Early-onset Cohort Research Articles

Management of Early-Onset Type 2 Diabetes

Early-onset type 2 diabetes is experiencing a rapid global increase, coinciding with the escalating rates of obesity. In contrast to diagnoses later in life, an earlier diagnosis is associated with unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and premature mortality. Patients with early-onset type 2 diabetes appear to undergo a more aggressive clinical course, which can be exacerbated by the limited availability of treatments. The heightened burden of complications places individuals with early-onset type 2 diabetes at a substantial risk of multimorbidity, underscoring the urgency for interventions to reverse these concerning trends. While the pathophysiology and interventions for adolescent-onset (< 19 years) type 2 diabetes within the early-onset cohort have received considerable attention in research, young adults aged 19~39 years (a larger proportion numerically) remain insufficiently characterized and are notably absent in the current evidence guiding management. Current management approaches derived from trials in later-onset type 2 diabetes may not be suited for this specific demographic. This review provides a comprehensive summary of recent findings related to early-onset type 2 diabetes, aiming to contribute valuable insights that could shape future strategies for prevention, diagnosis, and treatment.

Comprehensive genomic analysis of early and late-onset hepatocellular carcinoma.

e16186 Background: Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer and is a leading cause of cancer-related death worldwide. HCC is highly therapy-resistant, and biomarker-driven therapies are emerging as important treatment options. Risk factors have been implied to distinguish early and late-onset patients. A high prevalence of non-cirrhotic HCC attributed to hepatitis B virus infection was found in young Asian patients. In late-onset patients, genetic aberrations accumulated with age in liver cirrhosis and other chronic liver diseases could provide the basis of tumorigenesis. Thus, diverse genomic alteration modes may underlie HCC of different onset ages, but the analysis is lacking. This study aims to explore genomic distinctions underlying early and late-onset HCC, thus facilitating personalized biomarker-driven treatments. Methods: The plasma and tumor samples from 222 Chinese HCCs underwent genomic profiling with hybridization capture-based targeted next-generation sequencing. The patients were categorized into early (male < 40 years or female < 50 years) or late (male ≥ 40 years or female ≥ 50 years) onset in accordance with the American Association for the Study of Liver Diseases guideline. We compared the clinical and molecular characteristics and explored differences between the early and late-onset cohorts. Results: The late-onset cohort accounts for 83.3% (185/222) of all HCC cases, and its male incidence rate is significantly higher than that of early-onset (88.6% vs 56.8%, p< 0.0001). More younger cases have a family history of HCC (21.6% vs 14.6%). The mean somatic alteration numbers per patient are comparable between early and late-onset (8.30 vs 9.92). While TP53, TERT, and MCL1 are the most frequently mutated genes in both cohorts, we identified eight genes with significantly higher mutation frequencies in early-onset. OncoKB Levels 1 to 4 actionable alterations are present in 48.7% and 44.3% of younger and older patients, respectively, whereas the early-onset cohort has a significant enrichment of actionable MDM2 alterations (10.8% vs 1.1%, p= 0.0078). The prevalence of DNA Damage Response and Repair (DDR) gene mutations (35.1% vs 48.6%) and tumor mutation burden (TMB, mean: 4.17 muts/Mb vs 8.11 muts/Mb) are elevated in older patients. Notably, individuals harboring DDR mutations are associated with higher TMB in late-onset (mean TMB in DDR-mutated: 10.44 vs DDR- wildtype: 5.90, p= 0.0016) but not early-onset (mean TMB in DDR-mutated: 3.47 vs DDR- wildtype: 4.54, p= 0.280). Conclusions: Tumors from early and late-onset HCC demonstrated differences in genes and other biomarkers relevant to cancer biology and response to therapy. Specifically, DDR-mutated patients in the late-onset cohort are associated with higher TMB and may benefit from combining targeted and immunotherapy. Future studies are warranted to examine the response to biomarker-driven treatment strategies.

