HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study

Abstract

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the Atherosclerosis Risk in the Communities study with H63D genotyping (N=10902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type/wild type, H63D/wild type, and H63D/H63D were 71.1%, 24.6% and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure (p=0.004), diastolic blood pressure (0.012), and more frequently had hypertension (p<0.001). Compared to wild type/wild type, H63D/wild type and H63D/H63D participants had a 2–4% and 4–7% absolute increase in hypertension risk at each visit, respectively. The population attributable risk of H63D for hypertension among individuals aged 45–64 was 3.2% (95% CI 1.3–5.1%) and 1.3% (95% CI 0.0–2.4%) among individuals >65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome (p>0.05). H63D/wild type and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE-H63D variant confers an increased risk for hypertension per allele and, given its frequency accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.

INTRODUCTION

Hereditary hemochromatosis is an autosomal recessive disorder that results in disturbances of iron metabolism and eventual iron overload. Genetic alteration in the coding of the major histocompatibility complex class I-like transmembrane protein (HFE) causes increased cellular iron uptake from the intestine.¹ Iron accumulation in tissues releases free radicals, causing oxidant-mediated cellular injury and development of cardiomyopathy.² While iron itself may be toxic to the myocardium, other pathways of injury have been proposed. Iron overload can cause peroxidation of LDL cholesterol leading to atherosclerosis and coronary artery disease.³ In addition, a large recent genome wide association study (GWAS) identified a genetic variant in iron metabolism, HFE H63D (rs1799945), as a novel variant also associated with the prevalence of hypertension, which could also predispose to cardiomyopathy.⁴

HFE C282Y is the most common mutation identified in patients with a clinical diagnosis of hemochromatosis, and therefore the vast majority of studies analyzing hemochromatosis variants and cardiovascular disease have focused on it, while little attention has been paid to H63D, a much more common variant in the population. Studies suggest up to 25% of individuals of European descent are carriers for the H63D variant.^{1, 5, 6} Although phenotypic penetrance for hemochromatosis is low, H63D carriers still demonstrate higher levels of ferritin and transferrin saturation.⁷ Patients with the C282Y variant may be at increased risk for HF, but data evaluating whether H63D carriers share an increased risk are scarce.

Though H63D is associated with hypertension based upon GWAS data, quantifying the population attributable risks provides important, relevant data from a public health perspective. In addition, whether the H63D variant is associated with left ventricular (LV) remodeling and heart failure (HF) or other adverse cardiovascular events has not been studied. The Atherosclerosis Risk in the Community (ARIC) study is a large, community-based study of the natural history of atherosclerosis related diseases. Given long-term follow-up, comprehensive echocardiographic data, and adjudicated outcomes, ARIC is an ideal platform to study the relationship between the HFE H63D variant and cardiovascular disease.

METHODS

Consistent with policies related to the ARIC study, data and study materials are not made publically available.

ARIC study design and objectives

The design of the ARIC study has been described in detail previously.⁸ ARIC is a prospective observational study designed to study the natural history of atherosclerosis risk factors in 4 communities across the United States (Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; and Washington County, MD) comprised of 15,792 men and women, aged 45–64 years recruited between 1987 and 1989 (visit 1). Participants were examined approximately every 3 years until 1998, with a second examination in 1990–1992, a third in 1993–1995, and a fourth in 1996–1998. Participants returned for visit 5 between June 2011 and August 2013, during which comprehensive echocardiographic data were obtained. Annual telephone interviews were conducted in between visits. The institutional review board at each participating site approved the study protocol, and informed consent was obtained in writing at each examination. For the present study, we analyzed white participants (N=11,478) in whom the H63D is common and associated with hypertension.⁴ We excluded participants with missing genotypic data (either due to lack of consent or inadequate quality) for rs1799945 (N=576), leaving 10,902 participants for analysis.

