified 6 variants (3 in APOB and 3 in LDLR) significantly associated with elevated maxLDL (P<0.05/102=4.9×10–4). Carrying each rare allele on average increased 2.5 to 24.6 mg/dL maxLDL among the MVP participants (Table 5). Four variants (3 in APOB and 1 in LDLR) coded for missense mutations. Notably, the synonymous variant in LDLR (rs368889457) had the largest effect size (24.6±4.9 mg/dL; P=6.60×10–7) and lowest minor allele frequency (9.44×10–5).
Table 5. NonClinVar P/LP Rare Variants in APOB and PCSK9 Associated With Elevated maxLDL Among Multiethnic Veterans
SNP IDrs IDChr:BasepairGeneFunctionEffective AlleleMAFBeta±SEP Value
AX-83185920rs1513332622:21225111APOBMissenseT1.04×10–424.1±4.59.58×10–8
AX-40824279rs127208542:21229905APOBMissenseC0.0058592.5±0.67.27×10–5
AX-83134365rs726530602:21257697APOBMissenseC0.00027822.7±2.71.42×10–16
AX-86688464rs36888945719:11224355LDLRSynonymousA9.44×10–524.6±4.96.60×10–7
AX-56828551rs1724888219:11227525LDLRIntronA0.0019984.5±1.01.89×10–5
AX-32617011rs4550899119:11233886LDLRMissenseT0.0057364.4±0.62.39×10–12
chr indicates chromosome; LDL, low-density lipoprotein; MAF, minor allele frequency; maxLDL, maximum LDL cholesterol level over an interval of 15 y; P/LP, pathogenic and likely pathogenic; and SNP, single nucleotide polymorphism.

