Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

Body composition and risk factors for cardiovascular disease in global multi-ethnic populations.

BACKGROUND: No large-scale studies have compared associations between body composition and cardiovascular risk factors across multi-ethnic populations. METHODS: Population-based surveys included 30,721 Malay, 10,865 Indian and 25,296 Chinese adults from The Malaysian Cohort, and 413,737 White adults from UK Biobank. Sex-specific linear regression models estimated associations of anthropometry and body composition (body mass index [BMI], waist circumference [WC], fat mass, appendicular lean mass) with systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), triglycerides and HbA1c. RESULTS: Compared to Malay and Indian participants, Chinese adults had lower BMI and fat mass while White participants were taller with more appendicular lean mass. For BMI and fat mass, positive associations with SBP and HbA1c were strongest among the Chinese and Malay and weaker in White participants. Associations with triglycerides were considerably weaker in those of Indian ethnicity (eg 0.09 [0.02] mmol/L per 5 kg/m2 BMI in men, vs 0.38 [0.02] in Chinese). For appendicular lean mass, there were weak associations among men; but stronger positive associations with SBP, triglycerides, and HbA1c, and inverse associations with LDL-C, among Malay and Indian women. Associations between WC and risk factors were generally strongest in Chinese and weakest in Indian ethnicities, although this pattern was reversed for HbA1c. CONCLUSION: There were distinct patterns of adiposity and body composition and cardiovascular risk factors across ethnic groups. We need to better understand the mechanisms relating body composition with cardiovascular risk to attenuate the increasing global burden of obesity-related disease.

Tumour occurrence in women with Turner syndrome: A narrative review and single-centre case series.

BACKGROUND: Population studies suggest cancer morbidity may be different in Turner syndrome (TS) compared to the background female population. However, significant variability is observed in cancer associations likely due to heterogeneity in patient cohorts. We explored the prevalence and patterns of cancer amongst a cohort of women with TS attending a dedicated TS clinic. METHODS: Retrospective analysis of the patient database was performed to identify TS women who developed cancer. Population data (available before 2015) from the National Cancer Registration and Analysis Service database were used for comparison. RESULTS: Out of 156 TS women, median age of 32 (range 18-73) years, 9 (5.8%) had a recorded cancer diagnosis. Types of cancers were, bilateral gonadoblastoma, type 1 gastric neuroendocrine tumour (NET), appendiceal-NET, gastrointestinal stromal tumour, plasma cell dyscrasia, synovial sarcoma, cervical cancer, medulloblastoma and aplastic anaemia. Median age at cancer diagnosis was 35 (range 7-58) years and two were detected incidentally. Five women had 45,X karyotype, three received growth hormone treatment and all except one received oestrogen replacement therapy. The cancer prevalence of the background age-matched female population was 4.4%. CONCLUSIONS: We confirm the previous observations that women with TS do not appear to be at overall increased risk of common malignancies. Our small cohort showed a spectrum of rare malignancies that are not typically associated with TS, except for a single patient with a gonadoblastoma. The slightly higher prevalence of cancer in our cohort might simply represent increased cancer prevalence in the background population, or might be related to small sample size and regular monitoring of these women due to TS per se.

Estimating lifetime risk of diabetes in the Chinese population.

In this Perspective, Fiona Bragg and Zhengming Chen discuss the burden of diabetes in the Chinese Population.

Predictive value of circulating NMR metabolic biomarkers for type 2 diabetes risk in the UK Biobank study.

