High-sensitivity C-reactive protein,low-grade systemic inflammation and type 2 diabetes mellitus: A two-sample Mendelian randomization study

Background and aims

The role of inflammation in type 2 diabetes mellitus (T2D) remains unclear. We investigated the associations of high sensitivity C-reactive protein (hsCRP) concentration with T2D and glycemic traits using two-sample Mendelian Randomization.

Milk consumption and the risk of type 2 diabetes: A systematic review of Mendelian randomization studies

AimsPreviously, no relationship between milk consumption and the risk of type 2 diabetes has been found in prospective cohorts. However, Mendelian randomization allows researchers to almost bypass much residual confounding, providing a more precise effect estimate.This systematic review aims to investigate the risk of type 2 diabetes and levels of HbA1c by assessing all Mendelian Randomization studies investigating this subject matter.Data synthesisPubMed and EMBASE were searched from October 2021 through February 2023. Inclusion and exclusion criteria were formulated to filter out irrelevant studies. Studies were qualitatively assessed with STROBE-MR together with a list of five MR criteria. Six studies were identified, containing several thousand participants. All studies used the SNP rs4988235 as the main exposure and type 2 diabetes and/or HbA1c as the main outcome. Five studies were graded as “good” with STROBE-MR, with one graded as “fair”. For the six MR criteria, five studies were graded “good” in four criteria, while two studies were graded “good” in two criteria. Overall, genetically predicted milk consumption did not seem to be associated with an increased risk of type 2 diabetes.ConclusionsThis systematic review found that genetically predicted milk consumption did not seem to increase the risk of type 2 diabetes. Future Mendelian randomization studies concerning this topic should consider conducting two-sample Mendelian Randomization studies, in order to derive a more valid effect estimate.     

Mendelian randomization study indicates lack of causal associations between iron status and lung cancer

Observational studies provided conflicting results on the association between iron status and the risk of lung cancer. The aim of our study was to investigate the effect of genetically determined iron status on lung cancer risk using a mendelian randomization (MR) approach.Single-nucleotide polymorphisms for iron status were selected from a genome-wide meta-analysis of 48,972 subjects. Genetic association estimates for risk of lung cancer were derived from a Genome-Wide Association Study (GWAS) summary performed by the International Lung Cancer Consortium. The inverse-variance weighted method was used for the main analyses and sensitivity analyses.MR analysis demonstrated that increased genetically-predicted iron status did not causally increase risk of lung cancer. The odds ratios were 1.11 (95% CI, 0.92, 1.34; P = .26), 0.76 (95% CI, 0.52, 1.12; P = .17), 1.09 (95% CI, 0.86, 1.38; P = .47), and 0.91 (95% CI, 0.81, 1.02; P = .11) per 1 standard deviation increment of serum iron, ferritin, transferrin saturation, and transferrin levels, respectively. No observed indication of heterogeneity (P for Q > 0.05) or pleiotropy (P for intercept > 0.05) were found from the sensitivity analysis.The MR study indicated that genetic iron status was not causally associated with the risk of lung cancer, the causal relationship between iron status and lung cancer needs to be further elucidated by additional studies that strictly control for confounding factors.     

Causal associations between COVID-19 and atrial fibrillation: A bidirectional Mendelian randomization study

Background and aimsObservational studies showed that coronavirus disease (2019) (COVID-19) attacks universally and its most menacing progression uniquely endangers the elderly with cardiovascular disease (CVD). The causal association between COVID-19 infection or its severity and susceptibility of atrial fibrillation (AF) remains unknown.Methods and resultsThe bidirectional causal relationship between COVID-19 (including COVID-19, hospitalized COVID-19 compared with not hospitalized COVID-19, hospitalized COVID-19 compared with the general population, and severe COVID-19) and AF are determined by using two-sample Mendelian randomization (MR) analysis. Genetically predicted severe COVID-19 was not significantly associated with the risk of AF [odds ratio (OR), 1.037; 95% confidence interval (CI), 1.005–1.071; P = 0.023, q = 0.115]. In addition, genetically predicted AF was also not causally associated with severe COVID-19 (OR, 0.993; 95% CI, 0.888–1.111; P = 0.905, q = 0.905). There was no evidence to support the association between genetically determined COVID-19 and the risk of AF (OR, 1.111; 95% CI, 0.971–1.272; P = 0.127, q = 0.318), and vice versa (OR, 1.016; 95% CI, 0.976–1.058; P = 0.430, q = 0.851). Besides, no significant association was observed for hospitalized COVID-19 with AF. MR-Egger analysis indicated no evidence of directional pleiotropy.ConclusionOverall, this MR study provides no clear evidence that COVID-19 is causally associated with the risk of AF.     

