Concept of a “standard human” is slowly being abandoned and patent stratification is the “new big thing” in medical research. Despite the technical success of the human genome project and millions of people being sequenced, translation of genetic information into clinical use is limited. Important aspect of biology that is not contained in our genome is lifestyle, which is a major factor in disease development. Collecting lifestyle data and measuring biomarkers that respond to lifestyle is needed to enable efficient patient stratification for personalised medicine.

1. www.genos-glyco.com
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Big data in personalised medicine
Gordan Lauc
University of Zagreb & Genos Glycoscience Research Laboratory
CSO of GlycanAge
WO2014203010; US2016103137, WO2012042020; WO2011015944; WO2009044213

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Up to 80% of „smart” drugs and lifestyle interventions are wasted,
because of the lack of biomarkers for personalised medicine

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Despite technical success, the Human Genome Project did not fulfill
expectations of both general and scientific public

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Genes do not define everything
Only 20% of longevity and 30% of most complex diseases is genetic

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Glycans are responsible
for a large part of inter-
individual variations

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Lesson from genetics: Nearly all published
results from small studies are false
Ionniadis, PLOS Medicine, 2(8): e124, 2005
Button, Nat Rev Neurosci,
14:365, 2013
John Ioannidis

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IgG glycans in children with alergies
WRONG

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Advancing from low- to high-throughput is not a simple task
F. Vučković
Ivo Ugrina
Normalizat
ion
Batch-
correction
Confounders
Correction for age,
gender,
relatedness...
Correction for
multiple testing
Randomization
Structure of
experimental
error
L. Klarić

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Genome wide association studies (GWAS) initiated
revolution in genetics

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Modelling of big data can also be very wrong…

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The ZOE COVID Study
Predicting COVID-19 since March 2020
• 4.8 million users across the UK, US and Sweden
• 850,000 daily contributors
• Predicts "Symptomatic COVID" via ZOE algorithm
• Over 800 million health reports and 30 million
tests
• 1 million infections (confirmed by PCR or LFT)
• Detecting hotspots and changes in R before other
surveys for only a fraction of the cost
• Quantified side effects of vaccines early
• Discovered waning vaccines after 6 months
Prof. Tim
Spector

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Tracking of individual
patients in Barcelona
provided early
evidence for strong
seasonality of
COVID-19
Kifer et al, MedRxiv, July 2020
Kifer et al, Frontiers in Medicine, 2021

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Initial observation was replicated in multiple hospitals
Kifer et al, MedRxiv, July 2020; Kifer et al, Frontiers in Medicine, 2021

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Mucosal barrier is our first line of defence against
respiratory pathogens, but it has to be well hydrated
Kudo et al, PNAS, 2019,

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Croatian model of identification of war victims was the most
successful program of identification of war victims because we
implemented “sanity check” of DNA data
Prof. Dragan
Primorac
Prof. Milovan
Kubat

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Average life expectancy is increasing globally

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Maximal human lifespan did not change much in the last
2000 years
Roman empress Livia
Drusilla, wife of Augustus,
lived until she was 86 or 87
years old

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Both epigenetic and
glycan clocks of ageing
were first published on
December 10th, 2013
Prof. Steve
Horvath

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Horvath’s epigenetic clock is using 353 CpG sites to
predict chronological age of an individual
Horvath, Genome Biol, 2013

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Many different epigenetic age tests are available

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Glycan clock of ageing is based on the analysis of 24 individual
glycan structures attached to immunoglobulin G
Kristic et al, J. Gerontol, 2014
Lauc and Sinclair, Aging, 2020
Disclosure: Gordan Lauc is named as an inventor on the
GlycanAge patent and is a co-founder of GlycanAge LTD

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Accelerations in glycan
and epigenetic clocks do
not correlate
Macdonald-Dunlop E, et al
Aging 14:623-659, 2022

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Genes, epigenetics, polypeptides and glycans
Gene (20,000) Epigenetics (28 M CpG)
Protein (>100,000) Glycoprotein (>100 M)

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Glycans are the ultimate layer of molecular complexity and the
most neglected molecules of cellular communication
Glycation (HbA1c, AGE) is
something completely different
The majority of proteins are glycosylated

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Glycans are very complex and their
analysis is challenging

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With 150,000 analysed samples
Genos is the global leader in
high-throughput glycomics
Cohort Plasma glycome IgG Glycome
10001 Dalmatian 2,000 5,000
Orcades 2,000* 3,000
TwinsUK 10,000 10,500
KORA - 2,000
SABRE 2,000 -
EPIC 3,500 3,500
Global population study - 2,700
FINNRISK - 1,200
Estonian biobank - 1,300
China 1,000 2,000
CRC 2,000 2,000
IBD 3,000 5,700
SLE - 1,200
Type 1 Diabetes 3,000 1,000
Type 2 Diabetes 3,000 4,000
Down syndrome - 800
Low back pain 6,000 2000
PTSD 600 600
Total 39,100 48,500
Adam
Butterworth
Mohamed
Abdel Mohsen
Karsten Suchre
Jan Krumsiek
Tim Spector
Frances Williams
Nenad Sestan
David Sinclair
Peter Nigrovic
Samia Mora
Nish Chaturvedi
Steve Pavletic
Y. Aulchenko, F. Kolpakov,
M. Filipenko
Mark McCarthy
Jack Satsangi
Joana Melia

