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SFI Centre for Research Training in Genomic Data Science: Nutrigenomic evaluation of antioxidant status with cognitive outcomes in the Northern Ireland Cohort of Longitudinal Ageing


   School of Medicine, Dentistry & Biomedical Sciences

  Dr G McKay, Prof AJ McKnight, Dr H Roche  Sunday, July 03, 2022  Competition Funded PhD Project (UK Students Only)

About the Project

Start date: 1 September 2022

Multiple neuropathological processes underlie cognitive decline with increased age, a process influenced by modifiable (e.g. lifestyle) and non-modifiable (e.g. genetic) risk factors. The brain is especially vulnerable to reactive oxygen species as neurons possess relatively low levels of endogenous antioxidants to offset their high metabolic activity. This antioxidant deficit leads to oxidative damage of major cell components and elevated inflammation leading to neuronal cell death. Nutritional factors may prove beneficial for retaining healthy cognitive function, but the influence of dietary antioxidants remains unclear. Despite numerous studies exploring whether lower antioxidant levels are associated with reduced cognitive function, findings have been inconsistent, in part due to insufficient consideration of potential confounders and an inability to deliberate the underlying molecular influences.

Previous studies have shown vitamin E (VE) bioavailability is modulated, in part, by a combination of polymorphisms in at least 11 genes, accounting for up to 82% of genetic variation present. These genes are involved in the complex interactions that underlie antioxidant intake, absorption efficiency, blood clearance (e.g., liver secretion and tissue assimilation), utilisation and catabolism. As such, the therapeutic potential of antioxidant supplementation or dietary intervention is dependent on an individual’s underlying genetic architecture. Therefore, improved understanding will enable a stratified approach to progress intervention study design and enhance likely effect on outcomes.

Previously, we reported antagonistic interactions between VE isoforms that may alter functionality and bioavailability, highlighting concerns for clinical trials investigating VE supplementation.1 Furthermore, APOE status has been shown to influence antioxidant status and we previously reported significantly lower alpha-tocopherol and higher gammatocopherol by APOE status, with APOE2 characterised as more neuroprotective.1

We will evaluate antioxidant levels, including retinol, α-tocopherol, γ-tocopherol, and six carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein, lycopene, zeaxanthin), in 3,000 well characterised participants of the Northern Ireland Cohort of Longitudinal Ageing (NICOLA). We will use previously collected data from validated food frequency questionnaires, together with genome-wide and epigenome-wide association data to evaluate (epi)genetic variation associated with antioxidant status and measures of cognition.

We hypothesize that molecular variation in older populations may influence serum antioxidant levels which in turn may impact cognitive outcomes.

Aim 1: Evaluation of antioxidant profiles with cognitive function in NICOLA participants. Statistical approaches will include data comparisons using Pearson correlation coefficients and Bland-Altman plots in combination with cognitive measures (MMSE and MoCA) and regression analyses with adjustment for potential confounders.

Aim 2: Identification of genetic and epigenetic variants associated with antioxidant status from NICOLA participants (Illumina Infinium CoreExome chip; ~550k variants and the Infinium MethylationEpic array [~850k methylation sites]) have been imputed and available for mixed model linear regression analyses with adjustment for confounders and population stratification. Major developments in methods for deriving causal inference through instrumental variable analysis such as Mendelian randomisation approaches will be adopted.2 With 3,000 study participants we can detect as statistically significant at the 5% level, a correlation coefficient of 0.2 or greater with over 90% power (PASS: Power Analysis and Sample Size. Kaysville, Utah). Independent replication and validation will be facilitated through ongoing collaborations.3

Queen’s University Belfast is a partner of the SFI CRT in Genomics Data Science, which was formed in 2019. Over seven years of its operation, the Centre will train 100 PhD students in data analytical and computational skills that will help power the implementation of genomics on the island of Ireland. The Centre is built on a national cohort-based model of advanced training. At the outset of their training programme, each student cohort undertakes an intensive, semester-long series of training courses. Participation in the SFI CRT in Genomics Data Science includes a mandatory 3-month residential training programme for the students at NUI Galway, held in Semester 1 (start of September to mid-December) of Year 1 of the PhD programme. Through their experience of working and living together on this phase of the training programme, student cohorts form tight knit groups, enabling them to work collectively on the data science challenges they will encounter during their research. For more information on the SFI CRT in Genomics Data Science and the residential training programme see: https://genomicsdatascience.ie/

Students would benefit from having some experience with bioinformatics / computational biology tools and analyses, although training in these areas will be provided in the residential training programme at the start of the project.