Definition of comorbidities and characteristics of laboratory testing

Hypertension was defined by a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or currently taking antihypertensive medication, similar to the Joint National Committee 7 (JNC7) definition for hypertension. Blood pressure was reported after averaging two readings. At visits 1–3 and 5, the average was taken from the last two of three readings, while only 2 readings were measured at visit 4. Diabetes was defined by a self-report of physician diagnosis of diabetes, fasting serum glucose of ≥126 mg/dl, a non-fasting glucose ≥200 mg/dl, or pharmacologic treatment for diabetes. Prevalent coronary heart disease was defined by electrocardiographic evidence of myocardial infarction, or reported history of myocardial infarction or revascularization. Prevalent HF at visit 1 was defined by use of medications for HF or satisfied Gothenburg criteria. Atrial fibrillation and flutter were defined by electrocardiographic evidence. All laboratory testing presented here were derived from visit 1. Iron studies in ARIC were obtained in a subsample, including 609 participants that met the present study inclusion criteria. There was a graded increase in the median (25^th-75^th percentile) ferritin levels from wild type (WT)/WT (110 ng/ml; 53–210 ng/ml) to H63D/WT (121 ng/ml; 52–240 ng/ml) and H63D/H63D (157 ng/ml; 71–617 ng/ml), though this was not statistically significant, likely due to lack of power (p=0.08).⁹ However, larger previous analyses of Caucasian patients have demonstrated increased iron stores (defined as transferrin saturation >45%) among H63D/wild type (WT) (12%) and H63D/H63D (15%) individuals compared to WT/WT individuals (5%).¹⁰

Genotyping

Genotyping for rs1799945 within the ARIC study was performed using the hME (homogeneous MassEXTEND) assay (Sequenom, Inc.; San Diego, CA, USA) in accordance with the manufacturer’s instructions. Custom designed primers utilized for the hME assay are as follows: PCR forward 5’-ACGTTGGATGTCTACTGGAAACCCATGGAG-3’, PCR reverse 5’-ACGTTGGATGTTGAAGCTTTGGGCTACGTG-3’, and extension 5’-CAGCTGTTCGTGTTCTATGAT-3’. The extension products were analyzed with the SpectroREADER (Sequenom, Inc.) which is a Bruker Biflex III matrix-assisted laser desorption/ionization – time of flight (MALDI-TOF) instrument. Mass spectra were collected and SpectroCALLER (Sequenom, Inc.) was used to automatically assign the genotype calls. All genotypes were visually checked for confirmation. Quality control criteria were used to filter SNPs containing possible errors. SNPs were excluded from analysis based on previously established thresholds for SNP call rates, Hardy–Weinberg P values, and minor allele frequencies.¹¹

Event Ascertainment

Longitudinal outcomes of the study included coronary heart disease, ischemic or hemorrhagic stroke, atrial fibrillation, HF, and mortality. Coronary heart disease was defined by definite or probable myocardial infarction, definite coronary heart disease death, coronary revascularization, or silent myocardial infarction detected by electrocardiography. Data on strokes were obtained using hospital records for possible stroke-related hospitalizations. Physician reviewers adjudicated all possible strokes and classified them as definite or probable ischemic or hemorrhagic events. Atrial fibrillation was defined by an electrocardiogram showing atrial fibrillation, hospital discharge coded as atrial fibrillation, or atrial fibrillation listed as a cause of death. HF was defined by HF hospitalization or HF death. Mortality data were obtained by trained abstractors who accrued information about all out-of-hospital deaths via death certificates, hospitalized patients, physician questionnaires, and next-of-kin interview. Events were ascertained during follow-up visits for the ARIC study as well as through annual calls to participants, ongoing surveillance of health department certificate files, and review of local hospital-discharge lists (with outcomes determined on the basis of International Classification of Diseases codes). Follow-up is complete through December 31, 2015 for all outcomes aside from atrial fibrillation (which is reported through December 31, 2011). The methods utilized for quality control, detection, and adjudication of events have been previously presented.^{3, 12–14}

Echocardiography

Comprehensive echocardiograms were performed at visit 5 (between 2011 and 2013), according to a study-specific protocol and were analyzed in a core laboratory; the protocol and reproducibility have been described previously.^{15, 16} Echocardiographic data were available for 4507 participants with genotype status at visit 5. Left ventricular function was also assessed by means of speckle-tracking echocardiography (TomTec Imaging Systems).¹⁷

Statistical analysis

Baseline characteristics were summarized using descriptive statistics for continuous variables and counts and percentages for categorical variables, stratified by genotype status (WT/WT, H63D/WT, and H63D/H63D). Unadjusted p-values for trend are shown.

