Text Box: Dr sashi Acharya 
Shiva hospital Birgunj
Shivahospital1999@hotmail.com
 

 

 

Text Box: Dr sashi Acharya 
Shiva hospital Birgunj
Nepal
Shivahospital1999@hotmail.com
 

 

 


 

Environmental factors dominate the expression of gene

 

Heart disease is now regarded as one of the genetically determined diseases. An inherited trait under the influence of some environmental factors such as overweight, high cholesterol diet, sedentary life style, alcohol consumption, and smoking can express the disease.  In November 2003, Cleveland Clinic researchers discovered the first gene ‘the heart attack gene’ (MEF2A gene) in Iowa family living in the American mid-west state having the extensive history of heart attacks with highest risk  especially at about the age of 60. The gene MEF2A is located in the region of 15th chromosome, plays a role in protecting the artery walls from building up plaque that can impede blood flow and lead to heart attacks said Dr. Eric J. Topol of the Cleveland Clinic chairman of the Department of Cardiovascular Medicine at The Cleveland Clinic and head of a team that discovered the gene. He added that this deletion mutation in MEF2A gene makes vessels more susceptible to plaque formation leading to heart disease. This heart attack gene is found in 1-2% of all U.S. patients suffering from heart attack and coronary artery disease. Till today it is not known that whether this gene plays a role in heart disease among people outside of Iowa families where the mutation is inherited. The risk of coronary heart disease (CHD) attributable to genes seems to be more at younger ages.

 

Genetic influences on lipoproteins- the cardiovascular risk factors:

Different lipoproteins are genetically involved to predict coronary heart disease. High LDL (low density lipoprotein) or bad fat and low HDL (high density lipoproteins) or good fat are now considered as the independent risk factors for CHD. An individual’s serum cholesterol level variation depends upon the level of expression in the genes determining different types of lipoproteins such as for LDL, Apo a, Apo B, HDL levels in blood.

 

LDL (bad cholesterol) and apoLipoprotein A or Apo (a):

LDLR-LDL receptors remove LDL in the blood .If LDL is not properly removed; it accumulates in the arteries and can lead to CHD.A defect or mutation in the low density lipoprotein receptor gene (LDLR) leads to a rough doubling in cholesterol concentration for heterozygote and greater increases for homozygote. Homozygote for LDLR has non functioning LDL receptor gene that clears LDL level from the blood.

 

Lp (a) and CHD:

Apo (a) is a glycoprotein that combines with LDL to form a particle called Lp (a). [Apo (a) +LDL =Lp(a)]. Lp (a) is a lipoprotein with an abnormal protein a, and is found elevated in approximately 30 % of patients with coronary heart disease. The concentration of Lp (a) in plasma is genetically determined. People with high plasma levels of Lp (a) have been found to be with an increased risk for atherothrombotic cardiovascular disease and the predictive of familial CHD. In some group of people level of apo B and Lp (a) may impact in the premature development of coronary artery disease dictating the need of more aggressive treatment of low-density lipoprotein cholesterol.

 

Some effects of Lp (a) on CHD:

·          Lp(a) is one of the best predictors of heart attack in young men, blockage of vein grafts following coronary bypass surgery, People with high Lp (a) levels over 30 mg/dL in their blood have a higher risk of developing plaques and  CHD as Lp(a) is frequently takes part in plaques formation inside the vessels.

·          Lp (a) is supposed to exert its deleterious effects by virtue of its resemblance to Plasminogen. Plasminogen is a substance produced by the body which helps in breaking down of blood clots. High plasma Lp (a) concentrations may compete with Plasminogen and thereby inhibiting its function of dissolving the clot and making favorable condition for clot formation.

 

Apolipoprotein A1:

Apolipoprotein A1 is a protein attached to high density lipoprotein HDL, the "good cholesterol. The level of Apo A 1 is directly proportional to the level of HDL. Lower the Apo A1 levels the lower the level of HDL level. Certain mutations in the Apo A1 gene result in low Apo A1 levels making the low HDL level the independent risk factor for coronary heart disease.

 

Apolipoprotein B gene (Apo B), and Familial Hypercholesterolemia (FH):

In 1985, Michael Brown and Joseph Goldstein were awarded a Nobel Prize for determining that a mutation in this gene was responsible for familial hypercholesterolemia (FH). FH is inherited in a dominant manner. However familial hypercholesterolemia as a result of inactivating mutations in the LDL receptor gene, affects only 1 in 500 individuals in most populations. In about 4% with a family history of hypercholesterolemia may have familial defect in the gene for apolipoprotein B. Apo B is the component of LDL that binds the receptor. The defect or mutation in this particular gene makes the receptor inactive or inefficient resulting very high LDL levels, elevated levels of triglyceride, and reduced levels of HDL.

