Background: The presence of a threshold effect has been proposed,
suggesting that beneficial effects from vitamin D supplementation
may only be present when the vitamin D concentration is below a
particular threshold.
Objectives: We investigated the associations of serum 25-
hydroxyvitamin D [25(OH)D] concentrations and genetic factors
with risks of total and subtypes of cardiovascular disease (CVD)
in individuals with type 2 diabetes (T2D), among whom vitamin D
deficiency or insufficiency is particularly common.
Methods: This prospective study included 15,103 individuals with
T2D who were initially free of CVD and had serum 25(OH)D
measurements in the UK Biobank. Incidences of total and subtypes
of CVD, including ischemic heart disease (IHD) and stroke, were
ascertained via electronic health records. Weighted genetic risk
scores (GRSs) were constructed for IHD and stroke.
Results: The mean serum 25(OH)D concentration was 43.4 nmol/L
(SD: 20.4 nmol/L), and 65.7% of participants had a vitamin D
concentration below 50 nmol/L. During a median of 11.2 years of
follow-up, 3534 incident CVD events were documented. Compared
with individuals with 25(OH)D concentrations <25 nmol/L,
participants with 25(OH)D concentrations ≥75 nmol/L had HRs
(95% CIs) of 0.75 (0.64, 0.88) for CVD, 0.69 (0.56, 0.84) for
IHD, and 0.74 (0.52, 1.06) for stroke. Participants with 25(OH)D
concentrations ≥50 nmol/L and low GRSs, as compared with
individuals with 25(OH)D concentrations <25 nmol/L and
high GRSs, had a 50% (39%, 65%) lower risk of IHD. No
significant interactions were demonstrated between serum 25(OH)D
concentrations and the GRSs and genetic variants in vitamin D
receptors (VDR).
Conclusions: Higher serum 25(OH)D concentrations were
significantly associated with lower risks of total CVD and IHD
among patients with T2D, regardless of their genetic susceptibility
and the genetic variants in VDR. Risk reductions tended to plateau
at serum 25(OH)D levels around 50 nmol/L. These findings
suggest that maintaining an adequate vitamin D status and avoiding
deficiency may help to prevent CVD complications among patients
with T2D. Am J Clin Nutr 2022;116:1389–1399.
Keywords: vitamin D, genetic risk score, cardiovascular disease,
type 2 diabetes, epidemiology
Introduction
Type 2 diabetes (T2D) has become a global public health
problem, with an estimated 537 million adults living with
diabetes worldwide in 2021 (1). Cardiovascular disease (CVD)
is a major cause of morbidity and mortality in patients with T2D
(2). It is of great importance to identify modifiable risk factors to
prevent or delay the development of CVD complications among
individuals with T2D.
This study was funded by grants from the Hubei Province Science Fund for
Distinguished Young Scholars (2021CFA048), the National Nature Science
Foundation of China (82073554, 81930124, 82021005), the Fundamental Research
Funds for the Central Universities (2021GCRC076, 2021GCRC075),
and the China Postdoctoral Science Foundation (2021M691129). .
Supplemental Figures 1–3 and Supplemental Tables 1–11 are available
from the “Supplementry data” link in the online posting of the article and
from the same link in the online table of contents at https://academic.oup.c
om/ajcn/.
Address correspondence to Gang Liu (e-mail: liugang026@hust.edu.cn).
Abbreviations used: CRP, C-reactive protein; CVD, cardiovascular disease;
eGFR, estimated glomerular filtration rate; GRS, genetic risk score;
HbA1c, glycated hemoglobin; IHD, ischemic heart disease; MET, metabolic
equivalent; MR, Mendelian randomization; PTH, parathyroid hormone;
RCS, restricted cubic spline; RCT, randomized controlled trial; T2D, type
2 diabetes; TG, triglycerides; VDR, vitamin D receptor; 25(OH)D, 25-
hydroxyvitamin D.
Received March 15, 2022. Accepted for publication June 28, 2022.
First published online June 30, 2022; doi: https://doi.org/10.1093/ajcn/
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