Family Coronary Heart Disease: A Call to Action

Abstract

A family history of coronary heart disease (CHD) is an accepted risk factor for cardiovascular events and is independent of common CHD risk factors. Advances in the understanding of genetic influences on CHD risk provide the opportunity to apply this knowledge and improve patient care. Utility of inherited cardiovascular risk testing exists by utilizing both phenotypes and genotypes and includes improved CHD risk prediction, selection of the most appropriate treatment, prediction of outcome, and family counseling. The major impediment to widespread clinical adoption of this concept involves un‐reimbursed staff time, educational needs, access to a standardized and efficient assessment mechanism, and privacy issues. The link between CHD and inheritance is indisputable and the evidence strong and consistent. For clinicians, the question is how to utilize this information, in an efficient manner, in order to improve patient care and detection of high‐risk family members. Copyright © 2010 Wiley Periodicals, Inc.

Robert Superko has no conflicts. Lakshmana Pendyala has no conflicts. Brenda Garrett is a consultant for CardioDx. Spencer King has no conflicts.

Supported in part by FEMA grant No. 2006‐FP‐01744 and the Cholesterol, Genetics and Heart Disease Institute.

Entire families sometimes show this tendency to early arteriosclerosis. A tendency which cannot be explained in any other way than that in the make‐up of the machine bad material was used for the tubing.

(Osler W. The Principles and Practice of Medicine. New York: D. Appleton & Co.; 1892:664.

The Need

Treatment of coronary heart disease (CHD) and the detection of individuals at high risk for CHD have made great advances in the past 2 decades.1 Programs designed to identify high‐risk individuals have been appropriately emphasized at the national and international level.2 Yet one aspect of CHD risk determination has been scientifically accepted but relatively underutilized in the clinical community, namely, incorporation of information gained from detailed analysis of family history and genetically linked blood test results into routine clinical care for the purpose of identifying very high‐risk individuals within family members.

A family history of CHD has long been accepted as a risk factor for future cardiovascular events and is independent of common CHD risk factors.3 With advances in our understanding of genetic influences on CHD risk, the time has come to apply this knowledge in routine clinical practice in order to improve patient care. Indeed, it may be past time. In 1989, Karl Berg wrote, “Knowledge of genetic factors in the etiology of coronary heart disease has not so far been adequately utilized in attempts to combat premature CHD. The time has now come to utilize genetic information in a setting of family‐oriented preventive medicine. This approach would greatly improve the efficiency of preventive efforts, utilizing predictive genetic testing and targeting counseling on those who need it most.”4 Clinical utility of this concept has now come of age and the purpose of this article is to illustrate the clinical utility of the incorporation of family‐oriented preventive cardiology into standard clinical practice.

A recent development in the availability of genetic testing makes the adoption of the family heart disease clinic model even more relevant. Heart disease gene testing is clinically available.5, 6 While appropriate clinical utility of some information remains unclear, practical clinical utility of inherited cardiovascular risk testing does exist utilizing both phenotypes and genotypes, and includes improved CHD risk prediction, selection of a treatment most likely to be successful in an individual patient, prediction of outcome, and family counseling.7, 8 The major impediment to widespread clinical adoption of this concept involves un‐reimbursed staff time, educational needs, and access to an efficient assessment mechanism. Privacy issues are addressed in the Federal Genetic Nondiscrimination Bill (Genetic Information Nondiscrimination Act H.R. 493 of 2008) that was signed into law by President Bush on May 22, 2008.9

Evidence for the Importance of Family History as a Major CHD Risk Factor

There are 4 clinically relevant sources of evidence linking CHD with inheritance and genetic issues; first, concentration of CHD in families, second, evidence derived from twin studies, third, the basic science of genetics, and fourth, phenotypes and genotypes linked by inheritance and knowledge regarding their clinical implications. A family history of “premature” heart disease is one of the most powerful determinants of CHD risk and is independent of the common CHD risk factors including smoking, hypertension, diabetes, and some lipids.10, 11 Numerous retrospective studies have been conducted indicating that the risk of CHD in siblings of victims of premature CHD, is approximately 50% for males and less for females.12, 13 In siblings of premature CHD patients the risk of dying from CHD was 5.2 times higher than a control population without such a family history. This risk can be compared to the 2‐fold to 3‐fold CHD risk associated with cigarette smoking.14

