INTRODUCTION
According to the World Health Organization Cancer,
Type II Diabetes and Cardiovascular Disease represent the world’s leading
causes of morbidity and mortality. Cancer accounted for 7.6 billion, or 13% of
all deaths, 346 million people have diabetes with 3.4 million of those dying as
a direct result of high blood sugar, and 17.3 million people died from
Cardiovascular disease in 2008, representing 30% of all global deaths
(Worldwide death rates from cancer, 2014; Worldwide death rates from diabetes,
2014; Worldwide death rates from cardiovascular disease, 2014). Population-based
epidemiological evidence has clarified the role of diet in preventing and
controlling morbidity and mortality resulting from these NCDs (non-communicable
diseases) (WHO 2003, Hobbs et al. 2014; McMahon & Amaya, 2013; Hosking
& Danthiir, 2013; Annema et al., 2011). Stemming from the overwhelming
evidence regarding dietary intake and disease risk, International Government
bodies have focused on encouraging higher relative consumption of fruits,
vegetables and whole grains within the population’s daily food intake via
evidence-based macro and micronutrient recommendations (Rodriguez & Miller,
2015; Australian Dietary Guidelines, 2013). The Recommended Daily Intake (RDI)
value, for example, reflects the levels of essential nutrients considered
adequate to meet the nutritional needs of most
healthy people and are based on age, gender, level of physical activity,
and pregnancy/lactation status (Brownie, Muggleston & Oliver, 2015). Recent genetic research however. indicates that individual genetic polymorphisms, such as those on
the MTHFR gene may result in substantial relative risk changes for the
aforementioned diseases through epigenetic mechanisms (Kasapoglu et al, 2015;
Huemer et al., 2016), requiring a far more individualised approach to
recommended nutrient intake and overall dietary pattern. Despite these emerging
variations in individual vs population genetic responses to diet and nutrient
intake, the application of Nutrigenetics and Nutrigenomics to individual
nutrition consultation and dietary recommendation remains ethically
controversial (Paulidis, Patrinos & Katsila, 2015; Ferguson, 2014). This
paper elucidates the relationship between the aforementioned NCDs and MTHFR
gene mutations and addresses both sides of the argument regarding current and
potential therapeutic applications, however, until definitive evidence is
presented supporting these therapeutic interventions, the usage is not recommended .
CURRENT DIAGNOSIS AND TREATMENT
Cancer, Type II Diabetes and Cardiovascular Disease
are all recognised as having both genetic and dietary/lifestyle aetiologies
(Eng, 2011; Printz, 2013; Nankervis, 2015; Dupas et al. 2016; Yu, 2016).
Hereditary breast and ovarian cancers are linked to BRCA1 and BRCA2 genes, while
MLH1 and MSH2 are linked to hereditary colon cancer (Eng, 2011). Type II
Diabetes is associated with 70 genomic regions that commonly involve mutations
in transcription factors HNF1á and HNF4á
that affect insulin secretion (Nankervis ,
2015). Cardiovascular disease has been associated with alcohol dehydrogenase,
aP2, CCR2 and CCR5, PPARG2, lymphotoxin-a, ABCA1, a common variant at 9p21,
NFKB1 and ADRb1 (Yu et al., 2016). More recently, mutations on the MTHFR gene
have been linked to all of these diseases in both homozygotic and heterozygotic
individuals. Pathogenic mutations associated with an autosomal recessive error
of folate metabolism lead to increased homocysteine levels and alteration of
gene expression via methylation (Levin & Varga, 2016).
Genetic predisposition is only one of many non-dietary
factors at play in the development and emergence of NCDs. Economic, social,
climatic, cultural, psychological and even polymorphisms in circadian genes
influence the hereditability of these diseases (Almon et al. 2012; Shanmugam et
al. 2013). As a result the global health community has recognised that social,
economic and political environments drive disease emergence just as, or more
strongly, than genetics, biology and individual choice. Combating the major
causes of chronic NCDs, rather than new symptom management in an acute care
setting is the major focus of the WHO’s Global Coordination Mechanism for NCDs.