BACKGROUND: Effective targeted prevention of type 2 diabetes (T2D) depends on accurate prediction of disease risk. We assessed the role of metabolomic profiling in improving T2D risk prediction beyond conventional risk factors. METHODS: Nuclear magnetic resonance (NMR) metabolomic profiling was undertaken on baseline plasma samples in 65,684 UK Biobank participants without diabetes and not taking lipid-lowering medication. Among a subset of 50,519 participants with data available on all relevant co-variates (sociodemographic characteristics, parental history of diabetes, lifestyle-including dietary-factors, anthropometric measures and fasting time), Cox regression yielded adjusted hazard ratios for the associations of 143 individual metabolic biomarkers (including lipids, lipoproteins, fatty acids, amino acids, ketone bodies and other low molecular weight metabolic biomarkers) and 11 metabolic biomarker principal components (PCs) (accounting for 90% of the total variance in individual biomarkers) with incident T2D. These 11 PCs were added to established models for T2D risk prediction among the full study population, and measures of risk discrimination (c-statistic) and reclassification (continuous net reclassification improvement [NRI], integrated discrimination index [IDI]) were assessed. RESULTS: During median 11.9 (IQR 11.1-12.6) years' follow-up, after accounting for multiple testing, 90 metabolic biomarkers showed independent associations with T2D risk among 50,519 participants (1211 incident T2D cases) and 76 showed associations after additional adjustment for HbA1c (false discovery rate controlled p < 0.01). Overall, 8 metabolic biomarker PCs were independently associated with T2D. Among the full study population of 65,684 participants, of whom 1719 developed T2D, addition of PCs to an established risk prediction model, including age, sex, parental history of diabetes, body mass index and HbA1c, improved T2D risk prediction as assessed by the c-statistic (increased from 0.802 [95% CI 0.791-0.812] to 0.830 [0.822-0.841]), continuous NRI (0.44 [0.38-0.49]) and relative (15.0% [10.5-20.4%]) and absolute (1.5 [1.0-1.9]) IDI. More modest improvements were observed when metabolic biomarker PCs were added to a more comprehensive established T2D risk prediction model additionally including waist circumference, blood pressure and plasma lipid concentrations (c-statistic, 0.829 [0.819-0.838] to 0.837 [0.831-0.848]; continuous NRI, 0.22 [0.17-0.28]; relative IDI, 6.3% [4.1-9.8%]; absolute IDI, 0.7 [0.4-1.1]). CONCLUSIONS: When added to conventional risk factors, circulating NMR-based metabolic biomarkers modestly enhanced T2D risk prediction.

Red meat, poultry and fish consumption and risk of diabetes: a 9 year prospective cohort study of the China Kadoorie Biobank.

AIMS/HYPOTHESIS: Previous evidence linking red meat consumption with diabetes risk mainly came from western countries, with little evidence from China, where patterns of meat consumption are different. Moreover, global evidence remains inconclusive about the associations of poultry and fish consumption with diabetes. Therefore we investigated the associations of red meat, poultry and fish intake with incidence of diabetes in a Chinese population. METHODS: The prospective China Kadoorie Biobank recruited ~512,000 adults (59% women, mean age 51 years) from ten rural and urban areas across China in 2004-2008. At the baseline survey, a validated interviewer-administered laptop-based questionnaire was used to collect information on the consumption frequency of major food groups including red meat, poultry, fish, fresh fruit and several others. During ~9 years of follow-up, 14,931 incidences of new-onset diabetes were recorded among 461,036 participants who had no prior diabetes, cardiovascular diseases or cancer at baseline. Cox regression analyses were performed to calculate adjusted HRs for incident diabetes associated with red meat, poultry and fish intake. RESULTS: At baseline, 47.0%, 1.3% and 8.9% of participants reported a regular consumption (i.e. ≥4 days/week) of red meat, poultry and fish, respectively. After adjusting for adiposity and other potential confounders, each 50 g/day increase in red meat and fish intake was associated with 11% (HR 1.11 [95% CI 1.04, 1.20]) and 6% (HR 1.06 [95% CI 1.00, 1.13]) higher risk of incident diabetes, respectively. For both, the associations were more pronounced among men and women from urban areas, with an HR (95% CI) of 1.42 (1.15, 1.74) and 1.18 (1.03, 1.36), respectively, per 50 g/day red meat intake and 1.15 (1.02, 1.30) and 1.11 (1.01, 1.23), respectively, per 50 g/day fish intake. There was no significant association between diabetes and poultry intake, either overall (HR 0.96 [95% CI 0.83, 1.12] per 50 g/day intake) or in specific population subgroups. CONCLUSIONS/INTERPRETATION: In Chinese adults, both red meat and fish, but not poultry, intake were positively associated with diabetes risk, particularly among urban participants. Our findings add new evidence linking red meat and fish intake with cardiometabolic diseases. DATA AVAILABILITY: Details of how to access the China Kadoorie Biobank data and rules of China Kadoorie Biobank data release are available from www.ckbiobank.org/site/Data+Access.

