Vitamin D Status, Vitamin D Receptor Polymorphisms, and Risk of Type 2 Diabetes: A Prospective Cohort Study.

Vitamin D status has been associated with risk of type 2 diabetes (T2D), but evidence is scarce regarding whether such relation differs by glycemic status. To prospectively investigate the association between serum 25-hydroxyvitamin D (25(OH)D) and risk of incident T2D across the glycemic spectrum and the modification effect of genetic variants in the vitamin D receptor (VDR). This prospective study included 379 699 participants without T2D at baseline from the UK Biobank. Analyses were performed according to glycemic status and HbA1c levels. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs. During a median of 14.1 years of follow-up, 6315 participants with normoglycemia and 9085 patients with prediabetes developed T2D. Compared with individuals with 25(OH)D < 25 nmol/L, the multivariable-adjusted HRs (95% CIs) of incident T2D for those with 25(OH)D ≥ 75 nmol/L was 0.62 (0.56, 0.70) among the normoglycemia group and 0.64 (0.58, 0.70) among the prediabetes group. A significant interaction was observed between 25(OH)D and VDR polymorphisms among participants with prediabetes (P interaction = .017), whereby the reduced HR of T2D associated with higher 25(OH)D was more prominent in those carrying the T allele of rs1544410. Triglyceride levels mediated 26% and 34% of the association between serum 25(OH)D and incident T2D among participants with normoglycemia and prediabetes, respectively. Higher serum 25(OH)D concentrations were associated with lower T2D risk across the glycemic spectrum below the threshold for diabetes, and the relations in prediabetes were modified by VDR polymorphisms. Improving the lipid profile, mainly triglycerides, accounted for part of the favorable associations.

Fu Y ，Lu M ，Zhang K ，Sun Y ，Tan X ，Wang N ，Xu F ，Jiang B ，Lu Y ，Wang B ... -  《-》

Relationship of Serum 25-Hydroxyvitamin D Concentrations, Diabetes, Vitamin D Receptor Gene Polymorphisms and Incident Venous Thromboembolism.

The association between vitamin D and the risk of venous thromboembolism (VTE) remains inconclusive. We aimed to explore the association of serum 25-hydroxyvitamin D (25OHD) with incident VTE among participants with and without diabetes, and examine the modifying effect of genetic susceptibility of VTE and vitamin D receptor (VDR) gene polymorphisms on this association. A total of 378,082 participants free of VTE at baseline from the UK Biobank were included. Serum 25OHD concentrations were measured by the chemiluminescent immunoassay method. The primary outcome was incident VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). The genetic risks of VTE were estimated using 297 single nucleotide polymorphisms (SNPs) associated with VTE. The VDR gene polymorphisms included SNPs of rs7975232, rs1544410, rs2228570 and rs731236. During a median follow-up duration of 12.5 years, 10,645 VTE cases were recorded. Serum 25OHD had a significantly stronger inverse association with incident VTE in participants with diabetes (per SD increment, adjusted HR: 0.87; 95% CI: 0.81-0.93) than in those without diabetes (per SD increment, adjusted HR: 0.97; 95% CI: 0.95-0.99; p-interaction = 0.003). Similar trends were found for incident DVT and PE. Among participants with diabetes, the genetic risk of VTE did not significantly modify the association between serum 25OHD and incident VTE (p-interaction = 0.607). However, a stronger inverse association of serum 25OHD with incident VTE was found in the VDR rs2228570 AA genotype (vs. GG/AG; p-interaction = 0.031). Serum 25OHD was inversely associated with the risk of VTE, especially among participants with diabetes, regardless of genetic risks of VTE.

Xiang H ，Zhou C ，Gan X ，Huang Y ，He P ，Ye Z ，Liu M ，Yang S ，Zhang Y ，Zhang Y ，Qin X ... -  《-》

Associations of Serum 25(OH)D With Risk of Recurrent Cardiovascular Events in Individuals With Coronary Heart Disease.

Few studies have examined the relationship between vitamin D and the risk of recurrent cardiovascular (CV) events in people with coronary heart disease (CHD). This study aimed to investigate the associations of serum 25-hydroxyvitamin D (25(OH)D) concentration and the vitamin D receptor (VDR) polymorphisms with the risk of recurrent CV events in individuals with established CHD. A total of 22 571 participants with CHD were included from the UK Biobank. Recurrent CV events, including myocardial infarction (MI), heart failure (HF), stroke, and CV disease mortality, were identified from electronic health records. Cox proportional-hazard models were used to calculate hazard ratios (HRs) and 95% CIs. The median (interquartile range) of serum 25(OH)D concentration was 44.8 nmol/L (range, 30.3-61.4 nmol/L), and 58.6% of participants had 25(OH)D below 50 nmol/L. During a median follow-up of 11.2 years, a total of 3998 recurrent CV events were documented. After multivariable adjustment, there was a nonlinear inverse relationship between serum 25(OH)D and recurrent CV events (P nonlinearity <.01), and the decreasing risk gradually leveled off at around 50 nmol/L. Compared with participants with serum 25(OH)D less than 25.0 nmol/L, the HRs (95% CIs) for participants with serum 25(OH)D of 50.0 to 74.9 nmol/L were 0.64 (0.58-0.71) for recurrent CV events, 0.78 (0.65-0.94) for MI, 0.66 (0.57-0.76) for HF, and 0.66 (0.52-0.84) for stroke. In addition, these associations were not modified by genetic variants in the VDR. In people with established CHD, higher serum 25(OH)D concentrations were nonlinearly associated with a lower risk of recurrent CV events, with a potential threshold around 50 nmol/L. These findings highlight the importance of maintaining adequate vitamin D status in the prevention of recurrent CV events among individuals with CHD.

