The optimal reference range of homeostasis model assessment of insulin resistance (HOMA-IR) in normal Chinese population has not been clearly defined. Here we address this issue using the Hong Kong ...Cardiovascular Risk Factor Prevalence Study (CRISPS), a prospective population-based cohort study with long-term follow-up.
In this study, normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) were defined according to the 1998 World Health Organization criteria. Dysglycemia referred to IFG, IGT or T2DM. This study comprised two parts. Part one was a cross-sectional study involving 2,649 Hong Kong Chinese subjects, aged 25-74 years, at baseline CRISPS-1 (1995-1996). The optimal HOMA-IR cut-offs for dysglycemia and T2DM were determined by the receiver-operating characteristic (ROC) curve. Part two was a prospective study involving 872 subjects who had persistent NGT at CRISPS-4 (2010-2012) after 15 years of follow-up.
At baseline, the optimal HOMA-IR cut-offs to identify dysglyceia and T2DM were 1.37 (AUC = 0.735; 95% confidence interval CI = 0.713-0.758; Sensitivity Se = 65.6%, Specificity Sp = 71.3% and 1.97 (AUC = 0.807; 95% CI = 0.777-0.886; Se = 65.5%, Sp = 82.9%) respectively. These cut-offs, derived from the cross-sectional study at baseline, corresponded closely to the 75th (1.44) and 90th (2.03) percentiles, respectively, of the HOMA-IR reference range derived from the prospective study of subjects with persistent NGT.
HOMA-IR cut-offs, of 1.4 and 2.0, which discriminated dysglycemia and T2DM respectively from NGT in Southern Chinese, can be usefully employed as references in clinical research involving the assessment of insulin resistance.
Thioamides antithyroid‐drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD‐induced agranulocytosis is important for clinical management. ...We performed a genome‐wide association study (GWAS) involving 20 patients with ATD‐induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single‐nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD‐induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8–103.7; P = 1.3 × 10‐24) and replication (OR = 37; 95% CI = 3.7–367.4; P = 9.6 × 10‐7). HLA‐B*38:02:01 was in complete linkage disequilibrium with rs185386680. High‐resolution HLA typing confirmed that HLA‐B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)‐induced agranulocytosis (OR = 265.5; 95% CI = 27.9–2528.0; P = 2.5 × 10‐14), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA‐B*38:02:01 in predicting CMZ/MMI‐induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis ...of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients.
Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID).
There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use HR 0.69 (95% CI 0.56-0.86; P < 0.001), with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban.
Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.
Context:
Serum alkaline phosphatase plays a role in vascular calcification. It is found in various tissues, whereas bone-specific alkaline phosphatase (BAP) more specifically reflects mineral ...metabolism. The relationship of serum alkaline phosphatase (total and bone-specific) with diabetes and metabolic syndrome (MetS), 2 major risk factors of vascular calcification, is largely unknown.
Objective:
We aimed to investigate the relationships between glucose metabolism, components of the MetS, and alkaline phosphatase.
Design and Setting:
This was a cross-sectional study of a nationally representative sample of the U.S. population in 1999 through 2004.
Participants:
Participants were 3773 nondiabetic participants of the National Health and Nutrition Examination Survey 1999–2004.
Main Outcome Measures:
We measured serum BAP and total alkaline phosphatase.
Results:
In multivariable linear regression, updated homeostasis model assessment (HOMA2) for insulin resistance (β = 0.068), HOMA2 for β-cell function (β = 0.081), insulin (β = 0.065), mean arterial pressure (β = 0.15), and high-density lipoprotein (HDL)-cholesterol (β = 0.209) were positively associated with BAP, whereas HOMA2 for insulin sensitivity (β = −0.065) was negatively associated with BAP. On the other hand, only mean arterial pressure and HDL-cholesterol were significantly associated with total alkaline phosphatase. Moreover, a structural equation model revealed that hypertension, low HDL, and insulin resistance had significant direct effects on serum BAP levels, whereas obesity and inflammation might have indirect effects on serum BAP levels. The overall model showed very good fit to the data (comparative fit index = 0.995, root mean square error of approximation = 0.037, and standardized root mean square residual = 0.006).
Conclusion:
Glucose metabolism and MetS are significantly related to serum BAP levels. How BAP mediates vascular calcification in diabetes and MetS warrants further studies.
Patients with diabetes are at a higher risk of pneumonia and pneumonia mortality. Sodium glucose co-transporter 2 inhibitors (SGLT2is), the latest class of glucose-lowering agents, were shown to ...reduce the risk of pneumonia in clinical trials. However, the real-world effectiveness of SGLT2is on the risk of pneumonia is largely unknown.
To investigate the associations between SGLT2is use and the risk of pneumonia and pneumonia mortality compared with dipeptidyl peptidase-4 inhibitors (DPP4is) using an electronic medical database in Hong Kong.
A retrospective cohort study. The "prevalent new-user" design was adopted to account for the previous exposure to the study drugs being compared. Propensity score (PS) matching (1:4) was used to balance the baseline characteristics of the 2 groups.
Electronic health data of type 2 diabetes patients using SGLT2is and DPP4is between 2015 and 2018 was collected from the Clinical Data Analysis and Reporting System.
Pneumonia incidence and mortality.
The PS-matched cohort consisted of 6664 users of SGLT2is and 26 656 users of DPP4is, with a mean follow-up of 3.8 years. Poisson regression showed that SGLT2is use was associated with lower risk of pneumonia compared with DPP4is with an absolute rate difference of 4.05 per 1000 person-years (95% CI, 2.61-5.51). The corresponding incidence rate ratio was 0.71 (95% CI, 0.62-0.81). Similar reduction in risk of pneumonia death was observed (hazard ratio 0.57; 95% CI, 0.42-0.77).