Sex differences in the association between socioeconomic status and diabetes prevalence and incidence in China: cross-sectional and prospective studies of 0.5 million adults.

AIMS/HYPOTHESIS: China has undergone rapid socioeconomic transition accompanied by lifestyle changes that are expected to have a profound impact on the health of its population. However, there is limited evidence from large nationwide studies about the relevance of socioeconomic status (SES) to risk of diabetes. We describe the associations of two key measures of SES with prevalent and incident diabetes in Chinese men and women. METHODS: The China Kadoorie Biobank study included 0.5 million adults aged 30-79 years recruited from ten diverse areas in China during 2004-2008. SES was assessed using the highest educational level attained and annual household income. Prevalent diabetes was identified from self-report and plasma glucose measurements. Incident diabetes was identified from linkage to disease and death registries and national health insurance claim databases. We estimated adjusted ORs and HRs for prevalent and incident diabetes associated with SES using logistic and Cox regression models, respectively. RESULTS: At baseline, 30,066 (5.9%) participants had previously diagnosed (3.1%) or screen-detected (2.8%) diabetes among 510,219 participants included for cross-sectional analyses. There were 480,153 people without prevalent diabetes at baseline, of whom 9544 (2.0%) had new-onset diabetes during follow-up (median 7 years). Adjusted ORs (95% CIs) for prevalent diabetes, comparing highest vs lowest educational level, were 1.21 (1.09, 1.35) in men and 0.69 (0.63, 0.76) in women; for incident diabetes, the corresponding HRs were 1.27 (1.07, 1.51) and 0.80 (0.67, 0.95), respectively. For household income, the adjusted ORs for prevalent diabetes, comparing highest vs lowest categories, were 1.45 (1.34, 1.56) in men and 1.26 (1.19, 1.34) in women; for incident diabetes, the HRs were 1.36 (1.19, 1.55) and 1.06 (0.95, 1.17), respectively. CONCLUSIONS/INTERPRETATION: Among Chinese adults, the associations between education and diabetes prevalence and incidence differed qualitatively between men and women, whereas higher household income was positively associated with diabetes prevalence and incidence in both sexes, with a stronger relationship in men than in women.

Central adiposity in relation to risk of liver cancer in Chinese adults: A prospective study of 0.5 million people.

Central adiposity is associated with liver cancer risk beyond general adiposity in Western populations. However, there is little prospective evidence in East Asian populations who are more likely to have central adiposity at given BMI levels. The prospective China Kadoorie Biobank recruited 512,713 adults aged 30-79 years from 10 diverse areas. During 10 years follow-up, 2,847 incident cases of liver cancer were identified. Cox regression was used to estimate adjusted hazard ratios (HR) for liver cancer associated with central adiposity, excluding individuals with cancers and liver diseases at baseline and the first 5 years of follow-up (1,049 incident liver cancer cases). Overall, mean waist circumference (WC) was 82.2 (SD 9.8) cm in men and 79.1 (9.5) cm in women. Central adiposity showed positive associations with liver cancer risk. Associations were strongest for WC and waist-to-hip ratio (WHR), with adjusted HRs per 1-SD of 1.09 (95%CI 1.01-1.18) and 1.12 (1.02-1.23), respectively. The positive associations became stronger when additionally adjusting for BMI (1.26 [1.09-1.46] and 1.14 [1.02-1.28]). The positive association of central obesity (WC ≥90 cm in men and ≥ 80 cm in women) with liver cancer increased progressively with the number of other presenting metabolic risk factors (physical inactivity, diabetes, and hypertension), with HRs of 1.07 (0.90-1.28), 1.17 (1.00-1.38), and 1.91 (1.40-2.59) in those with one, two, and three factors (p for trend 0.006). In this relatively lean Chinese population, there were positive associations of central adiposity with risk of liver cancer, with WHR and WC showing the strongest associations.

Diabetes, Plasma Glucose, and Incidence of Fatty Liver, Cirrhosis, and Liver Cancer: A Prospective Study of 0.5 Million People.