The association of the rs1799945 variant with systolic blood pressure, prevalent hypertension, and anti-hypertensive medication use at each of the 5 study visits was analyzed. We subsequently performed interaction analysis by sex and body mass index. We calculated the population attributable fraction as the percent of cases of hypertension that could be attributed to the H63D allele. In a sensitivity analysis, we defined hypertension as SBP ≥ 130 mmHg or DBP ≥ 80 mmHg, consistent with the latest recommendation for the definition of hypertension by professional societies.¹⁸ Next, we performed univariate Cox proportional hazards models to determine the relationship between the variant and adverse outcomes. Follow‐up time was calculated as the time from visit 1 to the time of the first event for each of the outcomes. For analyses regarding incident HF and atrial fibrillation, those with prevalent conditions at baseline at the time were excluded. Hazard ratios and associated 95% confidence intervals were calculated using Cox proportional hazards regression. Patients were censored if they were lost to follow-up or died (for non-mortality analyses). Cumulative incidence curves were calculated for each outcome.

In a subgroup analysis of individuals attending visit 5, we studied the association between genotype status and echocardiographic measures. P-values were calculated for trend using ANOVA or chi-squared test, as appropriate. All analyses were performed using STATA version 14 (StataCorp LLC; College Station, TX, USA), and a two-sided p-value < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics

Table 1 lists the baseline characteristics of the study population, stratified by genotype status for rs1799945. Of the study population of 10,902 white participants with available genotype, 2676 (24.6%) were heterozygous and 259 (2.4%) were homozygous for the H63D variant. The average age was 54.9±5.7 years and 47% were men. Participants with a variant in H63D had higher systolic blood pressure (p=0.004) and diastolic blood pressure (p=0.012), more frequently had hypertension (p<0.001), diabetes mellitus (p=0.007), took antihypertensive therapy (p=0.003), and had higher hemoglobin levels (p<0.001). There was no difference in age, sex, heart rate, body mass index, or renal function.

TABLE 1. Baseline Clinical Characteristics of the Study Sample by rs1799945.

Clinical Characteristics	WT/WT N=7967	H63D/WT N=2676	H63D/H63D N=259	P-value
Age, years	54.9 ± 5.7	54.8 ± 5.7	55.0 ± 5.6	0.91
Male, n (%)	3758 (47.2%)	1262 (47.2%)	126 (48.6%)	0.81
Physical Exam
Systolic blood pressure (mm Hg)*	118 ± 17	119 ± 17	121 ± 17	0.004
Diastolic blood pressure (mm Hg)*	71 ± 10	72 ± 10	72 ± 10	0.012
Heart rate (beats/minute)	67 ± 10	67 ± 10	67 ± 10	0.22
Body mass index (kg/m2)	27.0 ± 4.9	27.1 ± 4.8	27.3 ± 4.9	0.10
Comorbidities, n (%)
Hypertension	2090 (26.4%)	779 (29.2%)	86 (33.3%)	<0.001
Diabetes mellitus	693 (8.7%)	261 (9.8%)	35 (13.5%)	0.007
Coronary heart disease	398 (5.1%)	131 (5.0%)	16 (6.3 %)	0.74
Current smoker	1950 (24.5%)	685 (25.6%)	66 (25.5%)	0.26
Heart failure	315 (4.0%)	102 (3.9%)	10 (3.9%)	0.73
Atrial fibrillation or flutter	19 (0.2%)	7 (0.3%)	0 (0.0 %)	0.81
Medication Use, n (%)
Any anti-hypertensive medication	1522 (19.1%)	571 (21.3%)	61 (23.6%)	0.003
Glucose lowering medication	271 (3.4 %)	93 (3.5%)	15 (5.8 %)	0.22
Anti-anginal medication	213 (2.7 %)	76 (2.8 %)	11 (4.2 %)	0.24
Laboratory Testing
Estimated glomerular filtration rate (mL/min/1.78 m2)	90 ± 18	90 ± 18	90 ± 19	0.92
Hemoglobin (mg/dL)	14.1 ± 1.3	14.2 ± 1.3	14.3 ± 1.3	<0.001
Low density lipoprotein (mg/dL)	137± 38	138 ± 37	139 ± 37	0.48

P-value shown for trend.

