• Senior lecturer, Quantitative Genetics, Dept of Mathematics and Statistics • Established Masters degree programme in Quantitative Genetics that started in

2017 -> now graduating students! See https://www.otago.ac.nz/sciences/study/applied-science/majors/otago619406.html

About me… Current Roles…

• Senior lecturer, Quantitative Genetics, Dept of Mathematics and Statistics • Established Masters degree programme in Quantitative Genetics that started in

2017 -> now graduating students! • Current Research:

• Genomic prediction in health related characteristics• Co-lead Genomics Aotearoa Variome -> establish database of DNA sequence variation in

contemporary Māori • Co-lead Rakeiora Pathfinder project -> pilot for personalised medicine involving Ngāti

Porou Hauora• Kauri dieback, involving Ngāti Wai• Stat method development and evaluation for DNA-based methods for estimating breeding

values in ryegrass and kiwifruit (PhD students)• Implementation of genomic selection in Radiata pine• Māori perceptions of gene editing*

Current Roles…

Some of my Māori-related professional activities• Involved in Māori-specific

conversations/research regarding genetic technologies since 2001:• Established Te Arotūruki and co-developed TA

Process (JRSNZ 2008)• Otago University ‘Full Circle Theme’• University of Waikato ‘Te Mata Ira’ & ‘Te Hau Mihi

Ata’ projects• Various consultation with Māori communities

• Māori advisory roles • Scion (GE pine, kauri transcriptomics) • Royal Society of NZ Gene Editing expert panel • Reviewer for Te Tipu o te Wānanga

• Māori-specific education initiatives • Genetics modules in Science Wānanga for 11-4 year

old Māori high school students• Summer Internship of Indigenous Peoples in

Genomics (SING-Aotearoa)• Trained/ing 8 Māori graduate students in genetics

• Scientific Research• 24 years forestry-related genetics research• Genetics of gout in Maori and Pacific populations• GA-funded Aotearoa Variome project co-lead*• Co-led Māori components in successful NZ$35M

Genomics Aotearoa Proposal• Māori-specific roles in BioHeritage National

Science Challenge and BioProtection CoRE

• Iwi (= tribal) roles• Previously mandated representative for Ngāti

Rakaipaaka• Advisor for various iwi initiatives e.g. Ngāti Kohatu• Science advisor for various proposals in

Wairoa/Mahia area

• University-specific activities• Maths and Stats Dept Kaiawhina• Sci Div Māori Leadership roopu• Overviewing & teaching UoO Science Wānanga

Māori outreach• Teaching Māori ethical frameworks and consultation

requirements in 300- and 400-level science courses

STAT311 - Gout Case StudiesPhillip Wilcox

What is gout?

• Painful inflammatory response to presence of monosodium urate crystals in synovial fluid• Crystals can be present in asymptomatic individuals

• Crystals result from deposition of urates in blood• Test for hyperuricemia• Not everyone with hyperuricemia has gout • Urate levels can fall and appear normal during a flare

• Clinical diagnosis requires combination of history, exam, lab and (maybe) imaging

Gout is very treatable• Principles of management

• Rapid treatment of flares, then• Effective long-term prevention via urate lowering therapies

• Acute flare• Low dose colchicine (1-2 mg immediately; 0.6 mg/hr for 6 hr). Reduced further in

renal impairment• Non-steroidal anti-inflammatory drugs. Contraindicated in renal, CV and gastro

disease• Corticosteroids in patients with co-morbidities

• Urate-lowering therapy (ULT) • Central strategy• Indicated for those with >1 flare per year, tophi• Xanthine oxidase inhibitors (allopurinol, febuxostat)

• Allopurinol = Hypersensitivity syndrome (HLA-B*5801• Febuxostat = Recent FDA warning about increased risk of heart-related death

• Then uricosurics (probenecid, benzbromarone)

Impact of allopurinol on Serum urate

From: Taylor, T. H., J. N. Mecchella, R. J. Larson, K. D. Kerin and T. A. MacKenzie (2012). "Initiation of Allopurinol at First Medical Contact for Acute Attacks of Gout: A Randomized Clinical Trial." The American Journal of Medicine 125(11): 1126-1134.e1127.

Epidemiology: 3% European; 6% Māori; 8% PacificWinnard et al. Rheumatology 2012

Men

Women

Gout has been present in antiquity in the Pacific – a genetic disease impervious to environment

429-950 BP *

3240-2950 BP

260-330 BP

650-662 BP

Crude prevalence 35% (all males)

Crude prevalence 21% (14% females, 23.5% males)

Crude prevalence 14% (all males)

Crude prevalence 5.6% (6.6% of females, 7.5% of males)

Serum urate levels are under strong genetic control…

• Many genes involved BUT not all genes that impact SU are involved in gout• Differences in prevalence can be

(partly) explained by hereditary factors in ancestry-specific causative genes• May be under selection? If so, why?

• Family history of gout -> increased risk of gout

Tin, A., J. Marten, et al. (2019). "Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels." Nature Genetics 51(10): 1459-1474.

PRPSAP1 p.Arg35SerfsTer2: An Eastern Polynesian-specific risk variantEP 6%; WP 0.5%; others <0.01%

• Dysfunctional PRPSAP1 removes negative inhibition of phosphoribosylpyrophosphate synthetase 1 which is involved in purine synthesis.

• The Eastern Polynesian variants will contribute to over-production of urate

Causes vs Triggers

• Not the same thing• Cause: High SU (hyperuricemia) -> deposition of MSU crystals in joints

= high • Triggers: things that initiate an attack• Beer, red meat, shellfish, tomatoes• Varies by individual

• Diet still considered a causative factor by some -> leads to stigmatization of gout -> ’whakamā’ (shame) -> discourages sufferers from seeking medical help

Case Studies

1. Flynn et al. (2015) – examines the role of tomato as a gout trigger 2. Roberts et al. (2016) – examines the impact of variations in a specfic

gene (ABCG2) on response to allopurinol3. Taylor et al. (2012) – examines the impact of allopurinol dosing at vs

10 days after gout attack

Design considerations

• How were the hypotheses formulated?• What are the study designs?• Were the studies sufficiently well designed to test the hypotheses?• Are the analytical methods suitable?• Are the conclusions valid?• What are the practical implications of the results?• What are the ethical considerations? How have these been

addressed?