CardioRISQ for Physicians


The below text is intended to give an introduction about the novelty of CardioRISQ testing. It also outlines the basic principle of how CardioRISQ is performed and what its advantages are compared to other genetic tests used for multifactorial diseases.

The value of genetic testing is increasingly recognized to:

  • diagnose treatable subtypes of complex diseases that may include single gene disorders,
  • facilitate prevention of cumulative risk, and
  • formulate intervention plans tailored to the needs of the individual.

Since a disease is rarely a consequence of an abnormality in a single gene, multi-gene tests may be helpful to target interactions between genes and the environment as modifiable drivers of disease. A need therefore exists for information gathered by clinicians, genetic counselors and laboratory scientists to be combined, integrated and aligned with a patient's clinical workup to provide a deeper understanding of the disease mechanisms involved, on which to base the intervention strategy.

Pathology supported genetic testing - CardioRISQ

The diagnostic process begins with clinical observations and the need for objective and accurate pathological assessments to arrive at a specific diagnosis. Pathology results, similar to genetic test results, are interpreted within a clinical context as an accurate diagnosis depends on careful clinic-pathological correlation. Advanced technologies are increasingly used to stay abreast of expanding clinical requirements such as sub classification of cardiovascular diseases (e.g dyslipidaemia, venous thrombosis, cardiomyopathy) and prognostication of patients with breast carcinoma to guide the direction of therapeutic intervention. Through clinic-pathological correlation, all laboratory results including those obtained through molecular genetic applications, are finally interpreted and integrated with the patient's clinical findings and data from other special investigations. Identification of genetic subgroups at risk of drug side effects or with different treatment or dietary requirements provides a scientific basis for targeted intervention as opposed to a one-size-fits-all approach.

It is important to develop innovative approaches to risk management of complex multifactorial diseases, which could be applied in a clinical context where the genetic test results are fully integrated with relevant clinical information and other diagnostic pathology data. Provision of clinically-useful genetic information requires careful review of the literature to prevent the use of genetic alterations of unknown functional significance in genetic tests.

Where genetic tests, similar to some non-genetic pathology tests, have not been adequately validated the scarcity of sound scientific evidence rightfully challenges the ethical and scientific justification of routine application of these tests in clinical practice. However, the growing clinical demand for such tests pertaining for example to pharmacogenetics and nutrigenetics - to identify genetic determinants of differential responses to medical treatment or dietary intervention - drives the need to offer such tests in an appropriate clinical context and as part of an integrated pathology-based platform. Such an approach is often a logical addition to and expansion of well-established clinical practice to sub-classify complex diseases into treatable entities. A good example is cardiovascular disease referred to in more detail below, where correlation between the presence of well-established genetic and lifestyle risk factors and relevant biochemical profiles could be used to determine gene expression and monitor response to the intervention strategy applied.

CardioRISQ and Cardiovascular disease (multifactorial inheritance)

Although several autosomal dominant and recessive forms of cardiovascular disease (CVD) exists (e.g. familial hypercholesterolaemia, hypertrophic cardiomyopathy), low-penetrance genetic risk factors that interact with the environment play an important role in the clinical manifestation of most heart conditions. This is where CardioRISQ shows it's advantages.

Conventional methods are effective to identify and treat high-risk individuals; however, the majority of cardiovascular events occur in individuals considered to be at low or intermediate risk. The significance of early detection of patients with genetic forms of CVD, or where the impact of environmental risk factors may be stronger due to a genetic predisposition, is increasingly recognized. Interaction between multiple low-penetrance mutations are also important contributors to CVD risk due to a cumulative effect, as demonstrated by Kathiresan et al. (2008). Use of CardioRISQ to adjust risk stratification and reclassify patients into the next highest category of risk, could help to better identify those in need of vigorous intervention.

Figure 1: Risk management genetic testing includes evaluation of the current health status of the individual, documentation of the family history and pathology supported gene-based intervention, based on the overall risk profile.

As mentioned above CardioRISQ is not only a genetic test. The below table summarizes some of the data that are required for the test to be performed. All the data are directly input onto a secured on-line interface and later integrated to generate a medical report.

Table 1: Data that is required for the CardioRISQ test to be performed.

Personal and family medical conditions
Metabolic indicators and blood biochemistry
Environmental risk factors and nutrition
  • Angina
  • Alzheimer's disease
  • Cancer (specify type)
  • Chronic periodontitis
  • Chronic inflammation
  • Coronary heart disease
  • Deep vein thrombosis
  • Diabetes Type II
  • Familial hypercholesterolaemia
  • High blood cholesterol
  • High blood iron
  • High blood pressure
  • Hypothyroidism
  • Metabolic syndrome
  • Non-alcoholic fatty liver disease
  • Body mass index
  • Waist circumference
  • Hip circumference
  • Systolic blood pressure
  • Diastolic blood pressure
  • Total cholesterol
  • LDL-cholesterol
  • HDL-cholesterol
  • Triglycerides
  • Lipoprotein (a)
  • Homocysteine
  • Ultrasensitive C-reactive protein
  • Glucose,
  • Insulin
  • Serum ferritin
  • Transferrin saturation
  • Lifestyle assessment:
  • Physical activity
  • Smoking status
  • Alcohol consumption
  • Dietary intake –
  • Saturated fats
  • Trans fats
  • Fruit
  • Vegetables
  • Fibre
  • Folate
  • Hormone replacement therapy
  • Oral contraceptive use
  • Drug side effects
  • Food allergies
  • Food intolerances

Low-penetrance mutations determined.

The selection of genes and low-penetrance mutations included in the CardioRISQ test is based on the phenotypic expression (clinical manifestation), prevalence in the general population and availability of appropriate intervention or treatment options that may be required. (Kotze et al 2003, Kotze and Thiart 2003)

All together CardioRISQ determines 8 low-penetrance mutations in 5 genes which are involved in:

  • cholesterol and fat metabolism - ApoE
  • folate and homocysteine metabolism - MTHFR,
  • blood clotting and thrombophilia - FII, FV and
  • iron overload and oxidative stress - HFE

Table 2: Low-penetrance (LP) mutations determined in CardioRISQ test.

LP mutation
RS Numbers
  • ApoE
  • ApoE
  • FV
  • FII
  • HFE
  • HFE
  • C > T
  • T > C
  • C > T
  • A > C
  • G > A
  • G > A
  • G > A
  • G > C
  • rs429358
  • rs7412
  • rs1801133
  • rs1801131
  • rs6025
  • rs1799963
  • rs1800562
  • rs1799945

Relevant genetic variants that are being tested in CardioRISQ:

  • affect the function or level (expression) of the gene products,
  • affect biological processes involved in CVD or related disorders, and
  • have apparent metabolic/clinical implications, either alone or in combination with other genetic or environmental risk factors.


Data obtained from the clinical evaluation and genetic testing are pooled to generate a comprehensive test report that integrates clinical, metabolic, genetic and lifestyle risk factors into a treatment plan for the individual. The impact of this holistic approach on patient management depends:

  • on the number and type of genetic alterations detected in the DNA of the individual and
  • how gene expression is affected by these genetic alteration(s) in relation to environmental risk factors relevant to the patient.

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