The prevalence of diabetes is increasing rapidly in China. However, evidence is limited about its effects on chronic liver diseases and liver cancer. We examined the associations of diabetes with chronic liver diseases and liver cancer and of random plasma glucose (RPG) with these liver diseases among participants without diabetes in Chinese adults and the possible interaction by hepatitis B virus (HBV) infection. The prospective China Kadoorie Biobank recruited 512,891 adults. During 10 years of follow-up, 2,568 liver cancer, 2,082 cirrhosis, 1,298 hospitalized nonalcoholic fatty liver disease (NAFLD), and 244 hospitalized alcoholic liver disease (ALD) cases were recorded among 503,993 participants without prior history of cancer or chronic liver diseases at baseline. Cox regression was used to estimate hazard ratios (HRs) for each disease by diabetes status (previously diagnosed or screen-detected) and, among those without previously diagnosed diabetes, by levels of RPG. Overall 5.8% of participants had diabetes at baseline. Compared to those without diabetes, individuals with diabetes had adjusted HRs of 1.49 (95% confidence interval 1.30-1.70) for liver cancer, 1.81 (1.57-2.09) for cirrhosis, 1.76 (1.47-2.16) for NAFLD, and 2.24 (1.42-3.54) for ALD. The excess risks decreased but remained elevated in those with longer duration. Among those without previously diagnosed diabetes, RPG was positively associated with liver diseases, with adjusted HRs per 1 mmol/L higher RPG of 1.04 (1.03-1.06) for liver cancer, 1.07 (1.05-1.09) for cirrhosis, 1.07 (1.05-1.10) for NAFLD, and 1.10 (1.05-1.15) for ALD. These associations did not differ by HBV infection. CONCLUSION: In Chinese adults, diabetes and higher blood glucose levels among those without known diabetes are associated with higher risks of liver cancer and major chronic liver diseases.

Metabolic and lifestyle risk factors for acute pancreatitis in Chinese adults: A prospective cohort study of 0.5 million people.

BACKGROUND: Little prospective evidence exists about risk factors and prognosis of acute pancreatitis in China. We examined the associations of certain metabolic and lifestyle factors with risk of acute pancreatitis in Chinese adults. METHODS AND FINDINGS: The prospective China Kadoorie Biobank (CKB) recruited 512,891 adults aged 30 to 79 years from 5 urban and 5 rural areas between 25 June 2004 and 15 July 2008. During 9.2 years of follow-up (to 1 January 2015), 1,079 cases of acute pancreatitis were recorded. Cox regression was used to estimate adjusted hazard ratios (HRs) for acute pancreatitis associated with various metabolic and lifestyle factors among all or male (for smoking and alcohol drinking) participants. Overall, the mean waist circumference (WC) was 82.1 cm (SD 9.8) cm in men and 79.0 cm (SD 9.5) cm in women, 6% had diabetes, and 6% had gallbladder disease at baseline. WC was positively associated with risk of acute pancreatitis, with an adjusted HR of 1.35 (95% CI 1.27-1.43; p < 0.001) per 1-SD-higher WC. Individuals with diabetes or gallbladder disease had HRs of 1.34 (1.07-1.69; p = 0.01) and 2.42 (2.03-2.88; p < 0.001), respectively. Physical activity was inversely associated with risk of acute pancreatitis, with each 4 metabolic equivalent of task (MET) hours per day (MET-h/day) higher physical activity associated with an adjusted HR of 0.95 (0.91-0.99; p = 0.03). Compared with those without any metabolic risk factors (i.e., obesity, diabetes, gallbladder disease, and physical inactivity), the HRs of acute pancreatitis for those with 1, 2, or ≥3 risk factors were 1.61 (1.47-1.76), 2.36 (2.01-2.78), and 3.41 (2.46-4.72), respectively (p < 0.001). Among men, heavy alcohol drinkers (≥420 g/week) had an HR of 1.52 (1.11-2.09; p = 0.04, compared with abstainers), and current regular smokers had an HR of 1.45 (1.28-1.64; p = 0.02, compared with never smokers). Following a diagnosis of acute pancreatitis, there were higher risks of pancreatic cancer (HR = 8.26 [3.42-19.98]; p < 0.001; 13 pancreatic cancer cases) and death (1.53 [1.17-2.01]; p = 0.002; 89 deaths). Other diseases of the pancreas had similar risk factor profiles and prognosis to acute pancreatitis. The main study limitations are ascertainment of pancreatitis using hospital records and residual confounding. CONCLUSIONS: In this relatively lean Chinese population, several modifiable metabolic and lifestyle factors were associated with higher risks of acute pancreatitis, and individuals with acute pancreatitis had higher risks of pancreatic cancer and death.

Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults.

BACKGROUND: Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations. METHODS AND FINDINGS: Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%-18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%-23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: -1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data. CONCLUSIONS: The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes.

Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people.

BACKGROUND: Uncertainty remains about the associations of adiposity with intestinal cancer in China and by its anatomical subtype. METHODS: The prospective China Kadoorie Biobank recorded 3024 incident cases of colorectal (CRC) and 143 cases of small intestine (SIC) cancer during a 10-year follow-up among 509 568 participants without prior cancer at baseline. Cox regression was used to estimate adjusted hazard ratios (HRs) for specific cancers associated with adiposity. RESULTS: Overall mean body mass index (BMI) was 23.7 kg/m2. BMI was positively associated with CRC (HR per SD 1.10 [95% CI 1.06-1.14]), colon (1.13 [1.07-1.18]), and rectal (1.07 [1.02-1.13]) cancer. For waist circumference, the corresponding HRs per SD were 1.14 (1.10-1.18), 1.18 (1.13-1.24), and 1.11 (1.05-1.16), respectively. The adjusted HRs were somewhat greater in men than women. Adiposity was positively, but non-significantly, associated with SIC risk. CONCLUSIONS: Among relatively lean Chinese adults, adiposity was associated with risks of colon and rectal cancer, with the associations somewhat stronger in men than women.

Relationship of being threatened or injured with a weapon in school with suicidal ideation and attempt among school students: a school-based study in Zhejiang Province, China.

BACKGROUND: Suicide is the second leading cause of death among 15-29 year old youths globally, and the third most common external cause of death in China. School bullying can cause serious consequences among adolescents, including psychosocial problems, low self-esteem and post-traumatic stress disorder. Most studies examining the associations between being bullied in school and suicide are from Western, developed countries. Moreover, few studies focus on being threatened or injured with a weapon, which may cause serious body injury. Our study aimed to explore the relationship of being threatened or injured with a weapon in school with suicidal ideation and attempt among middle and high school students in Zhejiang Province, China. METHODS: A cross-sectional study of 23,543 students in grades 7-12 from 442 schools was carried out through an anonymous self-administered questionnaire between April and May 2017. Multivariable logistic regression models were used to examine the relationship of being threatened or injured with a weapon in school with suicidal ideation and attempt. RESULTS: 51.3% of participants were boys, and mean (SD) age was 15.6 (1.7) years. The overall prevalence of suicidal ideation and attempt were 16.1% (95%CI: 15.3-16.9) and 3.6% (95%CI: 3.3-4.0), respectively. Prevalence was higher among girls than boys (ideation: 19.1% vs. 13.3%. attempt: 4.4% vs. 2.9%). 13.2% of students reported being threatened or injured with a weapon in school in the past 12 months (95%CI: 11.9-14.5), higher among boys than girls (15.7% vs. 10.5%), and among rural students than urban students (13.9% vs. 11.6%). After adjustment for socio-demographic status, lifestyle factors, academic performance, self-reported health and mental health, the odds ratios for suicidal ideation and attempt among students who reported being threatened or injured with a weapon were 1.46 (1.31-1.61) and 1.68 (1.31-2.13) respectively, as compared with those who did not report being threatened or injured. CONCLUSIONS: Preventive measures for physical bullying in school need to be reinforced in China. Being threatened or injured with a weapon is associated with both suicidal ideation and attempt among middle and high school students. Suicide prevention should be an important component of psychological interventions for threatened or injured students.

Diabetes, plasma glucose and incidence of pancreatic cancer: A prospective study of 0.5 million Chinese adults and a meta-analysis of 22 cohort studies.

