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Chan et al. J Transl Genet Genom 2024;8:13-34 https://dx.doi.org/10.20517/jtgg.2023.36 Page 125

researchers advocate the use of polygenic risk scores to increase the cost-effectiveness of screening for high-
risk subjects for intervention and individualized treatment [105-107] .

In people with youth-onset diabetes (less than 18 years old), there are ongoing large-scale epidemiological,
[11]
[10]
genetic , and interventional studies to discover the causes and evaluate interventions. By contrast, there
are major research gaps in adults with YOD often diagnosed by physicians who are less familiar with rare
[12]
diseases . Amongst patients diagnosed before the age of 40 years, there is heterogeneity in etiologies and
phenotypes depending on whether they present during infancy, childhood, adolescence, or early adulthood.
Large-scale GWAS have identified different genetic variants associated with the age of diagnosis, with many
of them being associated with common forms of type 2 diabetes . These variants can be used to generate
[108]
polygenic risk scores to stratify risk for prevention and early intervention. Structured lifestyle modification
and medications including metformin and alpha-glucosidase inhibitors prevent or delay the onset of type 2
diabetes in people with impaired glucose tolerance . In the United States and China Diabetes Prevention
[109]
[3]
Program , metformin was most effective in people under the age of 45. Thus, by combining familial,
[110]
genetic, and clinical risk scores, it is possible to segment the 20%-30% of individuals at the highest risk of
developing YOD with less biological resilience for early intervention .
[111]
Likewise, while the early use of cheap generic medications such as statin and renin-angiotensin system
inhibitors are likely to be cost-effective in preventing cardiovascular-renal events in young patients with
type 2 diabetes , the cost-effectiveness of new drugs such as glucagon-like peptide 1 receptor agonist
[3]
(GLP1-RA), sodium-glucose-cotransporter 2 inhibitor (SGLT2i), and non-steroidal mineralocorticoid
[112]
receptor antagonist in young patients remain uncertain despite their high lifetime risk for
complications . In this connection, diagnosis of familial hypercholesterolemia followed by cascade
[113]
screening has been shown to be cost-effective for preventing premature cardiovascular disease through early
detection and intervention . While definitive trials are needed to prove the value of genetic testing, RCTs
[114]
have demonstrated that the provision of personalized [115,116] and genetic information on the risk of diabetes
complications empowered self-management and reduced negative emotions [117-119] .

USING BIOGENETIC MARKERS TO INCREASE THE PRECISION OF DIAGNOSIS AND
TREATMENT
There are considerable overlaps in clinical presentations and phenotypes amongst people with autoimmune
type 1 diabetes, LADA, MODY, type 2 diabetes, and other atypical forms of diabetes in young people. Once
diabetes develops, glucolipotoxicity, inflammation, and oxidative stress can cause dedifferentiation and
apoptosis of beta-cells and perpetuate glycemic deterioration [22,120] . For the same set of risk factors (e.g.,
smoking, obesity), there are considerable inter-individual variations in rates of decline of beta-cell
[81]
function . An estimated 50% of beta-cell function might have been lost at the time of diagnosis of
diabetes . Early optimization of glycemic control could restore beta-cell function and delay treatment
[122]
[121]
escalation [56,57] . These data support the use of biomarkers to improve the precision of diagnosis and
treatment to preserve beta-cell function . In the ongoing PRISM-RCT, we observed the importance of
[123]
nature and nurture in these young patients in whom varying combinations of genetic predispositions,
lifecourse factors, timeliness of diagnosis, lifestyles, and access to care can result in different presentations,
trajectories, and outcomes [Figures 3 and 4 and Table 2].

In Hong Kong Chinese patients with YOD, analysis of stored samples indicated that 8% had LADA, but the
majority had not been given early insulin treatment. Compared to their peers with classical type 1 diabetes,
patients with LADA had a 2.8 times higher risk of ESKD, likely due to poor glycemic control with delayed
insulin treatment. Amongst patients treated with insulin, the mean reduction in HbA1c at 6 months was