Further funding eligibility: ROI (and EU applicants with pre-settled/settled) status may be eligible for funding if 3 year UK residency met.

ENTRY REQUIREMENTS

You must hold or expect to get an upper second class honours degree from a university in the UK or Ireland, or qualifications and experience considered by the University as equivalent to that standard. Candidates who already hold a doctoral degree, or who have registered on a PhD for one year (or part-time equivalent) or not eligible.

English Language

Candidates applying from countries where the first language is not English should produce evidence of their competence through a qualification such as IELTS or TOEFL score.

The minimum recommended score for the School of Medicine, Dentistry and Biomedical Science is:

·        IELTS score of 6.0 with not less than 5.5 in each of the four component elements of listening, reading, speaking and writing taken within the last 2 years;

·        TOEFL score of 80+ (internet basted test), taken within the last 2 years, with minimum component scores of; Listening 17, Reading 18, Speaking 20, Writing 17);

·        A valid Certificate of Proficiency in English grade A or B;

·        A valid Certificate of Advanced English grade A; or

·        A first or upper second class honours degree from a university based in the UK, Republic of Ireland or other suitably quality assured location in a country deemed by the UK Border Agency to be majority English speaking.

For a list of English Language qualifications also accepted by the School and University please see the following link:

http://www.qub.ac.uk/International/International-students/Applying/English-language-requirements/#English

INTO Queen’s English Language Courses offers both pre-sessional and in-sessional courses in English for academic purposes and study skills. Courses vary in length and full information can be obtained at: https://www.qub.ac.uk/International/International-students/Applying/University-Preparation-Courses/INTOEnglishlanguagecoursesatQueens/


Funding Notes

Funded by the Department for the Economy (DfE). For UK domiciled students the value of an award includes the cost of approved tuition fees and maintenance support (Fees £4,596, Stipend £16,062 for 2022/23). To be considered eligible you must have been ordinarily resident in the UK for the full 3 year period prior to the start of the studentship and you must be ordinarily resident in Northern Ireland on the first day of the start of the studentship. For further information about eligibility criteria please refer to the DfE Postgraduate Studentship Terms and Conditions 2021-22 at View Website

References

1. Mullan K, Williams MA, Cardwell CR, McGuinness B, Passmore P, Silvestri G, Woodside JV, McKay GJ (2017). Serum concentrations of vitamin E and carotenoids
are altered in Alzheimer’s disease: a case control study. Alzheimer's & Dementia: Translational Research & Clinical Interventions 3(3):432-439.
2. Lukkunaprasit T, Rattanasiri S, Ongphiphadhanakul B, McKay GJ, Attia J, Thakkinstian A (2021). Causal associations of urate with cardiovascular risk factors:
Two-sample Mendelian Randomization. Front Genet 12:687279.17.
3. Fiorito G, McCrory C, Robinson O, Carmeli C, Rosales CO, Zhang Y, Colicino E, Dugué PA, Artaud F, McKay GJ, Jeong A, Mishra PP, Nøst TH, Krogh V, Panico S,
Sacerdote C, Tumino R, Palli D, Matullo G, Guarrera S, Gandini M, Bochud M, Dermitzakis E, Muka T, Schwartz J, Vokonas PS, Just A, Hodge AM, Giles GG,
Southey MC, Hurme MA, Young I, McKnight AJ, Kunze S, Waldenberger M, Peters A, Schwettmann L, Lund E, Baccarelli A, Milne RL, Kenny RA, Elbaz A, Brenner H,
Kee F, Voortman T, Probst-Hensch N, Lehtimäki T, Elliot P, Stringhini S, Vineis P, Polidoro S; BIOS Consortium; Lifepath consortium (2019). Socioeconomic position,
lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis. Aging (Albany NY) 11(7):2045-2070.
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