Diabetes is associated with an increased risk of pancreatic cancer (PC) in Western populations. Uncertainty remains, however, about the relevance of plasma glucose for PC among people without diabetes and about the associations of diabetes and high blood glucose with PC in China where the increase in diabetes prevalence has been very recent. The prospective China Kadoorie Biobank (CKB) study recruited 512,000 adults aged 30-79 years from 10 diverse areas of China during 2004-2008, recording 595 PC cases during 8 years of follow-up. Cox regression yielded adjusted hazard ratios (HRs) for PC associated with diabetes (previously diagnosed or screen-detected) and, among those without previously diagnosed diabetes, with levels of random plasma glucose (RPG). These were further meta-analysed with 22 published prospective studies. Overall 5.8% of CKB participants had diabetes at baseline. Diabetes was associated with almost twofold increased risk of PC (adjusted HR = 1.87, 95% CI 1.48-2.37), with excess risk higher in those with longer duration since diagnosis (p for trend = 0.01). Among those without previously diagnosed diabetes, each 1 mmol/L higher usual RPG was associated with a HR of 1.12 (1.04-1.21). In meta-analysis of CKB and 22 other studies, previously diagnosed diabetes was associated with a 52% excess risk (1.52, 1.43-1.63). Among those without diabetes, each 1 mmol/L higher blood glucose was associated with a 15% (1.15, 1.09-1.21) excess risk. In Chinese and non-Chinese populations, diabetes and higher blood glucose levels among those without diabetes are associated with an increased risk of PC.

Fresh fruit consumption in relation to incident diabetes and diabetic vascular complications: A 7-y prospective study of 0.5 million Chinese adults.

BACKGROUND: Despite the well-recognised health benefits of fresh fruit consumption, substantial uncertainties remain about its potential effects on incident diabetes and, among those with diabetes, on risks of death and major vascular complications. METHODS AND FINDINGS: Between June 2004 and July 2008, the nationwide China Kadoorie Biobank study recruited 0.5 million adults aged 30-79 (mean 51) y from ten diverse localities across China. During ~7 y of follow-up, 9,504 new diabetes cases were recorded among 482,591 participants without prevalent (previously diagnosed or screen-detected) diabetes at baseline, with an overall incidence rate of 2.8 per 1,000 person-years. Among 30,300 (5.9%) participants who had diabetes at baseline, 3,389 deaths occurred (overall mortality rate 16.5 per 1,000), along with 9,746 cases of macrovascular disease and 1,345 cases of microvascular disease. Cox regression yielded adjusted hazard ratios (HRs) associating each disease outcome with self-reported fresh fruit consumption, adjusting for potential confounders such as age, sex, region, socio-economic status, other lifestyle factors, body mass index, and family history of diabetes. Overall, 18.8% of participants reported consuming fresh fruit daily, and 6.4% never/rarely (non-consumers), with the proportion of non-consumers about three times higher in individuals with previously diagnosed diabetes (18.9%) than in those with screen-detected diabetes (6.7%) or no diabetes (6.0%). Among those without diabetes at baseline, higher fruit consumption was associated with significantly lower risk of developing diabetes (adjusted HR = 0.88 [95% CI 0.83-0.93] for daily versus non-consumers, p < 0.001, corresponding to a 0.2% difference in 5-y absolute risk), with a clear dose-response relationship. Among those with baseline diabetes, higher fruit consumption was associated with lower risks of all-cause mortality (adjusted HR = 0.83 [95% CI 0.74-0.93] per 100 g/d) and microvascular (0.72 [0.61-0.87]) and macrovascular (0.87 [0.82-0.93]) complications (p < 0.001), with similar HRs in individuals with previously diagnosed and screen-detected diabetes; estimated differences in 5-y absolute risk between daily and non-consumers were 1.9%, 1.1%, and 5.4%, respectively. The main limitation of this study was that, owing to its observational nature, we could not fully exclude the effects of residual confounding. CONCLUSION: In this large epidemiological study in Chinese adults, higher fresh fruit consumption was associated with significantly lower risk of diabetes and, among diabetic individuals, lower risks of death and development of major vascular complications.

