The medical application of gene analysis
Learn how genetic testings find their clinical application and which are the advantages.
Genetic testing for health care
The future of medicine, in which every human being is to sequence his entire genome in order to follow better, person-specific, preventive measures, is eagerly awaited by many medical professionals.
The fact that the approximately 30.000 human genes play a role for our health is indisputable. Currently, the largest German providers (www.novogenia.com) are already offering 800 different medical genetic testings. There are even more than 2.000  worldwide. Among them there are many diagnostic tests for monogenic, some very rare diseases, as well as the genetic component of common endemic diseases which is becoming increasingly clear.
Genetic tests may have different applications in practice. On the one hand they serve to confirm a suspected diagnosis (such as in the case of cystic fibrosis - CFTR gene ) or for risk assessment of first-degree relatives (breast cancer - BRCA1 & BRCA2 gene ).
While some genetic findings represent an absolute fate for the patient's health, the other only show the increase risk of developing a disease. Since the development of many diseases depends on the interplay between genes and the environment/lifestyle, new prevention possibilities arise.
„If we know our genetic predispositions even before the first symptoms manifest themselves, we can adjust our environment, so our lifestyles, so that we avoid certain risk factors and as such we may be able to prevent the development of disease."
means Dr. Daniel Wallerstorfer, scientific director of the Center for Human Genetics DNA Plus, Bavaria. There are now many well researched examples.
The familial hemochromatosis, or iron storage disease, for example, is triggered mainly by defects in the HFE gene . Most of the people carrying defects in both genes of this type (75- 96%) suffer from iron overload (high transferrin saturation and serum ferritin), and up to 50% of other symptoms, culminating with the clinical manifestation of hemochromatosis [3, 4]. Despite being very common, the disease is misdiagnosed in 67% of the cases, and not properly treated , which can lead to a number of complications such as joint disease, susceptibility to infections, diabetes mellitus and liver cirrhosis [9-12].
For the time being, the genetic testing is mainly used to confirm a diagnosis, and for risk assessment of close relatives, although it has great potential for the identification of the asymptomatic mutation carriers, and the prevention of the disease. The preventive treatment can be identical with the actual curative treatment of the hemochromatosis (phlebotomy therapy), calibrating the iron content through regular blood transfusions. The development of secondary disorders is almost impossible under doctor supervision, given this treatment [13, 14]. „Being informed of the risk represents a significant benefit for the people having these genetic defects" said Dr. Wallerstorfer. „Unfortunately, we still know very little about one’s own risks."
Genetic testing instead of medical history?
Although a history in genetic disorders with high penetrance and dominant inheritance can achieve similar results as a genetic analysis, it has serious limitations.
For example, in the case of Chorea Huntington, the dominant gene defect that causes that each individual suffers from the disease (the so-called complete penetrance) is easy to track through a medical family history . If a carrier of this defect has a child, chances are 50% that the child will also be a carrier. A medical history can only speculate and estimate the probability of disease to 50%. Only a genetic analysis may determine whether the genetic defect was inherited, and whether the child will suffer from the disease.
In diseases with incomplete penetrance (not all carriers of the mutation develop the disease), as the familial thrombophilia, it is even more difficult to draw relevant conclusions based on the medical history. These genetic defects are relatively frequent, in about 20-40% of thrombosis cases. Approximately one in twenty Europeans is genetically predisposed to thrombophilia and subjected to an 8-fold risk of thrombosis [16-18]. If untreated, 10% of the people having this predisposition develop a potentially fatal thrombosis . Since these gene defects do not always lead to disease, and there are 50% chances that they are passed to the next generation, tracking them through the family history is a very difficult, if even possible, task.
Diseases such as hemochromatosis or lactose intolerance are recessive, which means that a person may develop this intolerance, only if he inherited a defective gene from each parent. Carrying just one of the defective genes causes no symptoms, so without a genetic analysis it is impossible to know if a person is a carrier. Therefore, in these cases, a medical history is useless, since the disease cases occur sporadically, without other family members being affected.
The predictive value of genetic testing often varies from disease to disease, from gene to gene and even from mutation to mutation. Moreover, such genetic analyzes provide different information and opportunities for prevention, depending on the patient. Here are some examples of well-studied genetic predisposition and prevention options.
The presence of two genetic defects affecting the LCT gene predicts, with very high probability (>90%) the development of lactose intolerance [20-22]. However, the age at which the intolerance develops the first symptoms varies, depending on the general health condition of the person. While a lactose tolerance test (the hydrogen test, or the hydrogen breath test) is relevant for the current health condition, it cannot make any statements about the future health of the patient. A genetic analysis with positive findings, however, can predict with very high probability the occurrence of lactose intolerance in the future. A reduction of lactose in the diet, together with careful scrutinizing of the symptoms, may spare the patient from years of unexplained indigestions.