Prevention is prioritized (Allen, 2016). It is precisely this focus on prevention
however that is driving frantic research into the MTHFR gene mutations
implicated in chronic NCDs. Identifying at-risk individuals and adjusting
specific nutrient values according to their individual polymorphism has been
strongly embraced by both the scientific research community and the allied
health internet communities as a potentially powerful prevention strategy (Kasapoglu
et al. 2015; Shiao et al. 2016; Clarke et al. 2016; Culson et al. 2015; Lynch
2016; Skeptical Raptor’s blog 2015). The multi-system effects of genetic
methylation variation due to MTHFR polymorphisms do suggest that a greater
understanding of these mutations and the epigenetic effects of diet and
lifestyle on the phenotype may be key to targeted prevention of NCDs, however
individual genetic testing and its application to disease prevention is still
mired in controversy.
MTHFR COMMON MUTATIONS AND PHENOTYPIC EXPRESSION
MTHFR, the methylenetetrahydrofolate reductase gene
has been widely investigated regarding epigenetics and human disease (Mcbride
& Koehly 2017; Wade, Mcbride, Kardia & Brody, 2010). Showing an
autosomal recessive inheritance pattern, the two most common loci exhibiting
polymorphism mutations
on the gene are
C677T and A1298C. These two single nucleotide polymorphisms are about 2,000
base-pairs apart (http://ghr.nlm.nih.gov/gene/MTHFR).
The MTHFR enzyme, coded by the MTHFR gene is responsible for homocysteine
remethylation to methionine. It catalyzes reduction of 5,10-
methylenetetrahydrofolate to 5-methylenetetrahydrofolate, the most common form
of folate in blood, tissues and cerebrospinal fluid. This folate form
acts as a methyl donor for the methylation of homocysteine to methionine. In
those with MTHFR deficiency, this methylation is decreased so plasma levels of
homocysteine remain elevated while methionine levels are at low concentrations
(Burda et al. 2015). Low methionine then leads to a lack of
S-adenosylmethionine which is the primary donor for many important methylation
reactions including creatine synthesis and RNA and DNA methylation (Huemer et
al. 2016 ).
Figure 1:
Simplified metabolic pathways involving 5,10-methylenetetrahydrofolate
reductase (MTHFR) adapted from Botto
& Young, 2000.
Enzyme function in affected individuals varies
according to hereditability patterns. With an MTHFR 677TT homozygous mutation,
70% of enzyme function is lost compared to 35% in a heterozygous mutation. In
MTHFR 1298CC mutations the respective loss of function is 30% (homozygous) and
15% (heterozygous). In rare cases, individuals can exhibit compound
polymorphisms or mutations at both loci and will be at increased risk of developing
health problems with both neurological and vascular symptoms (Shiao & Yu,
2016).
The resulting low plasma folate/high plasma
homocysteine levels associated with MTHFR mutation and their association with
Cancer, Cardiovascular disease, neurodevelopmental disease and Type II Diabetes
have been repeatedly researched, as folate, the MTHFR gene, and methylation
pathways are critical to basic biological processes involving DNA and protein
methylation as well as DNA replication
and mutation (Inoue-Choi et al. 2013; Jamaluddin, Young & Wang, 2007;
Crider et al. 2012). Additionally, individuals with gene mutations in
methylation pathways have been shown to be compromised in their ability to
process environmental pollutants, with air pollution causing as much damage as
that caused by cigarette smoking ( Kloog, Ridgeway, Koutrakis, Coull &
Schwartz, 2013).