Numerous prospective studies of the risk for CHD in first‐degree relatives have been conducted including the Nurses' Health Study, the Western Collaborative Study, the Health Professional Follow‐Up Study, the Rancho Bernardo Study, the Framingham Study, the British Regional Heart Study, and the Utah Cardiovascular Genetic Research Program.15, 16, 17, 18, 19 These prospective investigations indicate that the risk of myocardial infarction (MI) is at least 2‐fold greater if a family history of CHD is present. Studies in twins provide powerful evidence of the importance of family history and genetics. A total of 21 004 Swedish twins have been followed for 26 years and provide evidence that premature death from CHD is strongly influenced by genetic factors.20

Noninvasive Imaging and Families

The finding that the risk for CHD is approximately 50% in siblings of premature CHD patients has been reproduced utilizing noninvasive imaging.21 Taylor et alreported on 1619 asymptomatic males who underwent coronary artery calcium (CAC) testing and, after controlling for the Framingham risk score, found a family history of CHD to be highly predictive of a positive CAC score with odds ratios approaching 1.50.22 In a similar study of 8549 asymptomatic individuals, a family history of CHD in a parent increased the odds ratio to 1.3 in men and women and a family history in a sibling increased the odds ratio to 2.3.23 A total of 78% of individuals reporting a sibling with known CHD had a positive CAC score.

Phenotype Vs Genotype

The use of genetic knowledge to improve patient care does not require direct DNA analysis. Some genetic polymorphisms have been linked to increased CHD risk, but for many polymorphisms the link is weak and/or inconsistent.24 Phenotypes that have an inherited pattern of transmission are established as CHD risk factors and are common in the CHD population and in family members.25 A seminal paper, published in 1992, reported that 77% of CHD patients examined expressed an inherited dyslipidemia and 54% of the first‐degree and second‐degree relatives expressed the same dyslipidemia.26 A large portion of family CHD risk screening can be accomplished with phenotypic tests that are clinically available to physicians and their patients. Table 1 lists phenotypes that can have a familial linkage pattern in 1489 patients with established CHD.

Table 1.

Prevalence for the entire group (All) and for the group who were at high CHD risk (ATP‐HR) according to ATP‐III (LDL‐C < 100 mg/dL) and (HDL‐C > 40 mg/dL), and those who met ATP lipid goals (ATP‐NL; modified from reference 25)

	All	ATP‐NL	ATP‐HR	P
n	1489	874 (59%)	615 (41%)
Small LDL (< 257 A)	32.2%	20.4%	43.3%	0.0001
HDL2 < 20%	55.2%	42.1%	73.0%	0.0001
Lp(a) > 25 (mg/dL)	25.0%	25.1%	22.0%	0.29
Hcy > 14 (μ mol/L)	10.0%	11.3%	9.2%	0.32
Fibrinogen > 350 mg/dL	37.9%	36.7%	41.5%	0.25

Abbreviations: HCY, homorysteine; HDL2, high‐density lipoprotein; Lp(a), lipoprotein(a)

The success of identifying genes for single gene disorders has been remarkable over the past decade with over 2000 genes identified for the potential 6000 single gene disorders. These disorders such as familial hypercholesterolemia are rare occurring in less than one‐tenth of 1% of the population. However, common diseases such as CHD or MI are due to genes (polymorphisms) that occur more commonly and are polygenic disorders in which multiple genes, each contributing only a small percentage to the disease, predispose to the disorder.

Mapping the chromosomal location of polymorphisms predisposing to a polygenic disorder such as CHD requires thousands of unrelated individuals with half of them having the disease and the other half being healthy controls.27 This also requires hundreds of thousands of DNA markers which must be genotyped on the DNA of each of these individuals. The sequencing of the human genome followed by the HapMap Project showed that 99.5% of the DNA sequence (3 billion nucleotides) across all human beings is identical.28 It is estimated that over 80% of the 0.5% genetic variation difference is due to substitutions of single nucleotides (single nucleotide polymorphisms or SNPs).

Figure 2.