No causal association between plasma homocysteine levels and atrial fibrillation: A Mendelian randomization study

Background and aimsAlthough several studies have shown an association between plasma homocysteine (Hcy) levels and atrial fibrillation (AF), the causality remains unclear. We undertook a Mendelian randomization (MR) study to investigate the causal association between Hcy and AF.Methods and resultsSingle-nucleotide polymorphisms (SNPs) which genome-wide significantly associated with plasma Hcy levels were obtained from a genome-wide meta-analysis (N = 44 147). MR analyses including the random-effect inverse variance-weighted (IVW) meta-analysis, weighted median analysis, and MR-Egger regression were used to estimate the associations between the selected SNPs and AF based on a meta-analysis of genome-wide association study for AF (N = 588 190). The MR analyses revealed no causal role of genetically elevated plasma Hcy levels with AF risk (random-effect IVW, odds ratio per 1 SD increase in Hcy levels = 0.972, 95% confidence interval = 0.919 to 1.027, P = 0.308). The results were consistent with the weighted median method, MR-Egger and the analysis after excluding the pleiotropic SNPs. No heterogeneity and directional pleiotropy were observed in sensitivity analyses.ConclusionThe findings suggested that plasma Hcy levels were not causally associated with AF.     

Association of plasma polyunsaturated fatty acids with arterial blood pressure: A Mendelian randomization study

High polyunsaturated fatty acids (PUFAs) intake is recommended for primary and secondary prevention of cardiovascular disease (CVD). However, the association of PUFAs with blood pressure (BP) is still controversial. In the present study, two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship of PUFAs with BP, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP).Genetic instruments and summary statistics for two-sample MR analysis were obtained from 3 large-scale genome-wide association studies (GWASs). Eight single nucleotide polymorphisms (SNPs) significantly (P < 5 × 10⁻⁸) related to 6 PUFAs were used as instrumental variables. Conventional inverse-variance weighted method was adopted to evaluate the causality of PUFAs with BP; the Weighted Median, MR-egger, and Leave-one-out method were used for sensitivity analyses.As a result, there was no evidence of a causal association between all PUFAs and SBP. In addition, arachidonic acid (AA, β = −0.04, P < .001) and eicosapentaenoic acid (EPA, β = −0.47, P = .02) were negatively associated with DBP, while linoleic acid (LA, β = 0.03, P = .005) and α-linolenic acid (ALA, β = 3.83, P < .001) were positively associated with DBP. There was no evidence of a causal relationship between either docosapentaenoic acid (DPA) or docosahexaenoic acid (DHA) with DBP.In conclusion, a genetic predisposition to plasma polyunsaturated fatty acid (PUFA) had a divergent effect on DBP, independent of SBP. It suggested that it is helpful for lower DBP level to supplemental intake of AA and EPA or promote the conversion of LA and ALA to AA and EPA respectively, which need to be further validated with randomized controlled studies.     

Genetically increased circulating 25(OH)D level reduces the risk of type 2 diabetes in subjects with deficiency of vitamin D: A large-scale Mendelian randomization study

Observational studies have reported that Vitamin D deficiency and the risk type 2 diabetes are associated, but the causation is unclear. Mendelian randomization (MR) involving genetic variants as instrument variables (IVs) overcomes the reverse-casualty and unmeasured confounding. However, with limited sample size and IVs, previous MR studies showed inconsistent results. Leveraging by a largely increased sample size for both stages, we aim to provide an updated and precise estimate for the causality between Vitamin D and type 2 diabetes.A 2-sample multi-IVs MR was performed. IVs for circulating 25-hydroxyvitamin D (25(OH)D) were obtained from a genome-wide association study from UK biobank involving 329,247 subjects of European ancestry. The causal effect of 25(OH)D and type 2 diabetes was estimated using traditional inverse variance weighting and MR pleiotropy residual sum and outlier (MR-PRESSO) framework which provides a robust estimate by systematically filtering out IVs identified with potential pleiotropy effects.A higher genetically instrumented 25(OH)D was causally linked to reduced risk of type 2 diabetes risk by MR-PRESSO [odds ratio (OR) per standard deviation (SD) = 0.950, 95% confidence interval (CI) = 0.913–0.988, P = .010] after removing 13 (13/193) invalid IVs. In addition, we confirmed the causal role Vitamin D using 2 synthesis-related single-nucleotide polymorphisms (SNPs) which are consistent with previous MR studies [OR per SD = 0.894, 95% CI = 0.816–0.979, P = .016].With a largely improved sample size, our results confirmed that genetically increased 25(OH)D concentration reduced the risk of type 2 diabetes and provided a more precise estimate for the effect size. The updated result empowers the role of Vitamin D and provides nontrivial evidence for interventional studies.     

Allometric body shape indices,type 2 diabetes and kidney function: A two-sample Mendelian randomization study

Aim

To examine the association between body mass index (BMI)-independent allometric body shape indices and kidney function.

Materials and methods

We performed a two-sample Mendelian randomization (MR) analysis, using summary statistics from UK Biobank, CKDGen and DIAGRAM. BMI-independent allometric body shape indices were: A Body Shape Index (ABSI), Waist-Hip Index (WHI) and Hip Index (HI). Kidney function outcomes were: urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate and blood urea nitrogen. Furthermore, we investigated type 2 diabetes (T2D) as a potential mediator on the pathway to albuminuria. The main analysis was inverse variance-weighted random-effects MR in participants of European ancestry. We also performed several sensitivity MR analyses.