Discussion

The phenotypic expression of FH on LDL-C and the age of onset and severity of disease vary substantially by the causal gene and individual variants.7,8,11,12 Previous studies have focused on reporting either effects of selected FH variants, pedigrees or case groups without consideration of proper population controls, or compared results to population samples without sufficient sample size to assess individual variants. In this study, we overcame these limitations by analyzing the effect of 57 FH variants annotated as pathogenic among 331 107 subjects receiving care within the VA health care system. We confirmed several low-frequency pathogenic variants raising LDL-C of MVP participants. Among these pathogenic variants, APOB gene on average carried the most severe mutations among 3 tested genes. However, such observation was restricted to the variants measured on the MVP genotyping array. The generalization of the observation to the entirety APOB variants should be cautious and requires complete coverage of genetic mutations in future population studies. We observed notable heterogeneity in the effects of these variants on LDL-C, suggesting the annotation of their pathogenicity is imperfect. Because most P/LP variants for FH have not been validated at a population level, concluding pathogenicity on the basis of a variant’s putative disruption of the gene’s function or its protein product may be insufficient.
We investigated the distribution of FH variants among participants of EA (n=214 455) and AA (n=57 850) separately to address the limited knowledge of FH variant distribution among AAs in comparison to EAs.13 We found that all except one P/LP variants associated with maxLDL had carrier frequencies that were >3-fold different between the EA and AA. Several variants, including the one with the largest effect on maxLDL among all tested P/LP variants (rs121908030 of LDLR), were predominantly observed among AAs. Additionally, the joint carrier frequency of deleterious FH variants in AA (1:362) is also higher than that in EA (1:462). Such differences in FH variant distribution between races demand in-depth genotyping efforts to discover and validate FH variants and other rare pathogenic variants among large multiethnic populations.
The current estimated prevalence of FH is ≈1:250 in the United States1 and other Western countries.14–17 Recent exome-sequencing based screenings have reported frequencies for FH carriers of 1:2228 and 1:2112 in an electronic health record-based cohort and a coronary artery disease case-control population, respectively. However, the latter study included only 7% of African ancestry. In this multiethnic study, the calculated FH carrier frequency was dependent on the inclusion and exclusion criteria of individual variants and race/ethnicity. The overall results were substantially influenced by a few common variants. When 3 variants with moderate LDL-raising effects were included, the FH carrier frequencies were 1:128, 1:234, and 1:50 among all, European American alone, and African American alone participants, respectively. Notably, the FH carrier frequency among European Americans is consistent with previous studies (1:211) that included up to 7% of African Ancestry.2 A single variant rs141502002 (PSCK9), which is associated with moderately increased maxLDL (9.4±1.1 mg/dL, P=3.7×10–17) was predominantly observed among AA and accounted for 81% of LDL-raising FH variant carriers in this ethnic group. After excluding the 3 variants with moderate effects on maxLDL, we estimated a lower FH carrier frequency (1:443) using a more stringent inclusion criteria of LDL-raising FH variants (mean increase >20 mg/dL) in this microarray-based genotyping study.
Using a PheWAS approach, we explored the phenotypic effects of FH variants for >1000 clinical diagnoses in the electronic health record. We identified that FH variant carriers with elevated risk for diagnoses related to CHD or hypercholesterolemia, but no obvious pleiotropic effects on other clinical diagnosis. Although we assembled one of the largest samples of FH carriers, the number of some less frequent clinical diagnoses may partially explain why we did not observe strong pleiotropic effect of FH variants on other disease outcomes. Using refined phenotyping algorithms of CHD and peripheral artery disease, we confirmed the genetic association with CHD with and without adjustment of maxLDL, but not with peripheral artery disease. Because FH carriers in the MVP achieved comparable LDL-C to noncarriers after statin treatment, the residual risk for CHD adjusted for maxLDL suggests that earlier and more aggressive treatments may be needed to further reduce the CHD risk among FH carriers.
Our study has several important limitations. First, our genotyping platform limited the assessment of the phenotypic effects of FH variants genotyped on the MVP biobank array but did not include all documented FH variants. However, the number of identified carriers with moderate to more severe form of FH variants should account for a large proportion of all deleterious FH variants, most having extremely low frequency in the population. Large-scale sequencing studies may ultimately be necessary to provide complete identification of FH variants in multiethnic populations. Second, our study included predominantly male veterans (<10% women) over the age of 50 years, which is not representative of the general population. Future larger-scale genomic studies of FH need to cover broader demographics, especially younger participants,18 because severe FH often leads to greater cardiovascular disease risk in young- and middle-aged adults. Lastly, the older age of MVP participants may introduce ascertainment bias by not including individuals with more severe clinical outcomes (eg, death) at a younger age. Although we were not able to quantify such bias using available data, such a loss of severe FH patients may have resulted in an observed phenotypic effect of ≥1 FH variants that is lower than the true overall effect of that variant on LDL-C.
Both genetic and environmental factors can potentially modify the effects of FH variants on LDL-C. Because there were no previous reports of such gene-gene or gene-environment interactions for FH pathogenicity, we assumed the independence between pathogenic variants and other genetic (eg, protective variants) or environmental factors in present study. Other molecular factors such as lipoprotein (a) may also influence the genetic effects of FH variants, particularly in regards to race differences. Because lipoprotein (a) was not systematically measured, we did not examine its influence on FH variants in present study.
FH patients have elevated LDL-C throughout life but are underdiagnosed and undertreated in the general population. Effective treatment to reduce the risk of developing atherosclerotic diseases requires timely diagnosis at the youngest age possible. Universal screening through gene sequencing has the potential to identify all individuals with FH but is not yet feasible or cost effective. Because FH is an autosomal dominant disorder, targeted screening (eg, cascade screening19 and child-parent screening20,21) among the family members of index cases may be more efficient. Positive genotyping of pathogenic FH variants is often used as a critical component of the diagnosis.18,22,23
The precision of a genetic diagnosis depends on accurate annotation of pathogenicity. Our findings of heterogeneous phenotypic effects within and across individual FH variants highlight the limitations in the ability to correctly classify the pathogenicity of many of these variants hindering a clinician’s optimal interpretation and application of the results of genetic tests for FH. Given the wide range of individual FH variants’ effects on LDL-C, we suggest including additional components of the evidence to better annotate the pathogenicity in current databases, such as ClinVar. Such annotation components should add the summary statistics from family-based or population-based studies of individual disease-causing variants to assist the researchers to accurately assess and rank the evidence of pathogenicity beyond putatively functional changes. Broadly, we recommend extra caution when interpreting the potential effect on LDL-C of a purported FH variant that has not been examined in large-scale population studies. This extra caution includes the search for additional evidence of pathogenicity through the careful documentation of a family history of hyperlipidemia and CHD. Importantly, both cholesterol-based and genotype-based testing for the diagnosis of FH should continue to be used.24 Among individuals with no family history or other pathognomonic clinical signs of FH, cholesterol level may serve as a primary testing, with gene testing adding to cardiovascular disease risk prediction in certain individuals carrying validated pathogenic variants.