Despite the effect of MTHFR mutations on the most
fundamental biological processes and the broader implications of these effects,
many recent studies have found inconclusive evidence for high plasma
homocysteine levels and resulting disease states
(Marti-Carvajal et al. 2009; Greenland et
al. 2010). With conflicting results and uncertainty as to clinical
implications, most worldwide health authorities recommend against testing for MTHFR polymorphisms (Levin & Varga, 2016). Further,
high plasma homocysteine and low folate levels can be routinely and
inexpensively treated via dietary changes or supplementation with folate, B12
and B6 (Prachi et al. 2010) although the form of folate
supplementation (Folic acid vs. Folinic acid) is still hotly debated (Hyland et
al. 2010; Diekman et al. 2014). According to the Academy of Nutrition and
Dietetics:
"There is
insufficient evidence regarding C677T polymorphism in the MTHFR gene to modify
current folate recommendations from those provided in the Dietary Reference Intakes ."
(Camp & Trujillo, 2014).
Despite this statement, pilot studies have been
undertaken to treat C677T polymorphisms via dietary intervention, with results
suggesting that personalized dietary recommendations based on individual
genetic makeup and nutritional status are not only effective, but may reduce
further somatic complications and the social costs of these diseases (Di Renzo
et al. 2014 ).
ETHICS
With over 10% of the Australian population homozygous
or compound heterozygous for these polymorphisms, it is perhaps not surprising
that referrals for MTHFR polymorphism testing and counselling are on the
increase (Long & Goldblatt, 2016), despite no clinically significant
interventions that can reasonably be offered to carrier of the polymorphism
(MTHFR Support Australia). Companies like 23andMe and Navigenics offer genetic
testing for as little as US $99 to absolutely anyone with internet access,
although as they are both American companies, GINA (the Genetic Information
Nondiscrimination Act) does not apply to Australian consumers of their
services. The Australian Law Reform Commission outlines that although insurance
companies, for example, cannot ask an
individual to undergo genetic testing, they have every right to pursue whatever
genetic information may be available for underwriting purposes (ALRC, 2016). It
could be argued that the ethics of genetic testing is at least as complex as
the genome itself. While genetic testing enables the detection of new diseases
and leads to improved clinical interventions, there remains a high level of
concern regarding its social implications (Alper et al. 2002).
Knowing about the intricacies of one’s genome affects
how people see themselves, their social identity, and even leads to new kinds
of individual risk behaviours ( Arribas-Ayllon, Sarangi & Clark, 2011). The
argument quickly boils down to the ‘the right to know’ vs ‘the right not to know’ and must focus on both
individual autonomy and societal mores simultaneously (Hunt, Castaneda &
Voog, 2006; Gross & Shwval, 2008). The increased anxiety, social stigma and
potential discrimination resulting from poorly interpreted or incomplete
genetic testing may actually end up opposing one of the oldest medical
principles of all: Primum non nocere (Domaradzki,
2015). A psychiatrist friend of mine suggested that I start this paper with “It
was a dark and stormy night on Wisteria Lane…”
and although he was being as facetious as is expected of a long-term friend and academic, his suggested literary trope for this topic (‘mystery’) was not entirely misplaced. The palpable public fear and mistrust of scientific method and genetic manipulation, whether actual or simply the fear of one portion of humanity holding greater power over the individual through advanced knowledge in genetics, cannot be dismissed lightly. With every advance in epigenetics and nutrigenomics comes a responsibility for balanced and ethical stewardship of information accessibility and dissemination (Pinigree, 2008).
and although he was being as facetious as is expected of a long-term friend and academic, his suggested literary trope for this topic (‘mystery’) was not entirely misplaced. The palpable public fear and mistrust of scientific method and genetic manipulation, whether actual or simply the fear of one portion of humanity holding greater power over the individual through advanced knowledge in genetics, cannot be dismissed lightly. With every advance in epigenetics and nutrigenomics comes a responsibility for balanced and ethical stewardship of information accessibility and dissemination (Pinigree, 2008).
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Great blog.. Here I found lot of information on genetic testing. I want to know how genetic diet testing help to get more fit life. Thanks
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