Functional impact of somatic mutations in early-onset (EO) versus average onset (AO) microsatellite stable (MSS) stage III colorectal cancer (CRC).

3613 Background: Analysis of the IDEA database demonstrates significantly worse disease-free survival in high-risk stage III EO CRC vs AO CRC, regardless of adjuvant therapy intensity or duration. Critically this analysis omits somatic mutational data and germline status. Enrichment of TP53 in EO metastatic CRC (mCRC) is well described and functionality of individual TP53 mutations has been proposed as a potential mechanism of chemotherapy resistance. The prognostic and functional impact of somatic mutations merits analysis in the EO high-risk Stage III cohort. Methods: The Memorial Sloan Kettering MSKCC IMPACT database was queried for MSS Stage III AO CRC (≥50 yrs) and EO CRC ( < 50 yrs) patients(pts); clinico-pathological characteristics, systemic therapies received, and survival outcomes were reviewed. MSI, POLE mutated or hereditary syndrome associated tumors were excluded. We further classified TP53 mutations as GOF (gain of function) versus non GOF/ LOF (loss of function) (Pan M, JCO. 2022, Muller PA, Cancer cell. 2014). Results: 272 pts were included in the analysis (EO = 184, AO = 88). 50% of the EO and 62.5 % of the AO cohorts were male. Tumors were predominantly adenocarcinoma (EO 89% vs AO 91%), moderately differentiated (EO 78% vs AO 74%) and left sided (EO 77% vs AO 48.8%). 87% of the EO and 63.6 % of the AO cohort were TP53mut (p value 0.0003); TP53mut was enriched in the EO cohort regardless of sidedness but there was no significant difference in TP53 mutations between EO high vs low risk. Classifying by 7 putative GOF mutations (R175H, R248Q/W, R249S, R273H/L and R282W) 28.7% of the EO cohort harbored a GOF mutation vs 19.6% of the AO cohort. There was no statistically significant survival difference between pts with TP53mut tumors vs TP53 wild type (TP53wt) in the entire cohort (AO+EO) (p 0.041) or EO or AO cohorts (p 0.049). There was no significant difference in survival outcomes across all cohorts of TP53mut groups, both high and low risk, both GOF and non GOF, treated with 3 vs 6 months of chemotherapy (p 0.67). The EO TP53wt group was enriched relative to the EO TP53mut group for KRAS (60% vs 32%), BRAF (11% vs 4%), and PI3K driver alterations (PIK3CA, 20% vs 13%) and PTEN: (8% vs 3%) In the multivariate survival analysis of EO Stage III CRC BRAFmut status is highly statistically significant (p < 0.001). Conclusions: EO Stage III CRC is enriched for TP53 mutations regardless of sidedness and GOF mutations are identified in a higher proportion of EO CRC than AO CRC. We found no statistically significant difference in survival by TP53mut status across the entire MSS Stage III CRC cohort. There was no interaction between TP53mut status, duration of chemotherapy and overall survival. The functional impact of additional molecular features is being explored and the novel prognostic significance of BRAF demonstrated in this EO Stage III cohort requires further validation.

Similarities and differences between younger and older disease onset patients with newly diagnosed systemic lupus erythematosus.