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IgG glycans change
significantly with age
Štambuk et al,
Aging, 2020

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IgG glycome composition is an excellent
biomarker of chronological and biological age
Kristić et al, J Gerontol, 2014
Gudelj et al, Int J leg Med, 2015
Jasminka
Krištić
Ivan Gudelj

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Lifestyle is the most important
element of healthy longevity
Caloric restriction is known to be beneficial for health
and lifespan. Colman et al, Science, 2009
Prospective study on over 110,000 people
demonstrated that healthy lifestyle can extend
lifespan by up to a decade. Li et al, BMJ 2020

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There is no “standard human”
Diet
Physical
activity
Stress
Sleep
Diet
Physical
activity
Stress
Sleep
Diet
Physical
activity
Stress
Sleep
Caloric
restriction

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Changes of IgG glycome in many diseases resemble ageing
Diseases Age
IgG glycans are functional effectors that regulate inflammation

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Main Genos papers in 2017 – 2020
High-impact papers in
2017- 2020
IF RANK
Suchre et al, Nature Communications
8:14357, 2017
14.9 3/64
Shen et al, Nature Communications
8:447, 2017
14.9 3/64
Benedetti et al, Nature
Communications 8:1483, 2017
14.9 3/64
Lauc et al, Nature Communications
9:2916, 2018
14.9 3/64
Benedetti et al, Nature
Communications, 11:5153, 2020
14.9 3/64
Krištić et al, Nature Chemical Biology
14:516, 2018
15.1 5/290
Bermingham et al, Diabetes Care
41:79-87, 2018
19.1 4/143
Juszczak et al, Diabetes Care
42:17-26, 2019
19.1 4/143
High-impact papers in
2017 - 2020
IF RANK
Wittenbecher et al, Diabetes care
43:661-668, 2020
19.1 4/143
Šimurina et al, Gastroenterology
154:1320, 2018
20.8 1/80
Clerc et al, Gastroenterology 155:829-
843, 2018
20.8 1/80
Monaghan et al, Gastroenterology
157:1676-1678, 2019
20.8 1/80
Josipović et al, Nucl Acid Res
47(18):9637-9657, 2019
17.0 14/298
Klarić et al, Science Advances 6 (8):
eaax0301, 2020
14.1 4/71
Peng et al, Circulation, 140:2005–
2018, 2019
23.6 1/138
Menni et al, Circulation Research,
117.312174, 2018
14.0 1/70

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IgG glycome strongly associates with cardiovascular disease risk score
Prof. Tim
Spector
Menni et al
Circulation Res,
2018
Prof. Jim
Wilson
2,970 women
and 845 men
from UK

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Glycans predict cardiovascular events in a prospective cohort
Wittenbecher et al,
Diabetes care, 2020
HR per SD in woman = 0.7

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Supplementation with ManNAc
increased sialylation of IgG and
prevented hypertension in
obese mice
Peng et al
Circulation, 2019
Prof Philip
Shaul
Obesity related induction
of hypertension by
hyposialylated IgG is
mediated by FcγRIIB
Hyposialylation associates
with higher blood pressure
in humans

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Glycans predict type 2
diabetes in a
prospective cohort
Wittenbecher et al,
Diabetes Care,
2020

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Predictive potential of glycans for T2D was confirmed by
studying 2000 twins in three time points over 20 years
Cvetko et al, BMJ Open Diab Res Care, 2021

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Glycans are functional effectors of inflammaging that
contribute to multiple diseases
Schultze, Immunity, 2018

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Inflammation is one of the main
drivers of ageing and age-related
diseases
“You’re only as young as your
immune system” – Cover story of
the New Scientist on March 28,
2020

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Can we revert the glycan clock of biological age and
stop inflammageing?

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Anti-ageing can change the GlycanAge
Joseph Raffaele

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Glycan clock of aging can be reverted with lifestyle interventions
https://www.instagram.com/tv/CNAtuA7H
Cas/

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Bariatric surgery is
very effective in
rejuvenating the
IgG glycome
Cvetko et al, Int. J. Obesity 2021
One patient improved
for 37 glycan years in
six months

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Pace of glycan
ageing associates
with changes in
BMI
Cvetko et al, Int. J. Obesity 2021
The analysis of 2000 twins
in three time points over
15 years

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Caloric restriction strongly affects the IgG glycome
Meta-analysis of 700 individuals
on low-calory diet after 8 weeks
(median weight loss was 10.3 kg)
Caloric
restriction

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There is no standard human (Diogenes study)

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Physical activity can have beneficial effects on the
IgG glycome, but it can also make IgG glycome more
pro-inflammatory in some situations
Tijardović et al,
Front. Physiol., 2020
Dr Markus
Perola
Sarin,
Front. Immunol, 2019

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Gut microbiome is a very important element of health
and it also affects composition of the plasma glycome
Monaghan et al.
Gastroenterology 2019
Dr Maja Pučić
Baković
Dr Tanya
Monaghan

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Glycans integrates genetic, epigenetic and environmental factors
into a simple index that can be reliably quantified
Lauc & Sinclair, Aging, 2020
IgG glycans are functional effectors of inflammaging that
either promote or suppress low grade chronic inflammation

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R&D in Genos was funded with Euro >15 million through six
FP7, six H2020 projects, three ESI and 3 HrZZ projects