The risk of coronary disease is seven times higher in people with this muta­tion than in the general population. The patients with familial hypercholesterolemia associated with familial defective Apo B and better respond to treatment than do the patients without defective Apo B.

It is to be noted worthy that high level of apo B and Lp (a) the predictor for premature CHD indicates for more aggressive lipid lowering treatment.

 

Apolipoprotein E and its Isoform (Apo E Isoform):

The other gene affecting LDL cholesterol levels is Apo E, which has three major forms i.e. E2, E3, and E4. A normal combination is E 3/3 and accounts approximately for 78% of the population and is the most common variant. The E 3/4 configuration indicates one abnormal E4 gene, While E4 has a frequency of 15%-30%, and E2 a frequency of 7%. People with the E4 type of the gene have tendency of possessing higher cholesterol levels than the general population, but levels in people with the E2 are significantly lower. Heterozygote possessing alleles E3/E4 have choles­terol concentrations on average 10% higher than those of E3/E3. People with APOE4 genotype poorly respond to the drugs and better respond to cholesterol-lowering diet making themselves good candidate for diet therapy.Cholesterol-lowering diet can lead to 30-percent decrease in LDL cholesterol.." These genes didn't express among the people of developing country because the people were physically active and ate very low-fat diets.

Genetic and environmental risk factors interact in the expression of CHD:

Recent literatures have shown that Chinese people who are heterozygous for the LDL receptor gene mutation victimized with coronary disease less frequently than do people in Western countries and also believe that this is most probably because of their traditional Chinese food habits without excess of saturated fat as compared to their counterparts in the western countries showing the effect of environmental factor in the expression of the genes. Eighty percent of individuals who develop CHD have a total plasma cholesterol value within the same range as those who do not have CHD showing again the role of different environmental factor in the expression of the genes responsible for CHD.

 

Conclusion: It is very important to identify individuals at risk for heart disease as early as possible and to implement prophylactic and treatment strategies to reduce the impact of the inherited traits in time especially among those with strong positive family history of coronary heart disease. Despite the genetic predisposition to heart disease, heart healthy lifestyle modifications such as reducing extra weight, quitting smoking, adopting healthy diet and aerobic exercises and discouraging alcohol intake remains the most important step in cutting down the risk for CHD. Our main aim is to adopt heart healthy life styles to suppress the expression of the disease. In the next decade Genetic counseling and gene testing definitely may play an important role both in preventing and treating the coronary artery diseases. Till date it is known that the prevalence of the risk of CHD due to genetic effect is very low and contributes relatively little to the population burden of disease. For example familial hypercholesterolemia which is due to inactivating mutations in the LDL receptor gene affects only 1 in 500 individuals in most populations and the prevalence of heart attack gene is just 1-2%among the U.S. patients with heart attack. Genetic studies of coronary heart disease (CHD) need to be explored more to make any conclusive results.

 

References:

 

1.        Clinical review Science, medicine, and its future. Genetics and Cardiovascular risk. BMJ 2001;323:1409–12

2.        Evolving lipoprotein risk factors:lipoprotein(a)and oxidized low-density lipoprotein.Jialal Clin Chem 1998;44:1827-1832

3.        Measures, including the critical importance of not smoking, attention to diet, and attention to other risk factors and treatment with statins. BMJ 2001;323:1409–12

4.        Bhatnagar D, Morgan J, Siddiq S, Mackness MI, Miller JP, Durrington PN.Outcome of case finding among relatives of patients with known hetero­zygous familial hypercholesterolaemia. BMJ 2000;321:1497.

5.        Pimstone SN, Sun XM, du Souich C, Frohlich JJ, Hayden MR, Soutar AK.Phenotypic variation in heterozygous familial hypercholesterolemia: acomparison of Chinese patients with the same or similar mutations in theLDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol1998;18:309­15.

6.        Tybjaerg­Hansen A, Steffensen R, Meinertz H, Schnohr P, NordestgaardBG. Association of mutations in the apolipoprotein B gene with hyper­cholesterolemia and the risk of ischemic heart disease [see comments].N Engl J Med 1998;338:1577­84.

7.        Miserez AR, Keller U. Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B­100 and familial hyper­cholesterolemia. Arterioscler Thromb Vasc Biol 1995;15:1719­29.

8.        Lack of Increased Coronary Atherosclerotic Risk Due to Elevated Lipoprotein(a) in Women>55 years of Age.Sunayama et al.Circulation 1996;94:1263-1268.

9.        Judy McBride Attacking heart disease at its Genetic Base. Agricultural Research,  July, 1999