Several studies show that age at onset has an impact on the clinical-serological presentation, comorbidities and disease course of patients with systemic lupus erythematosus (SLE). We evaluated whether, in patients with recent onset SLE, the age at onset correlates with clinical-serological manifestations and with comorbidities. We analysed 171 patients with a SLE diagnosis obtained within 12 months of diagnosis enrolled in the Early Lupus project. Based on the age of onset of the first disease symptom, they were stratified into 2 groups: early onset (18-45 years) and late onset (>45 years). The analysis was replicated by stratifying patients based on age at diagnosis (fulfillment of ACR classification criteria). Each comparison was made at baseline and at 36 months of follow-up. Baseline: patients with late onset displayed comorbidities (hypertension, dyslipidemia and osteoporosis) more frequently than early onset group. 11.4% of late onset patients had a malignancy in medical history, not recorded in the early onset cohort. The two groups differed neither in organ involvement (domain BILAG) nor in disease activity (ECLAM). Patients with early onset showed a disease with signs of higher serologic activity (higher frequency of anti-dsDNA positivity and lower mean C3 and C4 levels) and had malar rash more frequently than the late onset group (36.2% vs. 18.2%, p=0.042). Similar results were obtained by stratifying patients by age of diagnosis (18-45 years and >45 years), except for the higher frequency of discoid rash in the group with age at diagnosis >45 years (18% vs. 6.6%, p=0.045). 36 months: the 2 groups of patients independently of the stratification applied did not differ in the accumulation of damage, but showed a different pattern of 8 organ involvement. Musculoskeletal involvement was more frequent both in the late onset group (18.6% vs. 7.3%, p=0.043) and in the group with age at diagnosis >45 years (20.4% vs. 5.9%, p=0.009) compared to their counterparts, while renal involvement was more frequent in the group with age at diagnosis 18-45 years (21.4% vs. 6.1%, p=0.03).A sub analysis at 36 months on patients without hypertension and osteoporosis at enrollment showed that patients with older age at onset had a higher frequency of these comorbidities, compared to their counterparts. In our cohort, younger disease SLE onset seems to correlate with a more active immunological profile, while late onset with a higher incidence of comorbidities.

Abstract P663: Polygenic Risk Scores for Plasma Levels of Fibrin D-Dimer and Tissue Plasminogen Activator Are Associated With Non-Lacunar Stroke

Introduction: Plasma concentrations of prothrombotic factors such as fibrinogen have previously been associated with ischemic stroke risk. To extend this observation, we examined the association of polygenic risk scores (PRS) for increased plasma levels of thrombosis-related factors with ischemic stroke. Our hypotheses were that these PRS would be more associated with early than late onset stroke and with non-lacunar than lacunar stroke. Methods: We identified 9053 late onset (≥ 60 years) stroke cases from the NINDS International Stroke Genetics Consortium (SiGN) with 24804 controls and 6594 early onset (< 60 years) stroke cases from the Genetics of Early Onset Ischemic Stroke Consortium with 30561 controls. We identified previously known loci associated with plasma levels of four thrombosis-related factors: fibrinogen, fibrin D-dimer, tPA and PAI-1 from prior GWAS studies and developed genome-wide PRS for plasma concentrations of these factors. We then used logistic regression to test the association of these scores with risk of stroke and stroke subtype. Results: PRS for fibrin D dimer levels were associated with increased risk for all stroke and specifically for older (p = 0.019), but not younger (p = 0.22) onset stroke. PRS for tPA levels were also marginally associated with older (p = 0.06), but not younger (p = 0.24) onset stroke. Genetic risk scores for both D dimer and tPA were associated with non-lacunar stroke (Table 1). Further analyses stratified by age revealed PRS for D dimer to be significantly associated with non-lacunar stroke (but not lacunar stroke) in both late and early onset cohorts. PRS for fibrinogen and PAI-1 were not associated with stroke. Conclusion: Genomic risk scores for thrombosis-related factors including D dimer and tPA levels were associated with risk for ischemic stroke, and specifically, non-lacunar stroke.

Abstract P5-10-04: Spectrum of hereditary breast and ovarian cancer gene variants in an African American cohort

