Genetic testing for individual MTHFR polymorphisms: Clinical relevance and ethical considerations in the top 3 worldwide causes of morbidity and mortality

“Within the next few years, you will be able to have your entire genome sequenced for about $1000. From the point of view of your future profession, leading on from your course (medical science, clinical science, pharmacy, nutrition etc), review the literature to find predictions or areas currently under research which rely on genetic information and could affect your future practise (e.g. diagnosis, services, treatment or advice). Explain, using examples of disease, how genetic information facilitates these changes in practise”.

Word count: 1485

GENETIC TESTING FOR INDIVIDUAL MTHFR POLYMORPHISMS: CLINCAL RELEVANCE AND ETHICAL CONSIDERATIONS IN THE TOP 3 WORLDWIDE CAUSES OF MORBIDITY AND MORTALITY.

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 ).

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[D13]  (Pinigree, 2008).

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	HD (100-85)	DI (85-75)	CR (75-65)	PS (65-50)	FL (<50)	Mark
Title & Introduction (/10)	Very focused & concise title & introduction, leading to a completely clear & logical plan. A  few significant diseases relevant to the students course are introduced	Focused & concise title & introduction, leading to a logical plan. A few diseases relevant to the students course are introduced	Title & introduction are reasonably well focused and concise. A disease relevant to the students course is introduced	Title & introduction are somewhat focused and concise. A few diseases which are irrelevant to the students course are introduced	Significant information in title & introduction is missing.  No diseases are introduced	10
Presentation of content relevant to the current diagnosis and treatment of disease, how this will change with genetic testing and description of ethical consequences (/45)	Very appropriate & accurate presentation of the literature throughout. Current diagnoses and treatment based on genetic information accurate. Common mutations identified. Concise changes to diagnosis and treatment as a result of genetic testing identified. Sound description of ethical issues as a result of DNA testing	Appropriate & mostly accurate presentation of the literature throughout. Current diagnoses and treatment based on genetic information included. Some common mutations identified. Some changes to diagnosis and treatment as a result of genetic testing identified.  Sound description of ethical issues as a result of DNA testing	Some minor inaccuracies and presentation of the literature throughout. Figures and tables Inaccurate current diagnoses and treatment based on genetic information included. Some common mutations identified. Some changes to diagnosis and treatment as a result of genetic testing identified. Brief description of ethical issues as a result of DNA testing	Some information presented which is inaccurate. Data not described in appropriate detai. Current diagnoses and treatment based on genetic information inaccurate. Common mutations identified. Minor changes to diagnosis and treatment as a result of genetic testing identified.  Some description of ethical issues as a result of DNA testing	No interpretation of relevant literature and inaccuracies present. Current diagnoses and treatment not based on genetic information. Common mutations not identified. Minor changes to diagnosis and treatment as a result of genetic testing identified.  No description of ethical issues as a result of DNA testing	45
Evidence of linking of information from various sources and critical analysis (/20)	Information from various sources and concepts is linked throughout the assignment. There is evidence of critical analysis of various sources. The balance of references is very good throughout the assignment	Information from various sources and concepts is linked throughout the assignment. There is limited critical analysis of various sources. The balance of references is very good throughout the assignment	There is some linkage of various sources and concepts throughout the assignment. There is very limited critical analysis The balance of references is very good throughout the assignment	There is some linkage of various sources and concepts throughout the assignment. There is no critical analysis the references are unbalanced.	No linking of concepts across the various parts of the assignment. Normal and abnormal situation are not clearly separated and information is presented under the wrong headings. No balance of references in the assignment (i.e.many references used for only one paragraph, one reference used for the rest of the assignment	20
Clarity of expression and logical flow of information (/10)	No grammatical or spelling errors. Professional expression & style used consistently. Sections distinct & literature review logically organised.	No more than 4 grammatical and spelling errors. Professional expression & style used consistently. Sections distinct & literature review logically organised	No more than 4 grammatical and spelling errors. Minor flaws in professional expression & style. Most of the literature review logically organised.	No more than 4 grammatical and spelling errors. Occasional flaws in professional expression & style and literature review not logically organised.	More than 4 grammatical and spelling errors.	10
References (/10)	More than 80% of the references used are from international peer reviewed journals and published after 2008. No errors in reference list and no more than 5 errors in citation style list (APA format).	More than 70% of the references used are from international peer reviewed journals and published after 2008. No errors in reference list and no more than 5 errors in citation style list (APA format).	More than 50% of the references used is from international peer reviewed journals and published after 2008. No errors in reference list and no more than 10 errors in citation style list (APA format).	Less than 50% of the references used is from international peer reviewed journals and published after 2008. No more than 2 errors in reference list and no more than 10 errors in citation style list (APA format).	Use of literature limited to a few articles & reviews. Poor attempt to explore literature. Major errors in citations & reference list.	8[D15]
Presentation (/5)	Word count clearly indicated. Full adherence to word limit and presentation guidelines in subject outline (3cm margin, double or 1.5 line spacing, 12pt font, numbered pages, header and footer, title page. Turnitin report included.	Word count clearly indicated. Full adherence to word limit and presentation guidelines in subject outline (3cm margin, double or 1.5 line spacing, 12pt font, numbered pages, header and footer, title page Turnitin report included.	Word count not indicated.Full adherence to word limit and presentation guidelines in subject outline (3cm margin, double or 1.5 line spacing, 12pt font, numbered pages, header and footer, title page. Turnitin report included.	Word count not indicated.No adherence to word limit and presentation guidelines in subject outline (3cm margin, double or 1.5 line spacing, 12pt font, numbered pages, header and footer, title page. Turnitin report not included.	Word count not indicated. No adherence to word limit and presentation guidelines in subject outline not adhered to (3cm margin, double or 1.5 line spacing,12pt font, numbered pages, header and footer, title page). Turnitin report not included.	5

Total = 98

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 [D13]a complicated subject but an excellent essay, clear, well researched, logical flow and thoughtful conclusions…exemplary! It would appear that you really enjoyed the exercise