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Indian J Med Res 127, February 2008, pp 106-109
Commentary
Challenges in identifying genetic risk factors for common multifactorial disorders
macular degeneration2. Most association studies fail to
identify the risk conferring allele not only due to
insufficient sample size; but heterogeneity of the
complex disorders1. Polymorphisms in many genes
interact with multiple known and unknown
environmental factors ultimately resulting in the disease
phenotype. It means that in each family and in each
individual the contribution of various genetic variations
to the disease phenotype may vary, and different
combinations of different genetic variations may give
rise to the similar phenotypes. Hence to get consistent
and statistically significant results of association studies
is difficult. This is obvious from the various studies of
methylene tetrahydrofolate reductase (MTHFR) gene
polymorphism in coronary artery disease and other
thrombotic disorders.
Advances in recombinant DNA technology have
opened up many new diagnostic tools for monogenic
disorders. DNA based techniques are also being used
in the diagnosis of infectious diseases, and diagnosis
and prognostication of cancers. Research in molecular
pathogenesis of these disorders is likely to bring up new
therapeutic strategies. The monogenic disorders account
for a small part of mortality and morbidity in the general
population, which is mainly contributed by complex
multifactorial disorders like diabetes, hypertension,
coronary artery disease, etc. Hence currently major
research is directed towards identification of genetic
risk factors for these common diseases. The aims are to
develop diagnostic tests to identify the individuals at
high risk and to develop novel preventive and
therapeutic strategies. In spite of very good molecular,
computational and statistical tools, the efforts in this
direction have till date not been very fruitful.
Rassoul et al3 in this issue have studied plasma
homocysteine level and 677 CàT polymorphism in
MTHFR gene in patients with coronary artery disease
(CAD) and concluded that the serum homocysteine level
was associated with severity of CAD, but MTHFR
polymorphism did not affect the severity of CAD 3.
There are other studies on hyperhomocysteinemia and
MTHFR polymorphism in atherosclerosis and coronary
artery disease4,5. The association between CAD and
MTHFR polymorphism has been noted a decade ago6.
Homozygosity for the C677T mutation in the MTHFR
gene is commonly but inconsistently associated with
hyperhomocysteinemia. MTHFR catalyzes the
conversion of methylenetetrahydrofolate to
methyltetrahydrofolate, the methyl donor in the
remethylation of homocysteine to methionine. A
677Cà T mutation in the MTHFR gene has been
associated with elevated homocysteine concentrations
in homozygous individuals as this change in nucleotide
is known to reduce enzymatic activity of MTHFR.
Hyperhomocysteinemia is an accepted risk factor for
coronary artery disease, but the determining factors are
Most of the genetic risks for common disease must
be conferred by low frequency alleles1. Most of these
factors account for a small proportion of the total risk
and their presence or absence will rarely increase or
reduce recurrence risk of the relevant disorder more
than two-fold. Thus, their diagnostic value is negligible.
The most commonly used method to identify genetic
risk factors for multifactorial disorders is association
study which compares prevalence of a genotype in a
group of patients with the disease in concern with that
in the control population. When one reviews the
literature over the last decade, it is seen that the genome
wide association studies have often yielded
contradictory results. Though billions of dollars have
been spent to identify DNA variants in human genome
that are more common in patients with a specific
complex disease than in healthy individuals, the search
for identification of major risk factors for complex
disorders have remained elusive1. Success is visible
recently in exceptional situations like age related
106
PHADKE: GENETIC RISK FACTORS FOR MULTIFACTORIAL DISORDERS
not fully understood. It may result from both
environmental and hereditary factors. Other genes may
also be influencing plasma homocysteine levels 7.
Environmental factors like diet, alcohol also affect the
serum homocysteine level8.
Though it has been presumed that MTHFR
polymorphism
677Cà T
acts
through
hyperhomocysteinemia; there have been studies to show
that these may have combinational effect. Mager et al9
have reported that hyperhomocysteinemia and the T/T
genotype had a stronger effect on the pathogenesis of
CAD when they are combined, and that a marked
increase (>15 mmol/l) in fasting plasma homocysteine
in T/T homozygotes was a risk factor for early onset of
CAD.
There are many studies refuting the association of
common polymorphism in MTHFR gene and CAD10-17.
Brilakis et al16 reported that the MTHFR TT genotype
was associated with hyperhomocysteinemia, but not
with significant CAD. A large case control study of more
than 2000 patients with CAD has not shown association
between MTHFR C677T and A1298C polymorphisms18.
In the analysis of the 12 studies, the odds ratio of CAD
associated with the TT genotype (homozygous C677T
polymorphism) was 1.1819. The meta-analysis showed
a slightly higher plasma homocysteine levels in
participants with the TT genotype vs. CC and CT
genotypes. Another meta-analysis also concluded that
although the C677T/MTHFR mutation is a major cause
of mild hyperhomocysteinemia, does not increase
cardiovascular risk20.
In addition to MTHFR C677T polymorphism, other
polymorphisms in MTHFR and other genes in the
pathway, namely, methionine synthase (MTR),
cystathionine-beta-synthase and methionine synthase
reductase (MTRR) are being studied knowing the
polygenic aetiology of hypermethionemia and CAD21,22.
The contribution to total plasma homocysteine levels
of the common mutations of genes coding for the
enzymes controlling homocysteine metabolism appears
to be modest23.
Indian groups have also studied association of
MTHFR 677Cà T with CAD. Alam et al have shown
that hyperhomocysteinemia appears to have a graded
effect on the risk of CAD as well as the severity and
extent of coronary atherosclerosis24. This study has also
shown that homozygous genotype of MTHFR is a
genetic risk factor for CAD in Indian population. On
the other hand, a study by Mukherjee et al25 has failed
107
to show the association of MTHFR C677T
polymorphism in Indian patients with CAD. Studies
done to see association of the polymorphism with
restenosis showed conflicting results26,27.
These studies bring out the difficulty in concluding
about small contribution of a genetic polymorphism to
a multifactorial disease. If MTHFR 677CàT is a risk
factor for CAD, it had a modest effect. Probably, the
homozygous T/T genotype is a modest but significant
risk factor for CAD at least in some populations.
However, this risk factor may be of great importance
as hyperhomocysteinemia because of the C677T
MTHFR allele may be corrected with oral folic acid
therapy28. Kauwell et al29 showed that TT homozygotes
on low folate diet had higher rise in plasma
homocysteine level as compared to heterozygotes on
low folate diet and the levels of plasma homocysteine
returned to normal on repletion of folate in the diet.
Thus, it is important to know whether MTHFR 677CàT
polymorphism is a risk factor for at least some cases of
CAD. It has been realized that CAD is an important
public health issue in India and further investigations
on the relationships between MTHFR genotypes and
the incidence of CAD based on larger samples are
necessary. Array based single nucleotide polymorphism
(SNP) typing (more than 500,000 SNPs are studied in
one experiment) and analysis of large cohorts of patients
have significantly enhanced the power of association
studies and have identified risk factors for myocardial
infarction30,31. Individual therapeutic strategies based on
single nucleotide polymorphism may become
increasingly important for preventive treatment against
polygenic CAD.
Shubha R. Phadke
Department of Medical Genetics
Sanjay Gandhi Post Graduate Institute of
Medical Sciences
Lucknow 226 014, India
[email protected]
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