By a single gene defect (Factor-V), the risk of thrombosis increased 8 times, and 10% of the patients will suffer from thrombosis at some point in their life. If the patient has two genetic defects, the risk increases about 80 times and, if left untreated, it will lead to the development of the disease in most of the cases. According to studies, genetic defects are involved in approximately 40% of thrombosis cases [6-19]. Lifestyle changes and drug therapies (particularly in high-risk situations, such as long flights or after surgery) may normalize these genetic predispositions.
These genetic predispositions are particularly dangerous for women. The use of contraceptives or hormone preparations doubles the individual risk of thrombosis, even without a genetic defect. When there is also a predisposition to thrombophilia, the risk of disease increases exponentially, up to 18 times [23, 24]. Therefore, it is recommended that women with a genetic disposition to thrombophilia switch to alternative non-hormonal contraceptives. The only problem is, there is hardly any woman concerned about this risk. The risk increases even more during pregnancy. The already 4-fold increased risk of thrombosis, increases now 60 times, due to the genetic predisposition; the condition should be strictly treated with low molecular weight heparin [25, 26].
A genetic defect in the APOB gene increases the likelihood of hypercholesterolemia to 78-fold, while some defects in the LDLR gene even up to 1233 times [27-29]. These forms of hypercholesterolemia are often indistinguishable from acquired cholesterolemia, but may require a different treatment.
About every third woman has a genetic defect that increases her risk of osteoporosis by 26%. One out of 33 women is carrying two defective genes, which increase the risk by 178% . To preserve the bone mass is much easier than to rebuild the lost bone mass, so it is important to identify the genetically susceptible individuals as soon as possible, for a timely intervention. If the risk is detected early, the corresponding portions of bone can be strengthen at a young age, and a diet rich in calcium, vitamin D and phosphate diets slow the evolution of the disease [31-34].
Gluten Intolerance/Celiac Disease
The consequential health risks, such as lactose intolerance, cancer including a twofold to fourfold increased risk of non-Hodgkin’s lymphoma, a more than 30-fold increased risk of small intestinal adenocarcinoma, and a 1.4-fold increased risk of death, can be normalized by adequate treatment and a gluten-free diet.
- Celiac disease and non-celiac gluten sensitivity
- Complications of coeliac disease: are all patients at risk?
- Delayed diagnosis of coeliac disease increases cancer risk
- Association of celiac disease and intestinal lymphomas and other cancers.
A common genetic defect in the CFH gene increases the risk of macular degeneration up to 4-12 times, depending on the number of gene defects. An individual's risk can be better determined through a classification into risk groups (1-fold/4-fold/12-fold) [38, 39]. High-risk patients should follow a diet rich in antioxidants, use UV protective sunglasses, and home-tests for the detection of visual field distortions; regular medical check-ups are also highly recommended [40-45].
Eating fruit is healthy, eating fat meat is unhealthy! Such general nutrition principles are well known, and it is recommended that everybody should follow a balanced diet. These rules, however, were created with the idea that they should apply to the general public, and individual characteristics were not considered.
For example, dairy products are a recommended source of calcium. A diet rich in calcium plays an essential role for individuals who are genetically predisposed to bone loss (Osteoporosis). As such, dairy products are highly recommended, unless that person is among the 20% of the population who are lactose intolerant, due to an inherited genetic defect . In this case, the patient should completely switch from dairy products to other sources of calcium, such as broccoli or dietary supplements. Genetic predisposition to elevated cholesterol or triglycerides (Atherosclerosis), diabetes mellitus type 2 (Diabetes), the gluten / grain intolerance (Celiac Disease), the iron storage disease (Hemochromatosis) or Macular Degeneration, all require specific dietary changes, in order to optimally prevent these diseases. Through genetic analysis, we can find out which food categories are particularly important for an individual, and which should be avoided, based on the genetic predisposition.
- Gupta N, Khan F, Tripathi M, Singh VP, Tewari S, Ramesh V, Sinha N, Agrawal S. Absence of factor V Leiden (G1691A) mutation, FII G20210A allele in coronary artery disease in North India. Indian J Med Sci 2003;57:535
- Brissot P, Moirand R, Jouanolle AM, Guyader D, Le Gall JY, Deugnier Y, David V. A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria. J Hepatol 1999;30:588-593
- Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-724
- CDCP, Centers for Disease Control and Prevention
- Fanen P, Hasnain A . Cystic Fibrosis and CFTR Gene. Atlas Genet Cytogenet Oncol Haematol. September 2001
- C. Sevilla et al. Testing for BRCA1 mutations: a cost-effectiveness analysis, European Journal of Human Genetics (2002) 10, 599 – 606
- Rochette, J., et al., Multicentric origin of hemochromatosis gene (HFE) mutations. Am J Hum Genet, 1999. 64(4): p. 1056-62.