Association Between Diabetes and Cause-Specific Mortality in Rural and Urban Areas of China.

Importance: In China, diabetes prevalence has increased substantially in recent decades, but there are no reliable estimates of the excess mortality currently associated with diabetes. Objectives: To assess the proportional excess mortality associated with diabetes and estimate the diabetes-related absolute excess mortality in rural and urban areas of China. Design, Setting, and Participants: A 7-year nationwide prospective study of 512 869 adults aged 30 to 79 years from 10 (5 rural and 5 urban) regions in China, who were recruited between June 2004 and July 2008 and were followed up until January 2014. Exposures: Diabetes (previously diagnosed or detected by screening) recorded at baseline. Main Outcomes and Measures: All-cause and cause-specific mortality, collected through established death registries. Cox regression was used to estimate adjusted mortality rate ratio (RR) comparing individuals with diabetes vs those without diabetes at baseline. Results: Among the 512 869 participants, the mean (SD) age was 51.5 (10.7) years, 59% (n = 302 618) were women, and 5.9% (n = 30 280) had diabetes (4.1% in rural areas, 8.1% in urban areas, 5.8% of men, 6.1% of women, 3.1% had been previously diagnosed, and 2.8% were detected by screening). During 3.64 million person-years of follow-up, there were 24 909 deaths, including 3384 among individuals with diabetes. Compared with adults without diabetes, individuals with diabetes had a significantly increased risk of all-cause mortality (1373 vs 646 deaths per 100 000; adjusted RR, 2.00 [95% CI, 1.93-2.08]), which was higher in rural areas than in urban areas (rural RR, 2.17 [95% CI, 2.07-2.29]; urban RR, 1.83 [95% CI, 1.73-1.94]). Presence of diabetes was associated with increased mortality from ischemic heart disease (3287 deaths; RR, 2.40 [95% CI, 2.19-2.63]), stroke (4444 deaths; RR, 1.98 [95% CI, 1.81-2.17]), chronic liver disease (481 deaths; RR, 2.32 [95% CI, 1.76-3.06]), infections (425 deaths; RR, 2.29 [95% CI, 1.76-2.99]), and cancer of the liver (1325 deaths; RR, 1.54 [95% CI, 1.28-1.86]), pancreas (357 deaths; RR, 1.84 [95% CI, 1.35-2.51]), female breast (217 deaths; RR, 1.84 [95% CI, 1.24-2.74]), and female reproductive system (210 deaths; RR, 1.81 [95% CI, 1.20-2.74]). For chronic kidney disease (365 deaths), the RR was higher in rural areas (18.69 [95% CI, 14.22-24.57]) than in urban areas (6.83 [95% CI, 4.73-9.88]). Among those with diabetes, 10% of all deaths (16% rural; 4% urban) were due to definite or probable diabetic ketoacidosis or coma (408 deaths). Conclusions and Relevance: Among adults in China, diabetes was associated with increased mortality from a range of cardiovascular and noncardiovascular diseases. Although diabetes was more common in urban areas, it was associated with greater excess mortality in rural areas.

Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have discovered many risk variants for type 2 diabetes. However, estimates of the contributions of risk variants to type 2 diabetes predisposition are often based on highly selected case-control samples, and reliable estimates of population-level effect sizes are missing, especially in non-European populations. METHODS: The individual and cumulative effects of 59 established type 2 diabetes risk loci were measured in a population-based China Kadoorie Biobank (CKB) study of 93,000 Chinese adults, including >7,100 diabetes cases. RESULTS: Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function, demonstrated significant interactions with several measures of adiposity (BMI, waist circumference [WC], WHR and percentage body fat [PBF]; all p interaction < 1 × 10(-4)), with a greater effect being observed in leaner adults. CONCLUSIONS/INTERPRETATION: Our study provides further evidence of shared genetic architecture for type 2 diabetes between Europeans and East Asians. It also indicates that even very large GWAS meta-analyses may be vulnerable to substantial inflation of effect size estimates, compared with those observed in large-scale population-based cohort studies. ACCESS TO RESEARCH MATERIALS: Details of how to access China Kadoorie Biobank data and details of the data release schedule are available from www.ckbiobank.org/site/Data+Access .