Abstract Background: Few reports describe the spectrum of mutations in breast and ovarian cancer predisposition genes found specifically in African Americans. Methods: 560 women who self-identified as African American (AA) from the University of Pennsylvania and Wayne State University were included in this IRB-approved, case-control study. Cases (n=218 with a personal history of breast and/or ovarian cancer) and controls (n=342 without breast or ovarian cancer) underwent germline genetic testing using the Color Genomics 19-gene breast and ovarian cancer risk panel. The subset of AA patients diagnosed with breast cancer ≤40 (n=185) was compared to an institutional cohort of white patients with breast cancer diagnosed ≤40 (n=189). Results: Of 218 AA cases, 70 had pathogenic or likely pathogenic (P/LP) mutations (BRCA1: n=36; BRCA2: n=24; TP53: n=3; RAD51D: n=2; ATM: n=2; CHEK2: n=2 and MSH6: n=1). Forty-two of 218 patients (19%) had at least one variant of uncertain significance (VUS). Of 342 AA controls, 5 women had P mutations in 5 distinct genes: BRCA2, ATM, BRIP1, PALB2 and PMS2. 55 control patients (16%) had at least one VUS. Many of the 75 P/LP mutations (cases, 70 mutations; controls, 5 mutations) in the full AA cohort were unique variants. In the 135 patients who had BRCA1/BRCA2 sequencing prior to testing under this protocol, the Color Genomics platform identified all 56 pathogenic mutations. Among AA patients diagnosed with breast cancer ≤40 (n=185), the incidence of TP53 and ATM pathogenic mutations was similar to the white, early-onset breast cancer cohort (n=189): TP53, 1% in both cohorts; ATM = 1% in AA patients and 2% in whites. However, no patients in the AA, early-onset cohort had germline CHEK2 mutations, compared to 4% of white, early-onset breast cancer patients (p=0.007). Conclusions: Taken together, the results of this study demonstrate the importance of considering germline mutation testing in the AA population. Examination of mutations and disease phenotypes within the AA population may facilitate understanding of the clinical risk associated with variants of uncertain significance. Further comparative data between the AA and white cohorts will be presented. Citation Format: Shah PD, Digiovanni L, Maxwell KN, Bradbury AR, Van Den Akker J, Kim S, Gil E, Simon MS, Nathanson KL, Domchek SM. Spectrum of hereditary breast and ovarian cancer gene variants in an African American cohort [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-10-04.

TERT Core Promotor Mutations in Early-Onset Bladder Cancer.

Activating mutations in the core promoter of the TERT gene have been described in many different tumor entities. In vitro models showed a two- to fourfold increase in transcriptional activity of the TERT promoter through creation of a consensus binding motif for Ets/TCF transcription factors caused by these mutations. TERT core promoter mutations are the most common mutations in bladder cancer with a frequency between 55.6% and 82.8% described so far, and are independent of stage and grade. Since limited data on molecular alterations of early-onset bladder tumors exists, we assessed the frequency of TERT core promoter mutations in early-onset bladder cancer. Two cohorts of bladder tumors (early-onset patient group; n=144 (age of onset of disease ≤45 years); unselected, consecutive group; n=125) were examined for TERT core promoter mutations. After microdissection and extraction of DNA the corresponding hotspot regions in the TERT core promoter were examined by Sanger-sequencing or a SNaPshot approach. A significantly lower frequency of TERT core promoter mutations was found in tumors from the early-onset cohort compared to the consecutive cohort (57.6% vs. 84.8%, p<0.001). Among the early-onset cohort cases younger than the cohort's median age of 39 years at disease onset showed a significantly reduced number of TERT promoter mutations (31/67, 46,3%) than cases aged between 39 and 45 years (52/77, 67.5%; p=0.012). This association was not found in the consecutive cases. Mutation status was independent of tumor stage and grade. We conclude that in tumors from early-onset bladder cancer patients TERT core promoter mutations are not as frequent as in bladder tumors from consecutive cases, but seem to play an important role there as well. In patients below 39 years of age TERT core promoter mutations are a more infrequent event, suggesting different mechanisms of tumorigenesis in these young patients.

HOXB13 G84E-related familial prostate cancers: a clinical, histologic, and molecular survey.