Absolute CHD risk reduction (%) in the 60% of the population that were KIF6 719Arg carriers compared to equally treated subjects who were KIF6 719Arg noncarriers in 4 large prospective clinical investigations of LDL‐C reduction and clinical event prevention. Abbreviations: CARE, Cholesterol and Recurrent Events; WOSCOPS, West of Scotland Coronary Prevention Study; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; PROVEIT, Pravastatin or Atorvastatin and Infection Therapy: Thrombolysis in Myocardial Infarction 22

In 2007, the first common gene for coronary artery disease using the 500K platform was identified.5 This is the first new risk factor for CHD reported since the 1964 Surgeon General's report on cigarette smoking. This polymorphism is located on the short arm (p) of chromosome 9 in the band region 2.1 and so it is referred to as 9p21. The initial results of the Ottawa Heart Study were subsequently confirmed in independent populations from Dallas, Houston, and Denmark for a total of 23,000 whites. 9p21 is very common, occurring in 75% of the white population with 50% inheriting a single copy (heterozygous) and 25% inheriting 2 copies (homozygous). Individuals having 2 copies of 9p21 have an increased relative risk for coronary artery disease (CAD) of about 40% and 20% for those with a single copy. The risk associated with 9p21 is independent of all known CHD risk factors.

Almost simultaneously, Helgadottir et al, 29 showed 9p21 was also associated with a similar increased risk for MI. Multiple studies have confirmed 9p21 to be a common risk factor for CAD in a total of over 65,000 whites.30, 31, 32 With such genetic testing it will be possible, at an earlier age, to enable comprehensive early prevention that may be valuable within family members.

Clinical Utility

The link between CHD and inheritance is indisputable and the evidence is strong and consistent. Determination of high CHD risk phenotypes in adult family members of patients with established CHD can have 5 important results that may benefit the patient. First, it can serve to alert family members of their personal risk potential when compared to the family member with established CHD; second it can alert the family member to important gene environment interactions that may affect their heart health; third, it helps to select the most appropriate screening blood tests for family members and avoids over utilization of laboratory services; fourth, it helps to identify family members who may benefit from noninvasive imaging; and fifth, it can assist in treatment decisions (Figure 1).

Figure 1.

Family pedigree example. A black marker in 1 of 4 corners represents the presence of 1 of 4 phenotypic markers (Lp[a], homocysteine, fibrinogen, hypoalphalipoproteinemia) and a “B” in the center of a square (men) or circle (women) represents the fifth phenotypic marker, LDL subclass pattern B

Matching the phenotype to the treatment allows personalization of therapy for family members and avoids use of treatments that can be less efficient.33 For example, family members with the atherosclerosis susceptibility (ATHS) trait respond particularly well to exercise‐induced weight loss and a diet restricted in simple carbohydrates as well as nicotinic acid and fibric acid derivatives.34, 35, 36, 37 Some genotype blood tests appear to have clinical utility. For example, in patients with elevated low‐density lipoprotein cholesterol (LDL‐C), the apolipoprotein E (apo E) 4 genotype is a common contributor to hypercholesterolemia and found in approximately 25% of patients with elevated LDL‐C.38 Subjects with the E4 genotype may respond to low fat diets with significantly greater LDL‐C reduction than subjects with the normal E3/3 genotype.39, 40

Noninvasive imaging in the form of CT scans for coronary calcification, is a common screening test. With knowledge of the presence of heart disease in the family, combined with the presence or absence of phenotypes that have a pattern of inheritance, noninvasive imaging can be more efficiently targeted to the individual family member most likely to benefit and over utilization of noninvasive imaging avoided.

Some genetic tests provide clinical insight into population subgroups that respond differently to the same drug treatment. A polymorphism in the promotor region of the hepatic lipase gene (HL‐514T) has been linked to reduced high‐density lipoprotein cholesterol (HDL‐C) and reduced high‐density lipoprotein subfraction 2 (HDL2), but also greater HDL‐C and HDL2 increase in response to combination lipid therapy, as well as, better coronary arteriographic outcome compared to patients without the ‐514T polymorphism.41 Substantial evidence indicates that the presence of the KIF6 polymorphism identifies individuals not only at increased CHD risk, but also those that benefit from more powerful statin treatment and is independent of LDL‐C and high sensitivity C‐reactive protein (hs‐CRP) reduction.42, 43, 44 For example, in the West of Scotland Study (WOSCOPS), a relative risk reduction of 31% was reported, which equated to an absolute risk reduction of 2.4%. A total of 46 patients required treatment in order to prevent 1 cardiovascular event, and in the Pravastatin or Atorvastatin Evaluation and Infection Therapy‐Thrombolysis in Myocardial Infarction 22 (PROVE‐IT TIMI22) study a 16% relative risk reduction and a 3.9% absolute risk reduction were observed for treatment with atorvastatin (80 mg/d) vs pravastatin (40 mg/d). A total of 26 patients required treatment in order to prevent 1 additional cardiovascular event.