Lin X ，Chen X ，Liu S ，Deng Y ，Wang Y ，Lu Q ，Li R ，Ou Y ，Tian Q ，Liao Y ，Cui G ，Yang K ，Pan A ，Liu G ... -  《-》

Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study.

Type 2 diabetes (T2D) has been linked to changes in DNA methylation levels, which can, in turn, alter transcriptional activity. However, most studies for epigenome-wide associations between T2D and DNA methylation comes from cross-sectional design. Few large-scale investigations have explored these associations longitudinally over multiple time-points. In this longitudinal study, we examined data from the Cooperative Health Research in the Region of Augsburg (KORA) F4 and FF4 studies, conducted approximately seven years apart. Leucocyte DNA methylation was assessed using the Illumina EPIC and 450K arrays. Linear mixed-effects models were employed to identify significant associations between methylation sites and diabetes status, as well as with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homoeostasis model assessment of beta cell function (HOMA-B), and homoeostasis model assessment of insulin resistance (HOMA-IR). Interaction effects between diabetes status and follow-up time were also examined. Additionally, we explored CpG sites associated with persistent prediabetes or T2D, as well as the progression from normal glucose tolerance (NGT) to prediabetes or T2D. Finally, we assessed the associations between the identified CpG sites and their corresponding gene expression levels. A total of 3,501 observations from 2,556 participants, with methylation measured at least once across two visits, were included in the analyses. We identified 64 sites associated with T2D including 15 novel sites as well as known associations like those with the thioredoxin-interacting protein (TXNIP) and ATP-binding cassette sub-family G member 1 (ABCG1) genes. Of these, eight CpG sites exhibited different rates of annual methylation change between the NGT and T2D groups, and seven CpG sites were linked to the progression from NGT to prediabetes or T2D, including those annotated to mannosidase alpha class 2a member 2 (MAN2A2) and carnitine palmitoyl transferase 1 A (CPT1A). Longitudinal analysis revealed significant associations between methylation and FPG at 128 sites, HbA1c at 41 sites, and HOMA-IR at 57 sites. Additionally, we identified 104 CpG-transcript pairs in whole blood, comprising 40 unique CpG sites and 96 unique gene transcripts. Our study identified novel differentially methylated loci linked to T2D as well as to changes in diabetes status through a longitudinal approach. We report CpG sites with different rates of annual methylation change and demonstrate that DNA methylation associated with T2D is linked to following transcriptional differences. These findings provide new insights into the molecular mechanisms of diabetes development.

Lai L ，Juntilla DL ，Del M ，Del C Gomez-Alonso M ，Grallert H ，Thorand B ，Farzeen A ，Rathmann W ，Winkelmann J ，Prokisch H ，Gieger C ，Herder C ，Peters A ，Waldenberger M ... -  《Cardiovascular Diabetology》

Associations of healthy lifestyle and family income to poverty ratio with all-cause mortality among people with prediabetes and diabetes: a prospective cohort study.

Family income to poverty ratio (PIR) may have independent effects on diet and lifestyle factors and the development of prediabetes and diabetes, as well as on mortality. It is unclear how the protective effect of a healthy lifestyle against death differs between individuals with different glucose metabolic profiles and whether PIR mediates this effect. This study aimed to explore whether healthy lifestyle and family PIR reduced the risk of all-cause mortality in participants with different metabolic status and the mediating role of PIR. In total, 21,411 participants from the 2001-2018 National Health and Nutrition Examination Survey (NHANES) and follow-up until 2019 were included. The weighted healthy lifestyle score was constructed based on smoking, alcohol consumption, physical activity, diet (HEI-2015), and body mass index. Generalized linear regression models were used to analyze the association between healthy lifestyle, PIR, and all-cause mortality. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals, Kaplan-Meier survival curve was used to analyze the all-cause mortality associated with PIR and lifestyle. Furthermore, the mediation proportion of PIR in all-cause mortality attributed to healthy lifestyle was analyzed among participants with normal glucose regulation, prediabetes, or diabetes after multivariable adjustment. There were significant differences in healthy lifestyle and PIR among people with normal glucose regulation, prediabetes and diabetes. During a mean follow-up of 92 months, participants with prediabetes or diabetes were also likely to have a higher mortality rate, respectively 583 (8.3%) and 263 (12.7%). More than 2 healthy lifestyles were associated with 42% (HR, 0.58; 95% CI, 0.35-0.95) to 76% (HR, 0.24; 95% CI, 0.12-0.44) reduced risk of all-cause mortality among participants with prediabetes, but among those with diabetes, who had ≥ 4 healthy lifestyles were associated with 72% reduced risk of all-cause mortality (HR, 0.28; 95% CI, 0.09-0.90). The middle and high PIR were associated with at least a 37% (HR, 0.63; 95% CI, 0.47-0.83) to 65% (HR, 0.35; 95% CI, 0.18-0.68) lower risk of all-cause mortality in participants with prediabetes and diabetes. Furthermore, PIR mediated 5.81-14.93% and 7.72-10.10% of the association between healthy lifestyle and all-cause mortality among normal glucose regulation and prediabetic participants, respectively. However, the mediating effect of PIR was not significant among diabetic participants. Our findings highlight the importance of promoting adherence to a healthy lifestyle and improving PIR in prediabetic patients to reduce the risk of all-cause mortality, and the protective effect is more significant with more healthy lifestyles and higher PIR. This study can help clinicians and health systems develop more targeted treatments for people with different metabolic levels.

Li Z ，Zhou L ，Wu Y ，Ding T ，Gan Y ，Fan X ... -  《BMC PUBLIC HEALTH》