Compared with DPP4is, SGLT2is use was associated with a reduced risk of pneumonia and pneumonia mortality in a real-world setting.
Aims/hypothesis
Genome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent advancements of ...exome-array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exomechip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population.
Methods
An exome-chip association study was conducted by genotyping 5640 Chinese individuals from Hong Kong, using a custom designed exome array, the Asian Exomechip. Single variant association analysis was conducted on 77,468 single nucleotide polymorphisms (SNPs). Fifteen SNPs were subsequently genotyped for replication analysis in an independent Chinese cohort comprising 12,362 individuals from Guangzhou. A combined analysis involving 7189 cases and 10,813 controls was performed.
Results
In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in
PAX4
, and two variants at the known loci,
CDKN2B-AS1
and
KCNQ1,
were significantly associated with type 2 diabetes with exome-wide significance (
p
discovery
< 6.45 × 10
−7
). The risk allele (T) of
PAX4
rs2233580 was associated with a younger age at diabetes diagnosis. This variant was replicated in an independent cohort and demonstrated a stronger association that reached genome-wide significance (
p
meta-analysis
p
meta
=
3.74 × 10
−15
) in the combined analysis.
Conclusions/interpretation
We identified the association of a
PAX4
Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of
PAX4
in the pathogenesis of type 2 diabetes. Our findings suggest
PAX4
is a possible effector gene of the 7q32 locus, previously identified from GWAS in Asians.
Adipocyte fatty acid-binding protein (A-FABP) is an adipokine shown to have adverse metabolic and proinflammatory effects, and contributes to atherosclerosis in mice. However, its role in ...cardiovascular diseases in humans remains to be established. In this case-control study, we investigated the association of serum A-FABP with ischemic stroke, and examined its association with early mortality.
Serum A-FABP was measured, using ELISA, in 306 subjects with acute ischemic stroke and 306 age-, sex-, and body mass index-matched controls. All controls were free of cardiovascular diseases. Serum A-FABP was also measured in another 60 ischemic stroke subjects who died within 3 months of acute stroke.
Serum A-FABP was higher in subjects with ischemic stroke as compared to controls (19.6 ng/mL 14.3-28.4 ng/mL vs 15.2 ng/mL 10.6-23.6 ng/mL in men and 32.4 ng/mL 24.5-45.7 ng/mL vs 22.0 ng/mL 14.3-34.0 ng/mL in women, stroke vs control, p<0.001). On logistic regression analyses with the model including hypertension, diabetes, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, lipid-lowering treatment, smoking, and A-FABP, serum A-FABP was independently associated with stroke (odds ratio 2.10, 95% confidence interval 1.50-2.94, p<0.001), and the associations of A-FABP with ischemic stroke were additive to conventional risk factors, as demonstrated on likelihood ratio tests (p<0.001). Furthermore, high serum A-FABP was associated with increased 3-month mortality in ischemic stroke subjects (odds ratio 2.65, 95% confidence interval 1.18-5.96, p=0.018), independent of age and NIH Stroke Scale score.
Serum A-FABP was significantly associated with ischemic stroke in our case-control study, and may serve as a useful prognostic indicator for early mortality.
Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 ...Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus,
, significantly associated with circulating FGF21 levels at genome-wide significance. In the combined analysis, the common missense variant of
, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels after adjustment for age and sex (
= 1.61 × 10
; β SE = 0.14 0.02), which remained significant on further adjustment for BMI (
= 3.01 × 10
; β SE = 0.15 0.02).
Leu446 may influence FGF21 expression via its ability to increase glucokinase (GCK) activity. This can lead to enhanced FGF21 expression via elevated fatty acid synthesis, consequent to the inhibition of carnitine/palmitoyl-transferase by malonyl-CoA, and via increased glucose-6-phosphate-mediated activation of the carbohydrate response element binding protein, known to regulate FGF21 gene expression. Our findings shed new light on the genetic regulation of FGF21 levels. Further investigations to dissect the relationship between GCKR and FGF21, with respect to the risk of metabolic diseases, are warranted.
Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, ...to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10(-7)), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci-PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser-also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.
Background
Previous observational studies have not found a conclusive association between serum 25‐hydroxyvitamin D (25(OH)D) levels and allergic rhinitis (AR) or allergic sensitization (AS).
...Objective
To investigate a causal association between 25(OH)D levels with risk of AR and AS, using a two‐sample Mendelian randomization (MR) approach.
Methods
Seven single nucleotide polymorphisms (SNPs), previously shown to be associated with serum 25(OH)D levels, were identified as instrumental variables. The primary outcome was AR, and the secondary outcomes were AS and non‐allergic rhinitis (NAR). The genome‐wide association (GWA) summary statistics of the outcomes were obtained from two cohort studies (EAGLE Consortium and UK Biobank). An MR analysis with random‐effects inverse‐variance weighted method was performed as the primary analysis to estimate overall effect size (odds ratio OR and 95% confidence interval CI). Sensitivity analysis using weighted median method and MR‐Egger regression method was conducted. A subgroup analysis based on 25(OH)D synthesis‐related SNPs was further applied.
Results
Serum 25(OH)D levels were not causally associated with risk of AR (OR: 0.960; 95% CI: 0.779‐1.184), AS (OR: 1.059; 95% CI: 0.686 to 1.634) or NAR (OR: 0.937; 95% CI: 0.588‐1.491). Subgroup analysis also showed null association between 25(OH)D synthesis‐related SNPs and the outcomes. Sensitivity analyses yielded similar results.
Conclusions and Clinical Relevance
This MR study found no evidence supporting a causal association between serum 25(OH)D levels and risk of AR, AS and NAR in European‐ancestry population. This argues against the previous postulation that vitamin D supplementation is effective in prevention of allergic diseases.
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