Recent genetic epidemiologic studies identified a germline mutation in the homeobox transcription factor, HOXB13 G84E, which is associated with markedly increased risk for prostate cancer, particularly early-onset hereditary prostate cancer. The histomorphologic and molecular features of cancers arising in such carriers have not been studied. Here, we reviewed prostatectomy specimens from 23 HOXB13 G84E mutation carriers, mapping the total cancer burden by anatomically distinct cancer focus and evaluating morphologic features. We also assessed basic molecular subtypes for all cancer foci (ERG/SPINK1 status) by dual immunohistochemistry staining on full sections. The cohort showed a median age of 58 years, a median serum PSA level of 5.7 ng/mL, and a median of 6 cancer foci (range, 1 to 14) per case. Of evaluable cases, dominant foci were Gleason score 6 in 23%, 3+4=7 in 41%, 4+3=7 in 23%, and ≥8 in 14%; biochemical recurrence was observed in 1 case over a median of 36 months follow-up. Histologic review found a high prevalence of cases showing cancers with a spectrum of features previously described with pseudohyperplastic carcinomas, with 45% of cases showing a dominant focus with such features. Molecular subtyping revealed a strikingly low prevalence of ERG cancer with increased prevalence of SPINK1 cancer (dominant focus ERG 17%, SPINK1 26%, ERG/SPINK1 52%, single ERG/SPINK1 focus 4%). One ERG/SPINK1 dominant focus showed aberrant p63 immunophenotype. In summary, HOXB13 G84E variant-related prostate cancers show frequent pseudohyperplastic-type features and markedly low prevalence of ERG cancers relative to unselected cases and, especially, to early-onset cohorts. These findings suggest that novel molecular pathways may drive disease in HOXB13 G84E carriers.

Impact of Sex and Age at Onset of Diabetes on Mortality From Ischemic Heart Disease in Patients With Type 1 Diabetes

OBJECTIVE To study whether ischemic heart disease (IHD) mortality among patients with type 1 diabetes (T1D) depends on the age at onset of diabetes and whether this effect is sex specific. RESEARCH DESIGN AND METHODS The study examined long-term IHD-specific mortality in a Finnish population-based cohort of patients with early-onset (0-14 years) and late-onset (15-29 years) T1D (n = 17,306). RESULTS During 433,782 person-years of follow-up, 478 deaths from IHD were observed. Within the early-onset cohort, the average crude mortality rate in women was 33.3% lower than in men, whereas in the late-onset cohort, mortality was only one-half that in men. In contrast, the standardized mortality ratio (SMR) was higher in women than in men (21.6 [95% CI 17.2-27.0] vs. 5.8 [5.1-6.6]). The difference in SMR between sexes was more striking in the early-onset cohort (women 52.8 [36.3-74.5], men 12.1 [9.2-15.8]). The SMR was also greater in women in the late-onset cohort (15.8 [11.8-20.7]) compared with men (5.0 [4.3-5.8]). The relative risk of dying from IHD was greatest in women aged <40 years and 40-60 years in the early- and late-onset cohorts, respectively. CONCLUSIONS The risk of mortality from IHD is exceptionally high in women with early-onset T1D compared with women in the background population. These observations underscore the importance of identifying risk factors early in women and delivering more-aggressive treatment after diagnosis.