Acknowledgments

This research is based on data from the Million Veteran Program (MVP), Office of Research and Development, Veterans Health Administration. This publication does not represent the views of the Department of Veterans Affairs or the US Government. We thank all Veteran participants in the MVP for donating their samples, information, and time to this project. In addition, we thank all the MVP staff working in the various operational domains, including the biorepository, recruitment sites, VA Central Office, and clinicians for all their efforts to ensure the success of the MVP.

Supplemental Material

File (circgenetics_circcvg-2018-002192_supp1.pdf)

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Published In

Go to Circulation: Genomic and Precision Medicine
Go to Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine
PubMed: 31106297

History

Received: 27 March 2018
Accepted: 1 November 2018
Published in print: December 2018
Published online: 11 December 2018

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Keywords

  1. atherosclerosis
  2. coronary disease
  3. familial hypercholesterolemia
  4. genetic testing
  5. pathogenicity
  6. PheWAS

Subjects

Authors

Affiliations

Yan V. Sun, PhD, MS [email protected]
Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA (Y.V.S., Q.H.)
Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA (Y.V.S.)
Scott M. Damrauer, MD
Corporal Michael Crescenz VA Medical Center, University of Pennsylvania, Philadelphia, PA (S.M.D.)
Qin Hui, PhD
Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA (Y.V.S., Q.H.)
Themistocles L. Assimes, MD, PhD
VA Palo Alto Health Care System, Department of Medicine, Stanford University School of Medicine, CA (T.L.A., P.S.T.).
Yuk-Lam Ho, MPH
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (Y.-L.H., J.H., S.P., J.P.H., J.M.G., K.C., C.J.O.).
Pradeep Natarajan, MD
Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N.).
Department of Medicine, Harvard Medical School, Program in Medical and Population Genetics, Broad Institute of Harvard & MIT, Cambridge, MA (P.N.).
Derek Klarin, MD
Massachusetts General Hospital, Boston, MA (D.K.).
Broad Institute of Harvard and MIT, Cambridge, MA (D.K.).
Jie Huang, PhD
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (Y.-L.H., J.H., S.P., J.P.H., J.M.G., K.C., C.J.O.).
Julie Lynch, PhD, RA
University of Massachusetts College of Nursing and Health Sciences, Boston, MA (J.L.).
Department of Veterans Affairs Salt Lake City, Health Care System, UT (J.L., S.L.D.).
Scott L. DuVall, PhD
Department of Veterans Affairs Salt Lake City, Health Care System, UT (J.L., S.L.D.).
School of Medicine, University of Utah, Salt Lake City, UT (S.L.D.).
Saiju Pyarajan, PhD
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (Y.-L.H., J.H., S.P., J.P.H., J.M.G., K.C., C.J.O.).
Jacqueline P. Honerlaw, MPH
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (Y.-L.H., J.H., S.P., J.P.H., J.M.G., K.C., C.J.O.).
J. Michael Gaziano, MD
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (Y.-L.H., J.H., S.P., J.P.H., J.M.G., K.C., C.J.O.).
Department of Medicine, Brigham and Women’s Hospital, Boston, MA (J.M.G., K.C.)
Kelly Cho, PhD, MPH
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (Y.-L.H., J.H., S.P., J.P.H., J.M.G., K.C., C.J.O.).
Department of Medicine, Brigham and Women’s Hospital, Boston, MA (J.M.G., K.C.)
Daniel J. Rader, MD
Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA (D.J.R.)
Christopher J. O’Donnell, MD, MPH
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (Y.-L.H., J.H., S.P., J.P.H., J.M.G., K.C., C.J.O.).
Harvard Medical School, Boston, MA (C.J.O.)
Philip S. Tsao, PhD
VA Palo Alto Health Care System, Department of Medicine, Stanford University School of Medicine, CA (T.L.A., P.S.T.).
Peter W. F. Wilson, MD [email protected]
Atlanta VA Medical Center and Emory Clinical Cardiovascular Research Institute, Atlanta, GA (P.W.F.W.).
On behalf of the VA Million Veteran Program*
Million Veteran Program (MVP) Executive Committee

