Diabetes and Risk of Arterial Stiffness: A Mendelian Randomization Analysis

Xu, Min; Huang, Ya; Xie, Liang; Peng, Kui; Ding, Lin; Lin, Lin; Po, Wang; Hao, Mingang; Sun, Yimin; Qi, Lü; Wang, Weiqing; Ning, Guang; Bi, Yufang

doi:10.2337/db15-1533

Cited by 73 publications

(55 citation statements)

References 48 publications

(29 reference statements)

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“…Hardy–Weinberg equilibrium, which must be conformed to determine that the instrumental variant is randomly allocated in the population, was evaluated with a χ 2 test. Rs671 in ALDH2 is located on chromosome 12 on which no allele predisposing to diabetes has been identified in East Asians . Therefore, confounding by linkage disequilibrium between rs671 and SNPs associated with diabetes is unlikely to occur.…”

Section: Methodsmentioning

confidence: 99%

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

et al. 2018

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Aim To assess the causality between alcohol intake, diabetes risk and related traits. Design Mendelian randomization (MR) study. Subgroup analysis, standard instrumental variable analysis and local average treatment effect (LATE) methods were applied to assess linear and non-linear causality. Setting China. Participants A total of 4536 participants, including 721 diabetes cases. Findings Carriage of an ALDH2 rs671 A allele reduced alcohol consumption by 44.63% [95% confidence interval (CI) = -49.44%, À39.37%]. In males, additional carriage of an A allele was significantly connected to decreased diabetes risk for the overall population [odds ratio (OR) = 0.716, 95% CI = 0.567-0.904, P = 0.005] or moderate drinkers (OR = 0.564, 95% CI = 0.355-0.894, P = 0.015). In instrumental variable (IV) analysis, increasing alcohol consumption by 1.7-fold was associated with an incidence-rate ratio of 1.32 (95% CI = 1.06-1.67, P = 0.014) for diabetes risk, and elevated alcohol intake was causally connected to natural log-transformed fasting, 2-hour post-load plasma glucose (β = 0.036, 95% CI = 0.018-0.054; β = 0.072, 95% CI = 0.035-0.108) and insulin resistance [homeostatic model assessment for IR (HOMA-IR] (β = 0.104, 95% CI = 0.039-0.169), but was not associated with beta-cell function (HOMA-beta). In addition, the LATE method did not identify significant U-shaped causality between alcohol consumption and diabetes-related traits. In females, the effects of alcohol intake on all the outcomes were non-significant.Conclusion Among men in China, higher alcohol intake appears to be causally associated with increased diabetes risk and worsened related traits, even for moderate drinkers. This study found no significant U-shaped causality between alcohol consumption and diabetes-related traits. M.P. and J.Z. contributed equally to this study.

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Section: Methodsmentioning

confidence: 99%

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

et al. 2018

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“…More recently, Xu et al [34] calculated a genetic risk score and used a Mendelian randomization analysis and, on this basis, argued for a causal relationship between T2DM and arterial stiffening in a Chinese population. We did not have a genetic risk score in the present study, but we see a positive association between T2DM and PWV scores.…”

Section: Discussionmentioning

confidence: 99%

Associations between Type 2 Diabetes Mellitus and Arterial Stiffness: A Prospective Analysis Based on the Maine-Syracuse Study

Elias

Crichton

Dearborn

et al. 2017

Pulse

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Background: The aim of this study was to investigate prospective associations between type 2 diabetes mellitus status and the gold standard non-invasive method for ascertaining arterial stiffness, carotid femoral pulse wave velocity. Methods: The prospective analysis employed 508 community-dwelling participants (mean age 61 years, 60% women) from the Maine-Syracuse Longitudinal Study. Pulse wave velocity at wave 7 (2006-2010) was compared between those with type 2 diabetes mellitus at wave 6 (2001-2006) (n = 52) and non-diabetics at wave 6 (n = 456), with adjustment for demographic factors, cardiovascular risk factors and lifestyle- and pulse wave velocity-related factors. Results: Type 2 diabetes mellitus status was associated with a significantly higher pulse wave velocity (12.5 ± 0.36 vs. 10.4 ± 0.12 m/s). Multivariate adjustment for other cardiovascular risk factors and lifestyle- and pulse wave velocity-related variables did not attenuate the findings. The risk of an elevated pulse wave velocity (≥12 m/s) was over 9 times higher for those with uncontrolled type 2 diabetes mellitus than for those without diabetes (OR 9.14, 95% CI 3.23-25.9, p < 0.001). Conclusions: Type 2 diabetes mellitus, particularly if uncontrolled, is significantly associated with risk of arterial stiffness later in life. Effective management of diabetes mellitus is an important element of protection from arterial stiffness.

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“…33 In addition, a causal association between T2D and arterial stiffness was found in a recent MR study. 34 Stiffening of the arteries may result in the development of atherosclerotic carotid plaques 35 and increased risk of large artery stroke. 36 The present study did not detect a statistically significant association between genetically predicted BMI and ischemic stroke or its subtypes.…”

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confidence: 99%

Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes

Larsson¹,

Scott²,

Traylor³

et al. 2017

Neurology

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Objective: To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes.Methods: MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNPstroke associations were derived from METASTROKE and the Stroke Genetics Network (n 5 18,476 ischemic stroke cases and 37,296 controls).Results: Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16-1.40, p 5 3.3 3 10 27 ) and small vessel stroke (OR 1.21, 95% CI 1.10-1.33, p 5 8.9 3 10 25 ) but not cardioembolic stroke (OR 1.06, 95% CI 0.97-1.15, p 5 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype. Conclusions:This study provides support that T2D may be causally associated with large artery stroke. Neurology ® 2017;89:454-460 GLOSSARY BMI 5 body mass index; CI 5 confidence interval; GWAS 5 genome-wide association studies; MR 5 mendelian randomization; NINDS 5 National Institute of Neurologic Disorders and Stroke; 1KG 5 1000 Genomes; OR 5 odds ratio; SiGN 5 Stroke Genetics Network; SNP 5 single nucleotide polymorphism; TOAST 5 Trial of Org 10172 in Acute Stroke Treatment; T2D 5 type 2 diabetes mellitus.Stroke is one of the leading causes of disability and death worldwide.1 The burden of stroke is projected to increase considerably in the next decades. Hence, there is a need to develop effective prevention strategies for stroke, which necessitates a better understanding of the underlying risk factors. About 80% of all strokes are ischemic, 1 but this term describes a syndrome caused by a number of different pathologies, which may have different treatments.2 The major etiologies of ischemic stroke are large artery atherosclerosis (large artery stroke), small vessel atherosclerosis (small vessel stroke), and cardioembolism (cardioembolic stroke). Recent data from genomewide association studies (GWAS) have shown that these subtypes have distinctive risk factor profiles and, by implication, diverse pathophysiologic bases. Type 2 diabetes mellitus (T2D) is associated with an increased risk of ischemic stroke, 4 but its relative contribution to different ischemic stroke subtypes is unknown. Moreover, several risk factors t...

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Diabetes and Risk of Arterial Stiffness: A Mendelian Randomization Analysis

Cited by 73 publications

References 48 publications

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

Associations between Type 2 Diabetes Mellitus and Arterial Stiffness: A Prospective Analysis Based on the Maine-Syracuse Study

Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes

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