Age of Onset

The incidence and prevalence of type 2 diabetes mellitus (T2DM) in young individuals (aged <40 years) have significantly increased in recent years, approximating two to threefold increase in the respective rates. Numerous risk factors including severe obesity, family history, ethnicity, maternal diabetes or gestational diabetes, and female sex contribute to a younger age of onset. In terms of pathogenesis, impaired insulin secretion is the key operating mechanism, alongside with ectopic adiposity-related insulin resistance. T2DM diagnosis in a young adult requires the exclusion of type 1 diabetes mellitus (T1DM), latent autoimmune diabetes of adults (LADA) and maturity-onset diabetes of the young (MODY). The establishment of such diagnosis is critical for prognosis, because early-onset T2DM is associated with rapid deterioration in pancreatic β-cell secretory function leading to earlier initiation of insulin therapy. Furthermore, mortality and lifetime risk of developing complications, especially microvascular, is increased in these patients compared to both later-onset T2DM and T1DM patients; also, the latter are often developed earlier in the course of disease. The management of early-onset T2DM follows the same guidelines as in later-onset T2DM; yet patients aged 18-39 years are underrepresented in the big clinical trials on which the development of guidelines is based. Finally, young people with T2DM face significant challenges associated with social determinants, which compromise their adherence to therapy and induce diabetes distress. Future research focusing on the pathogenesis of β-cell decline and complications, as well as on specific treatment shall lead to better understanding and management of early-onset T2DM.

ObjectivesRare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes have been strongly associated with a risk of developing chronic pancreatitis (CP). However, their potential impact on the age of disease onset and clinical outcomes, as well as their potential interactions with environmental risk factors, remain unclear. These issues are addressed here in a large Chinese CP cohort.MethodsWe performed targeted next-generation sequencing of the four CP-associated genes in 1061 Han Chinese CP patients and 1196 controls. To evaluate gene-environment interactions, the patients were divided into three subgroups, idiopathic CP (ICP; n = 715), alcoholic CP (ACP; n = 206), and smoking-associated CP (SCP; n = 140). The potential impact of rare pathogenic variants on the age of onset of CP and clinical outcomes was evaluated using the Kaplan-Meier model.ResultsWe identified rare pathogenic genotypes involving the SPINK1, PRSS1, CTRC, and/or CFTR genes in 535 (50.42%) CP patients but in only 71 (5.94%) controls (odds ratio = 16.12; P ConclusionsWe provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP. Extensive gene-environment interactions were also identified.

ObjectiveTo examine the association of midlife and late life multimorbidity, including severity of multimorbidity, with incident dementia.DesignProspective cohort study.SettingCivil service departments in London (Whitehall II study, study inception in 1985-88).Participants10 095 participants, aged 35 to 55 at baseline.Main outcome measureIncident dementia at follow-up between 1985 and 2019. Cause specific Cox proportional hazards regression was used to examine the association of multimorbidity overall and at age 55, 60, 65, and 70 with subsequent dementia, taking into account the competing risk of death.ResultsThe prevalence of multimorbidity (≥2 chronic diseases) was 6.6% (655/9937) at age 55 and 31.7% (2464/7783) at age 70; 639 cases of incident dementia occurred over a median follow-up of 31.7 years. After adjustment for sociodemographic factors and health behaviours, multimorbidity at age 55 was associated with subsequent risk of dementia (difference in incidence rate per 1000 person years 1.56, 95% confidence interval 0.62 to 2.77; hazard ratio 2.44, 95% confidence interval 1.82 to 3.26). The association weakened progressively with older age at onset of multimorbidity. At age 65, onset of multimorbidity before age 55 was associated with 3.86 (1.80 to 6.52) per 1000 person years higher incidence of dementia (hazard ratio 2.46, 1.80 to 2.26) and onset between 60 and 65 was associated with 1.85 (0.64 to 3.39) per 1000 person years higher incidence (1.51, 1.16 to 1.97). Severity of multimorbidity (≥3 chronic diseases) at age 55 was associated with a 5.22 (1.14 to 11.95) per 1000 person years higher incidence of dementia (hazard ratio 4.96, 2.54 to 9.67); the same analyses at age 70 showed 4.49 (2.33 to 7.19) per 1000 person years higher incidence (1.65, 1.25 to 2.18).ConclusionMultimorbidity, particularly when onset is in midlife rather than late life, has a robust association with subsequent dementia. The increasingly younger age at onset of multimorbidity makes prevention of multimorbidity in people with a first chronic disease important.