Research in brief

In a prospective study, 49 patients with an average age of 61 years who had acromegaly controlled by surgery, radiotherapy, or medical treatment for about 17 years, and who did not use bisphosphonates, were assessed for vertebral fractures over a follow-up of 2·5 years. At baseline, the prevalence of vertebral fractures was 63%, and at the end of the study, 20% of patients had progressive vertebral fractures. The progression rate was highest in men and in those with two or more fractures at baseline, but was independent of bone mineral density. These results suggest that abnormal bone quality persists in patients with acromegaly even if this condition is controlled with treatment. Female gender and young age at onset of type 1 diabetes are associated with increased risk of mortality from ischaemic heart disease, suggest new data. In 17 306 Finnish patients with early-onset (0–14 years) or late-onset (15–29 years) type 1 diabetes, 478 deaths from heart disease were reported over 433 782 person-years. The average crude mortality was lower in women than in men, but the overall standardised mortality ratio was higher in women (21·6) than in men (5·8). In the early-onset cohort, this ratio was even higher in women (52·8) than in men (12·1), and women younger than 40 years had the highest relative risk of death from heart disease. Heavy metals such as lead, mercury, and cadmium can act additively to increase the prevalence of metabolic disease, according to the Korea National Health and Nutrition Examination Survey, with data collected in 2009–10 from 1961 men and 1989 women aged 20 years or older. Specifically, the blood concentration of lead was associated with hypertension and elevated levels of triglycerides. The cumulative effect of a mixture of heavy metals was higher than that of each individual metal. Dextrose gel has now been shown to be safe and more effective than feeding alone in treating neonatal hypoglycaemia. 237 hypoglycaemic babies born at 35 weeks of gestation or older and aged 48 h or younger were randomly allocated to receive 40% dextrose gel 200 mg/kg (118 babies) or placebo gel (119 babies) in a double-blind study. Babies who remained hypoglycaemic 30 min after the initial dose were treated with up to six doses over 48 h. In babies receiving dextrose gel, there were fewer cases of treatment failure (a blood glucose concentration of less than 2·6 mmol/L 30 min after two doses), admittance to a neonatal intensive care unit for hypoglycaemia, and recurrent hypoglycaemia than in those treated with placebo gel. Patients with obesity who undergo bariatric surgery continue to use prescription opioid medications after surgery, a new study reports. In a retrospective analysis of data from 11 719 obese individuals aged 21 years and older who had surgery between 2005 and 2009, 77% of patients who were chronic opioid users before surgery increased their use of opioids in the year after surgery. The amount of weight lost after surgery—and the presence of preoperative depression and chronic pain—did not affect the postoperative use of chronic opioids, which highlights the importance of pain management in obese patients, especially after surgery. Over the long term, about half of patients that undergo bariatric surgery regain some of the weight that they lose during the 2 years after surgery. A new study now shows that removal of excess skin with plastic surgery (body contouring) could help patients maintain weight loss for a longer time after surgery. Weight changes of 98 patients who had both bariatric and plastic surgery were compared with those in 102 matched controls who had bariatric surgery alone. During the first 2 years after surgery, patients in both groups achieved a mean weight loss of 45·2 kg. After 7 years, patients who had plastic surgery had 3·6% (6·2 kg) mean weight regain, whereas those who had bariatric surgery alone had 10·8% (22·9 kg) weight regain. Body contouring could help improve long-term weight control in patients with morbid obesity after bariatric surgery.

Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer

Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10(-7) was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ≤ 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33-1.96; P = 9.5 × 10(-7)]. Four further associations at or close to the PBX1, RORα, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10(-6)). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10(-4) and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis.

Early-onset type 2 diabetes: higher burden of atherogenic apolipoprotein particles during statin treatment

To determine the burden of atherogenic apolipoprotein particles in early-onset type 2 diabetes (T2D) compared to those with later-onset disease during statin treatment. Early and later-onset T2D was defined as current age below and above 40 years respectively. Conventional lipid profile, LDL, non-HDL cholesterol, apolipoprotein B and A1 were determined in those without cardiovascular disease treated with simvastatin to achieve LDL cholesterol <2 mmol/l. Fifty subjects were recruited (early-onset n=24 and later-onset n=26). The mean age was 34.5 and 59.6 years and mean age of diagnosis was 29.1 and 49.1 years for early and later-onset T2D respectively. Obesity, dyslipidaemia, microalbuminuria, glycaemic control and diabetes complication burden were similar in both cohorts. Early-onset subjects received non-significantly higher simvastatin dose (37.5 vs. 31.9 mg daily, p=NS). On-treatment LDL cholesterol was similar in both cohorts (early vs. later-onset; 2.12 vs. 1.97 mmol/l, p=NS). Fasting triglyceride, non-HDL, apo B and B/A1 ratio were significantly higher in early-onset cohort. There was no difference in apo A1, HDL and total cholesterol/HDL ratio. Apo B level remained significantly higher among early-onset subjects after adjustment for insulin treatment. Lower current age and age of diagnosis were significant predictors of higher apo B level. The burden of atherogenic apolipoprotein particles was greater in early-onset T2D despite adequate statin treatment indicating an adverse phenotype for vascular disease.

Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study

Objective To examine short and long term time trends in mortality among patients with early onset (age 0-14 years) and late onset (15-29 years) type 1 diabetes and causes of...

Early-onset type 2 diabetes: High risk for premature diabetic retinopathy

Aim To examine the relationship between early-onset type 2 diabetes (T2D) and retinopathy in relation to the burden, severity, the extent of its premature development and associated predictive risk factors. Methods A cross sectional study using the hospital diabetes register and eye screening database to identify T2D subjects and to ascertain retinopathy severity. Early and later-onset cohort were defined as age of diagnosis <40 and >40 years respectively. Results 2516 subjects were identified of which 455 were diagnosed below 40 years. After 10 years of diagnosis, the prevalence of overall retinopathy was significantly higher in the early-onset cohort ( p < 0.05). For significant retinopathy (SigDR), there was a non-significant trend of higher prevalence with increasing diabetes duration in the early-onset cohort. The rate of increase for SigDR was greater in the early-onset cohort who experienced similar burden of SigDR up to 20 years earlier than the later-onset cohort. Hypertension ( p < 0.05), suboptimal glycaemic control ( p < 0.05) and long diabetes duration ( p < 0.05) were associated with risk of retinopathy whilst lower age of diagnosis and dyslipidaemia were not significant predictive factors. Conclusions Early-onset T2D subjects are at risk of developing premature retinopathy driven predominantly by hypertension and prolonged exposure to suboptimal diabetes control.

Variants at the 3p21 locus influence susceptibility and phenotype both in adults and early-onset patients with inflammatory bowel disease

To date, a number of high-profile studies have yielded over 50 inflammatory bowel disease (IBD) disease genes/loci. The polymorphisms rs9858542 (BSN) and rs3197999 (MST1), on 3p21 locus, have been found associated with susceptibility to IBD. We aimed to replicate these associations in adult and early-onset cohorts of IBD Italian patients, by analyzing also potential gene-gene interactions with variants in NOD2/CARD15, IL23R, ATG16L1, and IRGM genes, and investigating genotype-phenotype correlation. In all, 1808 patients with IBD, 855 with Crohn's disease (CD) and 953 with ulcerative colitis (UC), including 539 patients with their initial diagnosis <19 years of age, and 651 controls were analyzed for SNPs rs9858542 and rs3197999. BSN and MST1 were significantly associated with either CD (P(rs9858542) 2.5 x 10(-7); P(rs3197999) 3.9 x 10(-7)), and UC (P(rs9858542) = 3.1 x 10(-4); P(rs3197999) = 8 x 10(-4)). Prevalence of these variants was significantly increased in both adult and early-onset IBD patients. After stepwise logistic regression, the 2 variants were associated in adult UC with distal colitis (P(rs9858542) = 0.013, odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.16-3.59; P(rs3197999) = 0.018, OR 1.9, 95% CI 1.2-3.3), while the rs3197999 variant was inversely associated with occurrence of extraintestinal manifestations in adult CD(P = 0.017, OR 0.6, 95% CI 0.4-0.9). We confirmed the association of BSN and MST1 with IBD susceptibility, either in the adult or the early-onset cohorts. These variants appeared to influence either the distal location of the disease in the UC cohort and extraintestinal manifestations in CD patients.