^*Blood pressures displayed are not adjusted for medication use.

WT, wild type.

Association of genotype status with hypertension prevalence

Figure 1 shows the relationship between genotype status and hypertension prevalence at each of the 5 visits. There was a consistently increased and graded risk associated with the H63D variant at each of the 5 study visits, such that H63D/H63D had the highest risk followed by H63D/WT status (p<0.001). Table S1 details the systolic blood pressure and frequency of hypertension at each visit. When compared to WT/WT, carriers had a roughly 2–4% absolute increase in hypertension prevalence at each visit, while H63D/H63D participants had a 4–7% absolute increase risk at each visit. There was no interaction by sex or body mass index at visit 1 (p>0.10 for each interaction).

Figure 1: Prevalence of Hypertension at Each ARIC Follow-up Visit by Genotype Status.

Prevalence of hypertension is displayed at each of the 5 follow-up visits by genotype status of H63D. Visits occurred during the following years: 1 (1987–1989), 2 (1990–1992), 3 (1993–1995), 4 (1996–1998) and 5 (2011–2013). The table below shows the prevalence of hypertension at each visit, with p-values denoted for trend. WT = wild type; ARIC, Atherosclerosis Risk in Communities.

The population attributable fraction of the H63D allele for hypertension at visit 1, during middle age, was 3.2% (5% CI 1.3–5.1%). After adjusting for age, sex, and ARIC center, the estimate was stable (3.2%, 95% CI 1.3–5.0). By visit 5, the population attributable risk of H63D for hypertension declined to 1.3% (95% CI 0.0–2.4) and adjustment for the same covariates yielded a similar result (1.2%, 95% CI 0.2–2.3). However, after visit 1, there was generally no difference in mean systolic blood pressure associated with the H63D allele despite the increase in prevalence of hypertension, reflecting increased use of medical therapy for control of blood pressure as demonstrated in Table S1.

We performed a sensitivity analysis using the updated definition for hypertension (supplementary table S2). Using this definition, there was an increased risk for hypertension at visit 1 (WT/WT 39.3%, H63D/WT 42.1%, H63D/H63D 44.2%, p=0.005). The difference in hypertension prevalence associated with H63D persisted at most study visits. The population attributable fraction of the H63D allele for hypertension using the updated definition at visit 1 was 2.0% (5% CI 0.5–3.4%). By visit 5, the population attributable risk of H63D for hypertension declined to 1.3% (95% CI 0.2–2.4).

Association of genotype status with clinical outcomes

Table 2 shows event rates and crude hazard ratios for all outcomes (HF, coronary heart disease, stroke, atrial fibrillation, and mortality), stratified by rs1799945 genotype status. WT/WT was designated as the referent group. There was no significant relationship between genotype status and any outcome on univariate analysis or after age and sex adjustment (p>0.05 for all comparisons). Figure 2 shows cumulative incidence curves for each of the outcomes, demonstrating no difference by genotype status (p>0.10 for all outcomes).

TABLE 2. Event Rates and Crude and Hazard Ratios for Adverse Cardiovascular Outcomes by rs1799945.

Outcomes, n (%)	WT/WT N=7967	H63D/WT N=2676	H63D/H63D N=259	P-value
Heart failure
• Event rate (per 1000 person-years)	8.5 (8.1, 9.0)	9.1 (8.4, 10.0)	9.0 (6.8, 12.0)
• Crude model HR (95% CI)	ref	1.08 (0.97, 1.19)	1.07 (0.80, 1.43)	0.16
Coronary heart disease
• Event rate (per 1000 person-years)	11.4 (10.9, 11.9)	11.1 (10.2, 12.0)	13.2 (10.4, 16.7)
• Crude model HR (95% CI)	ref	0.97 (0.89, 1.06)	1.16 (0.91 1.48)	0.89
Ischemic or hemorrhagic stroke
• Event rate (per 1000 person-years)	3.3 (3.1, 3.6)	3.5 (3.0, 4.0)	4.7 (3.2 6.9)
• Crude model HR (95% CI)	ref	1.05 (0.90, 1.23)	1.43 (0.97, 2.12)	0.15
Atrial fibrillation
• Event rate (per 1000 person-years)	7.6 (7.1, 8.0)	8.1 (7.3, 8.9)	7.3 (5.3, 10.2)
• Crude model HR (95% CI)	ref	1.07 (0.96, 1.20)	0.98 (0.70, 1.37)	0.37
Mortality
• Event rate (per 1000 person-years)	17.7 (17.1, 18.3)	17.7 (16.7, 18.8)	20.5 (17.2, 24.5)
• Crude model HR (95% CI)	ref	1.01 (0.94, 1.08)	1.18 (0.98, 1.41)	0.30

P-value shown for trend.