Such knowledge would allow physicians to concentrate statin therapy and statin compliance efforts in those patients who derive the most benefit (KIF6 carriers), and identify another group of patients (KIF6 noncarriers) who may benefit less in regard to clinical events. For example, in the above WOSCOPS and PROVEIT examples, KIF6 719Arg carriers treated with pravastatin in WOSCOPS exhibited a relative risk reduction of 50%, compared with 9% in the noncarriers: the absolute risk reduction was 5.5% in the KIF6 carriers compared with 0.1% in the noncarriers. The number needed to treat was 18 in the KIF6 carriers and > 100 in the noncarriers. In the PROVEIT study, treatment of KIF6 719 Arg carriers with atorvastatin (80 mg/d) vs pravastatin (40 mg/d), resulted in a 41% relative risk reduction, compared with a 6% relative risk reduction in the noncarriers: the absolute risk reduction was 10% in carriers compared with 0.8% in noncarriers, and 10 patients in the KIF6 719Arg carrier group required treatment in order to prevent 1 event compared with 125 of the noncarriers. Table 2 lists phenotype and genotype tests that may provide useful information in the analysis of family heart disease risk in appropriately selected patients.

Table 2.

Examples of practical phenotype and genotype tests with an inherited link to CHD that are clinically available, associated risk, and approximate prevalence in a CHD population

Test	Associated Risk	Prevalence	Reference
Phenotypes
LDL‐C	Hypercholesterolemia	30%–50%	2
Fasting triglycerides	Hypertriglyceridemia	40%–60%	26
LDL‐C + triglycerides	Familial combined	20%	7
	Hyperlipidemia
HDL‐C	Hypoalphalipoproteinemia	10% male CHD	2
LDL size	LDL pattern B	50% male CHD	34
HDL2	CHD	50%	41
HyperApoB	CHD	50%	26
Lp(a)	CHD, PVD	30%	4
Hyperhomocysteinemia	CHD, PVD	10%	25
Insulin resistance	CHD, diabetes	50%	2
Fibrinogen	Hyperfibrinogenemia	25%	25
Genotypes
LDL‐R	Hypercholesterolemia	1:500	2
Familial defective ApoB	Hypercholesterolemia	1:500	25
9p21	CHD	50%	5
KIF6	CHD	50%	42

Abbreviations: 9p21, is the myocardial risk SNP⁵; FEMA, Federal Emergency Management Association; KIF6, KIF6 719Arg carrier state; LDLR, LDL receptor; PVD, peripheral vascular disease

Road Blocks to Uniform Acceptance and Cost Effectiveness Issues

While the justification for family heart disease risk screening is robust and extensive, practical application in the medical community is relatively weak. We have conducted a family heart disease clinic model for 15 years and while greatly appreciated by family members, it is time consuming with low financial reimbursement.

There is a need for an efficient and cost effective family heart screening program that could be easily incorporated into a busy clinical practice and not have an adverse impact on staff efficiency. Such a program is eminently amenable to computerization and modern electronic tools. Web‐based programs currently exist through the Centers for Disease Control Family History website and supported by the U.S. Surgeon General's Family History Initiative.45, 46 At the present time such programs can be utilized and customized by patients and physicians in order to help promote the utilization of medical family information to improve health care.

Conclusion

A need exists for an efficient and cost‐effective mechanism to identify first‐degree relatives of patients with CHD that have a predisposition to CHD associated with inherited characteristics that can be utilized in a busy clinician's office. Such a mechanism would assist in early CHD high‐risk detection and application of appropriate preventive measures in those who need it the most. Further, such a program has the potential to reduce health care costs by focusing limited health care resources on a population that has a very high probability of incurring a CHD event, and in patients with existing CHD, focus treatments on those who derive the most benefit. The start of such an effort has been initiated by the CDC and the office of the U.S. Surgeon General.