Early onset type 2 diabetes mellitus: a harbinger for complications in later years--clinical observation from a secondary care cohort

Little is known about the complication burden in later years among early onset type 2 diabetes mellitus (T2DM). To determine the magnitude of diabetes complications and adequacy of risk factor management and to test the hypothesis that diabetes duration is an important contributing factor to these complications. A cross-sectional study of secondary care diabetes population. Data on glycaemic control, cardiovascular risk factors (overweight/obesity, hypertension, dyslipidaemia), cardiovascular disease (CVD) and microvascular complications among those diagnosed before (early onset) and after (later onset) 40 years of age at different diabetes durations (<10, 10-20 and >20 years) were analysed. A total of 2733 subjects were identified, of which 527 had diabetes diagnosed below the age of 40 years. By the sixth decade of life, early onset cohort experienced high complication burden (CVD: 37.2%, retinopathy: 59.3% and neuropathy: 53.1%). Complication prevalence increased with diabetes duration but the increment rate was greater among early onset cohort. Compared with those diagnosed after 40, early onset cohort experienced similar burden of microvascular complications approximately 13-20 years earlier. Diabetes duration was a significant predictor for microvascular and CVD complications. Prevalence of CVD risk factors was high ( approximately 80-93%) regardless of the age of diagnosis and diabetes duration. Early onset subjects were more likely to have poorer glucose control ( approximately 70-78%), untreated hypertension (26.3%) and a substantial number did not receive statin treatment for primary prevention (34.8%). Early onset T2DM subjects are at substantial risk of developing diabetes complications in later years but at an earlier stage than later onset cohort and prolonged exposure to adverse diabetic milieu is an important contributing factor. Management of risk factors for diabetes complications was inadequate among early onset subjects.

Contribution of the NOD1/CARD4 insertion/deletion polymorphism +32656 to inflammatory bowel disease in Northern Europe#

NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype-phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.

Cardiovascular risk profile of early and later onset type 2 diabetes

AbstractThe aim of this study was to determine the cardiovascular disease (CVD) risk profile between early (&lt;40 years of age) and later (&gt;40 years of age) onset type 2 diabetes (T2DM) patients without prior history of CVD.A cross‐sectional study was undertaken on hospital‐based patients identified from the diabetes register. T2DM patients without prior history of CVD were included for analysis. The CVD risk profile as defined by obesity, dyslipidaemia and hypertension was compared between early and later onset T2DM patients. The proportion of lipid and blood pressure lowering treatment in each group was also determined.In all, 1057 T2DM patients were identified of whom 67 (6.3%) and 990 (93.7%) were aged below and above 40 years, respectively. Sixty‐seven and 667 patients did not have CVD complications in the early and later onset cohorts, respectively. Despite being ∼three decades younger with a shorter duration of diabetes, early onset patients had poorer glycaemic control compared to the later onset cohort. A significant proportion of these young diabetic patients had hypertension (∼80%) and adverse dyslipidaemic profile (∼80%) with higher triglyceride and lower HDL. Morbid obesity (body mass index &gt;40) was more common among the early onset cohort (∼25%). Significantly less early onset patients were treated with statin and anti‐hypertensive medications particularly among female subjects.It was concluded that, despite having an adverse CVD risk profile, early onset patients with T2DM were less likely to receive cardio‐protective treatment. Copyright © 2007 John Wiley &amp; Sons.

Human leucocyte antigen-A2 increases risk of Alzheimer's disease but does not affect age of onset in a Scottish population

The use of non-steroidal anti-inflammatory drugs has been associated with a reduced incidence of Alzheimer's disease (AD), suggesting that attenuation of the inflammatory response may be beneficial. Several, but not all, genetic association studies have shown human leucocyte antigen (HLA)-A2, a major histocompatibility complex class I antigen-binding transmembrane protein has an increased frequency in AD compared to controls, and in some reports is associated with a lowered age of onset. We further investigated the role of HLA-A2 in an independent sample of AD cases, including a large early onset cohort. The results of this current study and meta analysis of all studies available to date support previous evidence of an excess of HLA-A2 in AD, but found no evidence of a relationship with age of onset.