WT, wild type.

Figure 2: Cumulative Incidence Curves for Heart Failure, Coronary Heart Disease, Stroke, Atrial Fibrillation, and Mortality by Genotype Status.

Cumulative incidence curves for each of the study outcomes by genotype status. P-value shown for logrank test. WT = wild type.

Echocardiographic correlates by genotype status

To determine whether the increased risk of hypertension among H63D carriers and homozygotes translated into echocardiographic changes in structure and function, we performed a sub-analysis among the 4507 surviving participants who attended the 5^th visit (Table S3). Participants with H63D/WT and H63D/H63D genotypes demonstrated smaller LV end-diastolic dimension, greater LV interventricular wall thickness, and lower mitral inflow E/A ratio (p<0.05 for all comparisons). There was no difference in ejection fraction, LV mass, LV hypertrophy, or LV longitudinal or circumferential strain (p>0.05 for all comparisons).

DISCUSSION

In a large study of unselected white participants with greater than 25 years of follow-up, we found that the presence of the HFE H63D variant increased the risk of hypertension significantly among both heterozygotes and homozygotes for the variant. The population attributable fraction of H63D for hypertension was 3.2% in middle age (ages 45–64) and 1.3% among patients at least 65 years old. Despite the increase in hypertension risk, a statistically increased risk for HF, coronary heart disease, stroke, atrial fibrillation, or mortality was not detected. In an subanalysis, participants with the H63D variant displayed only mild evidence of LV remodeling. The lack of significant echocardiographic remodeling and increased rates of adverse events may have been related to effective blood pressure control through medical therapy, as systolic blood pressures were equivalent between genotype groups in follow-up visits despite the greater prevalence of hypertension.

Despite the greater increase in hypertension among participants with the H63D variant, there was no significant increase in adverse cardiovascular events. Significant blood pressure control is likely responsible for this, and reinforces the importance of anti-hypertensive therapy in reducing cardiovascular risk whether hypertension derives from genetic or environmental etiologies. It is possible that the lack of blood pressure difference at visits subsequent to intake may have been due to increased medical surveillance of the hypertensive participants after enrollment.

The increased risk for hypertension with H63D has been demonstrated in a recent, large GWAS study.⁴ In our study, H63D heterozygotes and homozygotes had a 2–4% and 4–7% absolute increase in the prevalence at hypertension at each visit, respectively. The population attributable risk for each H63D allele in middle age was 3.2%, which declined to 1.2% in late life. The decrease in the risk for hypertension related to H63D as well as the decreasing population attributable risk are likely related to increasing prominence of other causes of hypertension with aging. This observation may also explain the lack of increased risk for several adverse outcomes over time. While we specifically studied white participants from ARIC, this likely translates to a substantial number of cases of hypertension in the United States that can be attributed to H63D.¹⁹

How the H63D variant may contribute to hypertension remains unclear. H63D may increase iron stores, produce oxidative stress,² and cause toxic injury to the vascular endothelium,²⁰ as high iron stores are associated with vascular stiffness.²¹ However, there are important inconsistencies with this hypothesis. For example, while patients with H63D variants have increased iron saturation compared to controls,¹⁰ such patients rarely develop significant iron overload or related complications. Further, when patients with the H63D variant present with clinical hemochromatosis, it is often a milder form when compared to C282Y/C282Y variants, who possess higher burdens of iron overload, particularly when disease is manifest.²² In addition, despite the higher ferritin levels and transferrin saturation among patients with the C282Y/C282Y genotype, there does not appear to be a significant increased risk for hypertension among patients with the C282Y variant.^{4, 11, 23}.