- CDCP, Centers for Disease Control and Prevention
- NIH, Institutes of Health
- Burt, M.J., et al., The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut, 1998. 43(6): p. 830-6
- Niederau C, F.R., Pürschel A, Stremmel W, Häussinger D, Strohmeyer G, Long-term survivalin patients with hereditary hemochromatosis. Gastroenterology 1996(110): p. 1107-1119.
- GFHEV Guidelines
- Walker, F.O.: Huntington's disease. Lancet, 2007; 369: 218–28
- Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997;89:2817-21
- Mansourati J, Da Costa A, Munier S, Mercier B, Tardy B, Ferec C, et al. Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography. Thromb Haemost 2000;83:822-5
- Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998;97:1037-41
- Thom W. Rooke, Vascular Medicine and endovascular Interventions: Blackwell Futura, 2007, Chapter 5, Page 65.
- Beja-Pereira, A.; Luikart, G.; England, P. R.; Bradley, D. G.; Jann, O. C.; Bertorelle, G.; Chamberlain, A. T.; Nunes, T. P.; Metodiev, S.; Ferrand, N.; Erhardt, G. : Gene-culture coevolution between cattle milk protein genes and human lactase genes. Nature Genet. 35: 311-313, 2003. Note: Erratum: Nature Genet. 35: 106 only, 2003.
- Tuula H. Vesa et al.: Lactose Intolerance, in: Journal of the American College of Nutrition, Vol. 19, No. 90002, 165S-175S (2000)
- Enattah, N. S.; Sahi, T.; Savilahti, E.; Terwilliger, J. D.; Peltonen, L.; Jarvela, I. : Identification of a variant associated with adult-type hypolactasia. Nature Genet. 30: 233-237, 2002.
- Gomes, M. P. V., Deitcher, S. R. (2004). Risk of Venous Thromboembolic Disease Associated With Hormonal Contraceptives and Hormone Replacement Therapy: A Clinical Review. Arch Intern Med 164: 1965-1976
- Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects; Kitty W, Arch Intern Med, Vol 160, Jan 10, 2000.
- Trends in the Incidence of Venous Thromboembolism during Pregnancy or Postpartum: A 30-Year Population-Based Study: John A. Heit, Ann Intern Med. 2005;143:697-706.
- Thrombophilia and pregnancy: The gynecologist: Springer Berlin: Volume 36, Number 11 / November 2003 F. Dermarmels Biasiutti.
- Tybjaerg-Hansen A, Humphries SE. Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis 1992;96:91-107
- Hobbs et al. 1992 Hum Mut 1:445
- Defesche et al. 1998 FH workshop 1997
- Mann V, Ralston SH. Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Bone. 2003;32:711-7.
- Report of a Joint WHO/FAO/UNU Expert Consultation(2007) Protein and amino acid requirements in human nutrition, pp224-226
- Report of a Joint WHO/FAO/UNU Expert Consultation(2002), Human Vitamin and Mineral Requirements, pp166-167
- Bolland MJ, Barber PA, Doughty RN, et al (2008). "Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial". BMJ 336: 262
- Jackson RD, LaCroix AZ, Gass M, et al (2006). "Calcium plus vitamin D supplementation and the risk of fractures". N. Engl. J. Med. 354 (7): 669–83
- Internal medicine, Gerd Herold et al, 2008
- Am J Med. 1967; 42: 899-912
- Hardwick, C. Prognosis in coeliac disease. Arch Dis Child 1939; 14:279.
- Wegscheider BJ, Weger M, Renner W, et al. Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration. Ophthalmology. 2007.114:738-42.
- Montezuma SR, Sobrin L, Seddon JM. Review of genetics in age related macular degeneration. Semin Ophthalmol. 2007;22:229-40.
- Ophthalmology, Franz Grehn, 30th edition, 2008
- MDS Manual, Health Manual, 2nd Edition
- Haines, J. L.; Hauser, M. A.; Schmidt, S.; Scott, W. K.; Olson, L. M.; Gallins, P.; Spencer, K. L.; Kwan, S. Y.; Noureddine, M.; Gilbert, J. R.; Schnetz-Boutaud, N.; Agarwal, A.; Postel, E. A.; Pericak-Vance, M. A. : Complement factor H variant increases the risk of age-related macular degeneration. Science 308: 419-421, 2005
- Diagnoses at the ocular fundus, Thieme, Bernd Kirchhof, Martin Reim, Sebastian Wolf, 2003
- Ch. 25, Disorders of the Eye, Jonathan C. Horton, in Harrison's Principles of Internal Medicine, 16th ed.
- German Ophthalmological Society (DOG)
-  www.ncbi.nlm.nih.gov/