BackgroundThe global increase in the incidence of early-onset cancers (defined as cancers diagnosed at 20-49 years old) is a serious public health problem. We investigated 1) whether the incidence trend of early-onset cancers differs from that of later-onset cancers and 2) whether both the incidence and mortality of early-onset cancers have increased concurrently.MethodsWe utilized age-standardized incidence and mortality rates for early-onset and later-onset cancers diagnosed between 2000 and 2017 from the Cancer Incidence in Five Continents and World Health Organization (WHO) mortality databases. The national obesity prevalence among adults aged 20-49 years was obtained from the National Clinical Database. Using joinpoint regression models, we calculated average annual percentage changes (AAPCs) for cancer incidence and mortality by cancer types and countries. We additionally conducted human development index (HDI)-stratified analyses and assessed the correlation between the obesity prevalence in younger populations and early-onset cancer incidence by country. To investigate the more recent trend of early-onset cancer mortality, we extended our mortality analysis after 2017 for cancer types and countries with statistically significant positive AAPCs in both incidence and mortality of early-onset cancers between 2000 and 2017.ResultsOur analysis showed that 10 early-onset cancer types (thyroid cancer, breast cancer, melanoma, uterine cancer, colorectal cancer, kidney cancer, cervical cancer, pancreatic cancer, multiple myeloma, Hodgkin lymphoma) in females and 7 early-onset cancer types (thyroid cancer, kidney cancer, testis cancer, prostate cancer, colorectal cancer, melanoma, leukemia) in males had statistically significant positive AAPCs in at least 10 countries. Among these, the following early-onset cancer types had significantly higher AAPCs than later-onset cancer types in females: colorectal cancer (6 countries; AAPC range: 1.8-3.8%), cervical cancer (6 countries; AAPC range: 1.2-3.3%), pancreatic cancer (5 countries; AAPC range: 2.3-13.0%), and multiple myeloma (5 countries; AAPC range: 3.1-9.8%); in males: prostate cancer (12 countries; AAPC range: 3.9-18.4%), colorectal cancer (8 countries; AAPC range: 1.8-3.2%), and kidney cancer (6 countries; AAPC range: 2.0-6.0%). We observed statistically significant positive AAPCs in both the incidence and mortality of the following early-onset cancer types: uterine cancer (5 countries) and colorectal cancer (3 countries in females and 5 countries in males). The steeper increases in early-onset cancers compared with later-onset cancers were mainly observed in the very high-HDI country group, including early-onset colorectal cancer (AAPC = 2.4%, 95% CI 2.1-2.6 in females; AAPC = 2.0%, 95% CI 1.7-2.4 in males) to later-onset colorectal cancer (AAPC = -0.1%, 95% CI -0.2 to 0 in females; AAPC = -0.2%, 95% CI -0.3 to 0 in males). We observed strong positive correlations between the increasing obesity prevalence and the rising incidence of early-onset obesity-related cancers in several countries, including Australia (7 cancer types), United Kingdom (7 cancer types), Canada (7 cancer types), Republic of Korea (7 cancer types), and USA (6 cancer types) in females and United Kingdom (7 cancer types), Canada (6 cancer types), Australia (5 cancer types), Sweden (5 cancer types), and Republic of Korea (4 cancer types) in males. Although we did not observe an apparent spike after 2017 in many countries, we observed continued increases in the mortality of certain cancer types, such as uterine cancer (Japan, Republic of Korea, United Kingdom, USA, and Ecuador) in females and colorectal cancer (Argentina, Canada, United Kingdom, and USA) in males.ConclusionsThe increase in many early-onset cancer types was significantly higher than that of later-onset cancers, and the incidence and mortality of certain early-onset cancer types (such as colorectal cancer) increased simultaneously. Our study highlights global differences in cancer incidence and mortality trends of early-onset and later-onset cancers.