Therefore, the H63D variant may cause hypertension through altered hepcidin-signaling pathways, or perhaps pathways that do not directly involve iron overload.⁴ For example, HFE was recently shown to signal through ALK3, a bone morphogenetic protein (BMP),²⁴ and BMPs can have important downstream consequences on vascular development.²⁵ Further research into H63D as a potential pharmaceutical target would be helpful, though the benefit of such therapy would likely be more apparent during middle age (when H63D accounts for a greater risk for hypertension) rather than later in life.

The prevalence of H63D/WT (24.6%) and H63D/H63D (2.4%) variants in our study were consistent with previous population based estimates of the genotype among non-Hispanic whites.⁶ Interestingly, even H63D/H63D patients in our study did not have an increased risk for HF. This may be related to the lower disease penetrance conferred by the variant.^{10, 26} The importance of evaluating the cardiovascular risk by H63D genotype in an unbiased patient population cannot be overstated. Previous studies have typically employed case-control methodologies in patients with cardiomyopathies which can provide overestimates of the allelic risk,^27–30 as has been demonstrated in other potentially heritable cardiomyopathies.³¹

Given the rapid increase and availability of genetic testing, previous questions have been raised regarding the benefits of genetic screening for hemochromatosis, given its high genetic prevalence and the potential to intervene early to reduce iron stores. Our study does not support the use of widespread screening for the H63D variant, as it does not seem to confer a significantly increased risk for adverse events despite an increase in hypertension. Further, it is unclear whether iron overload is even responsible for the increased risk for hypertension. Our findings are inline with a consensus statement from the United States Preventative Services Task Force that recommends against screening for hemochromatosis in the general population.³²

Strengths of our study include the analysis of an unselected population in order to understand the true increased risk associated with the variant, large sample size, comprehensive delineation of patient characteristics, several adjudicated cardiovascular events, and long-term follow-up. There are some limitations of the study. Iron storage data were only available in a subset of ARIC participants, which limits our ability to correlate the increased risk of hypertension with iron saturation. Next, the definition of some comorbidities, including diabetes, are not updated for current guidelines. Further, echocardiograms were performed at visit 5, and therefore patients with more severe phenotypes might not have presented or passed prior to the visit. However, while potential survival bias may have led to an underestimate of the severity of echocardiographic remodeling associated with the variant, there was still no difference in long-term outcomes. Finally, we may have been underpowered to detect more subtle associations between H63D genotype and outcomes, and meta-analysis of large cohorts studies could be helpful to further evaluate an association between genotype and outcome.

NOVELTY AND SIGNIFICANCE.

WHAT IS NEW?

HFE-H63D, a common variant among individuals of Northern European descent, increases the risk for hypertension and, given its frequency, likely accounts for a substantial number of cases of hypertension in the United States alone. However, the variant did not confer an increased risk for adverse cardiovascular events nor was there significant remodeling in an echocardiographic substudy of elderly individuals.

WHAT IS RELEVANT?

Because iron loading is typically mild in patients with the HFE-H63D variant, while other variants that cause more substantial iron overload do not cause hypertension, our study highlights the possible pleiotropic effects of the HFE-H63D gene and novel mechanisms through which the gene causes hypertension. In addition, because we show in over 25 years of follow-up there was no increased risk for adverse cardiovascular events, our findings are inline with consensus statements that recommend against screening for hemochromatosis in the general population.

SUMMARY:

H63D, a common variant in the hemochromatosis gene, is also associated with hypertension. We analyzed white ARIC participants to determine population-level risks for hypertension, cardiac remodeling, and adverse events. The population attributable risk for hypertension among individuals was 3.2% (ages 45–65) and 1.3% (>65 years). After 25 years of follow-up, there was no relationship between H63D and any outcome, with minor differences in cardiac remodeling. HFE-H63D accounts for a substantial number of cases without an increased risk for adverse events or significant LV remodeling.

PERSPECTIVES.

The presence of the H63D variant confers an allelic dose-dependent increased risk for hypertension. However, there was no significant increased risk for adverse cardiovascular events nor significant LV remodeling in a subgroup analysis. The mitigation of adverse echocardiographic features and outcomes may have been related to effective blood pressure control within each group. Despite the high burden of the H63D variant among whites, our results do not support the routine use of genetic screening to identify such individuals early. Future research is warranted to clarify the mechanism through which H63D leads to hypertension.