Research Article

Genetic identification of familial hypercholesterolemia within a single U.S. health care system

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Science  23 Dec 2016:
Vol. 354, Issue 6319, aaf7000
DOI: 10.1126/science.aaf7000

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Unleashing the power of precision medicine

Precision medicine promises the ability to identify risks and treat patients on the basis of pathogenic genetic variation. Two studies combined exome sequencing results for over 50,000 people with their electronic health records. Dewey et al. found that ∼3.5% of individuals in their cohort had clinically actionable genetic variants. Many of these variants affected blood lipid levels that could influence cardiovascular health. Abul-Husn et al. extended these findings to investigate the genetics and treatment of familial hypercholesterolemia, a risk factor for cardiovascular disease, within their patient pool. Genetic screening helped identify at-risk patients who could benefit from increased treatment.

Science, this issue p. 10.1126/science.aaf6814, p. 10.1126/science.aaf7000

Structured Abstract


Familial hypercholesterolemia (FH) is a public health genomics priority but remains underdiagnosed and undertreated despite widespread cholesterol screening. This represents a missed opportunity to prevent FH-associated cardiovascular morbidity and mortality. Pathogenic variants in three genes (LDLR, APOB, and PCSK9) account for the majority of FH cases. We assessed the prevalence and clinical impact of FH-associated genomic variants in 50,726 individuals from the MyCode Community Health Initiative at Geisinger Health System who underwent exome sequencing as part of the DiscovEHR human genetics collaboration with the Regeneron Genetics Center.


Genetic testing for FH is uncommon in clinical practice in the United States, and the prevalence of FH variants in U.S. populations has not been well established. We sought to evaluate FH prevalence in a large integrated U.S. health care system using genomic sequencing and electronic health record (EHR) data. We determined the impact of FH variants on low-density lipoprotein cholesterol (LDL-C) levels and coronary artery disease (CAD) risk. We assessed the likelihood of FH variant carriers achieving a presequencing EHR-based FH diagnosis according to established clinical diagnostic criteria. Finally, we examined the rates of statin medication use and outcomes in FH variant carriers.


Thirty-five known and predicted pathogenic variants in LDLR, APOB, and PCSK9 were identified in 229 individuals. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variants were found in only 2.5% of individuals with severe hypercholesterolemia (maximum EHR-documented LDL-C ≥ 190 mg/dl) in the cohort, and a maximum LDL-C of ≥190 mg/dl was absent in 45% of FH variant carriers. Overall, FH variant carriers had 69 ± 3 mg/dl greater maximum LDL-C than sequenced noncarriers (P = 1.8 × 10−20) and had significantly increased odds of general and premature CAD [odds ratio (OR), 2.6 (P = 4.3 × 10−11) and 3.7 (P = 5.5 × 10−14), respectively]. The increased odds of general and premature CAD were most pronounced in carriers of LDLR predicted loss-of-function variants [OR, 5.5 (P = 7.7 × 10−13) and 10.3 (P = 9.8 × 10−19), respectively]. Fourteen FH variant carriers were deceased; chart review revealed that none of these individuals had a clinical diagnosis of FH. Before genetic testing, only 15% of FH variant carriers had an ICD-10 (International Classification of Diseases, 10th revision) diagnosis code for pure hypercholesterolemia or had been seen in a lipid clinic, suggesting that few had been previously diagnosed with FH. Retrospectively applying Dutch Lipid Clinic Network diagnostic criteria to EHR data, we found presequencing criteria supporting a probable or definite clinical diagnosis of FH in 24% of FH variant carriers, highlighting the limitations of using existing clinical criteria for EHR-based screening in the absence of genetic testing. Active statin use was identified in 58% and high-intensity statin use in 37% of FH variant carriers. Only 46% of carriers currently on statin therapy had a most recent LDL-C level below 100 mg/dl compared to 77% of noncarriers.


In summary, we show that large-scale genomic screening in patients with longitudinal EHR data has the ability to detect FH, uncover and characterize novel pathogenic variants, determine disease prevalence, and enhance overall knowledge of clinical impact and outcomes. The 1:256 prevalence of FH variants in this predominantly European-American cohort is in line with prevalence estimates from recent work in European cohorts. Our findings highlight the undertreatment of FH variant carriers and demonstrate a potential clinical benefit for large-scale sequencing initiatives in service of precision medicine.

Prevalence and clinical impact of FH variants in a large U.S. clinical care cohort.

(A) Distribution of 229 heterozygous carriers of an FH variant in the DiscovEHR cohort by FH gene. (B) Prevalence of an FH variant in the DiscovEHR cohort and according to recruitment site. (C) Prevalence of an FH variant among individuals with severe hypercholesterolemia (LDL-C ≥ 190 mg/dl). (D) Statin treatment rates and outcomes in FH variant carriers and noncarriers.


Familial hypercholesterolemia (FH) remains underdiagnosed despite widespread cholesterol screening. Exome sequencing and electronic health record (EHR) data of 50,726 individuals were used to assess the prevalence and clinical impact of FH-associated genomic variants in the Geisinger Health System. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variant carriers had significantly increased risk of coronary artery disease. Only 24% of carriers met EHR-based presequencing criteria for probable or definite FH diagnosis. Active statin use was identified in 58% of carriers; 46% of statin-treated carriers had a low-density lipoprotein cholesterol level below 100 mg/dl. Thus, we find that genomic screening can prompt the diagnosis of FH patients, most of whom are receiving inadequate lipid-lowering therapy.

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