Notes

*
A list of Members of VA Million Veteran Program are listed in the Appendix.
Guest Editor for this article is Christopher Semsarian, MBBS, PhD, MPH.
The Data Supplement is available at Supplemental Material.
Yan V. Sun, PhD, MS, Department of Epidemiology, Emory University Rollins, School of Public Health, 1518 Clifton Rd. NE, Atlanta, GA 30322, email [email protected]
Peter W.F. Wilson, MD, Atlanta VA Medical Center, Emory Clinical Cardiovascular Research Institute, 1670 Clairmont Rd, Decatur, Atlanta, GA 30033, email [email protected]

Disclosures

None.

Sources of Funding

This research was supported by award I01-BX003340, I01-BX003362 and I01-BX002641 from the Department of Veterans Affairs. Dr Sun is partially supported by National Institutes of Health grant R1NR13520.

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  1. Improved Genetic Characterization of Hypercholesterolemia in Latvian Patients with Familial Hypercholesterolemia: A Combined Monogenic and Polygenic Approach Using Whole-Genome Sequencing, International Journal of Molecular Sciences, 25, 24, (13466), (2024).https://doi.org/10.3390/ijms252413466
    Crossref
  2. Apolipoproteins in Health and Disease, International Journal of Molecular Sciences, 25, 13, (7048), (2024).https://doi.org/10.3390/ijms25137048
    Crossref
  3. Development and utility of a clinical research informatics application for participant recruitment and workflow management for a return of results pilot trial in familial hypercholesterolemia in the Million Veteran Program, JAMIA Open, 7, 1, (2024).https://doi.org/10.1093/jamiaopen/ooae020
    Crossref
  4. Design and pilot results from the Million Veteran Program Return Of Actionable Results (MVP-ROAR) Study, American Heart Journal, 276, (99-109), (2024).https://doi.org/10.1016/j.ahj.2024.04.021
    Crossref
  5. Advances in familial hypercholesterolemia, Advances In Clinical Chemistry, (167-201), (2024).https://doi.org/10.1016/bs.acc.2024.02.004
    Crossref
  6. Prevalence of FH-Causing Variants and Impact on LDL-C Concentration in European, South Asian, and African Ancestry Groups of the UK Biobank—Brief Report, Arteriosclerosis, Thrombosis, and Vascular Biology, 43, 9, (1737-1742), (2023)./doi/10.1161/ATVBAHA.123.319438
    Abstract
  7. Does low-density lipoprotein fully explain atherosclerotic risk in familial hypercholesterolemia?, Current Opinion in Lipidology, 34, 2, (52-58), (2023).https://doi.org/10.1097/MOL.0000000000000868
    Crossref
  8. Effects of PCSK9 missense variants on molecular conformation and biological activity in transfected HEK293FT cells, Gene, 851, (146979), (2023).https://doi.org/10.1016/j.gene.2022.146979
    Crossref
  9. Novel Finnish-enriched variants causing severe hypercholesterolemia and their clinical impact on coronary artery disease, Atherosclerosis, 386, (117327), (2023).https://doi.org/10.1016/j.atherosclerosis.2023.117327
    Crossref
  10. Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Clinically Observed Longitudinal Cholesterol Exposure, Circulation: Genomic and Precision Medicine, 15, 2, (e003501), (2022)./doi/10.1161/CIRCGEN.121.003501
    Abstract
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Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program
Circulation: Genomic and Precision Medicine
  • Vol. 11
  • No. 12

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