Parenthood and the risk of diabetes in men and women: a 7 year prospective study of 0.5 million individuals.

AIMS/HYPOTHESIS: In women, higher parity has been associated with increased risk of diabetes later in life. It is unclear, however, whether this association is mainly due to biological effects of childbearing, or to socioeconomic and lifestyle factors associated with childrearing. We assessed the association between number of children and diabetes risk separately in women and men. METHODS: Between 2004 and 2008, the nationwide China Kadoorie Biobank recruited 0.5 million individuals aged 30-79 (mean 51 years) from ten diverse regions across China. During 7 years of follow-up, 8,840 incident cases of diabetes were recorded among 463,347 participants without prior cardiovascular diseases or diabetes. Multivariable Cox regression yielded sex-specific HRs and 95% CIs for incident diabetes by number of children. RESULTS: Overall, ∼98% of all participants had children. In women, there was a J-shaped association between number of children and risk of diabetes. Compared with women with one child, the adjusted HRs for diabetes were 1.39 (95% CI 1.11, 1.73) for childless women, 1.12 (95% CI 1.07, 1.18) for those with two children, 1.23 (95% CI 1.16, 1.31) for those with three children, and 1.32 (95% CI 1.21, 1.44) for those with four or more children. In men, there was a similar association with risk of diabetes; the corresponding HRs were 1.28 (95% CI 1.02, 1.60), 1.19 (95% CI 1.12, 1.26), 1.32 (95% CI 1.21, 1.44) and 1.41 (95% CI 1.24, 1.60), respectively. In both sexes, the findings were broadly similar in different population subgroups. CONCLUSIONS/INTERPRETATION: The similarity between women and men in the association between number of children and risk of diabetes suggests that parenthood is most likely to affect diabetes risk through factors associated with childrearing rather than via biological effects of childbearing.

Risks and Population Burden of Cardiovascular Diseases Associated with Diabetes in China: A Prospective Study of 0.5 Million Adults.

BACKGROUND: In China, diabetes prevalence is rising rapidly, but little is known about the associated risks and population burden of cardiovascular diseases. We assess associations of diabetes with major cardiovascular diseases and the relevance of diabetes duration and other modifiable risk factors to these associations. METHODS AND FINDINGS: A nationwide prospective study recruited 512,891 men and women aged 30-79 y between 25 June 2004 and 15 July 2008 from ten diverse localities across China. During ~7 y of follow-up, 7,353 cardiovascular deaths and 25,451 non-fatal major cardiovascular events were recorded among 488,760 participants without prior cardiovascular disease at baseline. Cox regression yielded adjusted hazard ratios (HRs) comparing disease risks in individuals with diabetes to those without. Overall, 5.4% (n = 26,335) of participants had self-reported (2.7%) or screen-detected (2.7%) diabetes. Individuals with self-reported diabetes had an adjusted HR of 2.07 (95% CI 1.90-2.26) for cardiovascular mortality. There were significant excess risks of major coronary event (2.44, 95% CI 2.18-2.73), ischaemic stroke (1.68, 95% CI 1.60-1.77), and intracerebral haemorrhage (1.24, 95% CI 1.07-1.44). Screen-detected diabetes was also associated with significant, though more modest, excess cardiovascular risks, with corresponding HRs of 1.66 (95% CI 1.51-1.83), 1.62 (95% CI 1.40-1.86), 1.48 (95% CI 1.40-1.57), and 1.17 (95% CI 1.01-1.36), respectively. Misclassification of screen-detected diabetes may have caused these risk estimates to be underestimated, whilst lack of data on lipids may have resulted in residual confounding of diabetes-associated cardiovascular disease risks. Among individuals with diabetes, cardiovascular risk increased progressively with duration of diabetes and number of other presenting modifiable cardiovascular risk factors. Assuming a causal association, diabetes now accounts for ~0.5 million (489,676, 95% CI 335,777-681,202) cardiovascular deaths annually in China. CONCLUSIONS: Among Chinese adults, diabetes is associated with significantly increased risks of major cardiovascular diseases. The increasing prevalence and younger age of onset of diabetes foreshadow greater diabetes-attributable disease burden in China.