Results

A 1-standard deviation (SD) increase in genetically predicted ABSI and WHI levels was associated with higher UACR (β = 0.039 [95% confidence interval: 0.016, 0.063] log [UACR], P = 0.001 for ABSI, and β = 0.028 [0.012, 0.044] log [UACR], P = 6 x 10⁻⁴ for WHI) in women, but not in men. Meanwhile, a 1-SD increase in genetically predicted HI was associated with lower UACR in women (β = −0.021 [−0.041, 0.000] log [UACR], P = 0.05) and in men (β = −0.026 [−0.058, 0.005] log [UACR], P = 0.10). Corresponding estimates in individuals with diabetes were substantially augmented. Risk of T2D increased for genetically high ABSI and WHI in women (P < 6 x 10⁻¹⁹) only, but decreased for genetically high HI in both sexes (P < 9 x 10⁻³). No other associations were observed.

Conclusions

Genetically high HI was associated with decreased risk of albuminuria, mediated through decreased T2D risk in both sexes. Opposite associations applied to genetically high ABSI and WHI in women only.     

基于两样本孟德尔随机化方法探讨血清睾酮水平与动脉粥样硬化的因果关联

目的]探讨基因预测的血清睾酮水平与全身多部位动脉粥样硬化是否存在因果关系。 [方法]基于两项分别来自国外的关于睾酮与动脉粥样硬化的欧洲人群全基因组关联研究汇总数据库,采用两样本孟德尔随机化分析方法,将与睾酮相关的遗传变异数据作为工具变量,利用逆方差加权法、MR-Egger回归和加权中位数估计等方法评估睾酮与动脉粥样硬化之间的因果效应。 [结果]逆方差加权法分析结果显示,基因预测的血清睾酮水平与外周动脉粥样硬化的风险呈负相关(OR=0.93,95%CI:0.86～1.00,P＝0.01),睾酮升高可能减少患外周动脉粥样硬化的风险,而与脑动脉粥样硬化、冠状动脉粥样硬化及其他部位动脉粥样硬化(除脑动脉、冠状动脉和外周动脉)之间均未发现潜在因果关联的证据(P＞0.05)。 [结论]孟德尔随机化分析结果显示睾酮与外周动脉粥样硬化发生的风险有一定的因果关系,睾酮治疗在动脉粥样硬化防治中的前景值得开拓及进一步研究。     

A causal relationship between alcohol intake and type 2 diabetes mellitus: A two-sample Mendelian randomization study

Background and aimsWe investigated whether alcohol intake has a causal relationship with type 2 diabetes mellitus (T2DM) risk in adults of the Korean Genomic Epidemiology Study using two-sample Mendelian randomization (MR) analysis.Methods and resultsDaily alcohol intake was calculated based on the type, average amount, and frequency of alcohol consumption for six months before the interview. The participants were divided into low- and high-alcohol intake of 20 g/day. After adjusting for the covariates related to T2DM, the independent genetic variants (instrumental variables) related to alcohol intake were explored by GWAS analysis in a city hospital-based cohort (n = 58,701). SNPs with a significant level of p-value <5 × 10^?8 and linkage disequilibrium of r² < 0.001 were retrieved. MR methods were used to analyze the causality between alcohol intake and the T2DM risk, and the heterogeneity and leave-one-out sensitivity analyses were conducted in Ansan/Ansung plus rural cohorts (n = 13,598). High alcohol intake increased T2DM risk when the inverse-variance weighted (P = 0.012) and weighted median (P = 0.034) methods were used, but not when the MR-Egger method was used. No significant heterogeneity and horizontal pleiotropy between alcohol intake and T2DM were detected. A single genetic variant did not affect the causal association in a leave-one-out sensitivity analysis.ConclusionThis study supports that heavy alcohol intake appears to be causally associated with T2DM risk.     

2型糖尿病并发脂肪肝的临床研究

目的探讨2型糖尿病合并脂肪肝的主要危险因素。方法采用病例对照研究的方法观察338例2型糖尿病并发脂肪肝和无脂肪肝患者的年龄、身高、体重、腰围、臀围、体重指数（BMI）、腰臀比、空腹血糖（FBG）、C肽、糖化血红蛋白（HbAlc）、谷草转氨酶（AST）、谷丙转氨酶（ALT）、总胆红素（TBIL）、直接胆红素（DBIL）、碱性磷酸酶（ALP）、γ-谷氨酰转肽酶（γ-GT）、肌酐、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、2 h血糖、2 h C肽等指标：多因素相关分析采用Logistic逐步回归。结果2型糖尿病并发脂肪肝组与无脂肪肝组年龄、身高、FBG、2 h血糖、HbAlc、TBIL、DBIL、ALP、肌酐、TC、LDL无显著性差异（P〉0.05）,体重、BMI、腰围、臀围、腰臀比、空腹C肽、2hC肽、AST、ALT、γ-GT、TG、HDL有显著性差异（P〈0.01）;BMI（OR=1.22）、空腹C肽（OR=2.24）与2型糖尿病并发脂肪肝呈正相关,HDL（OR=0.26）与2型糖尿病并发脂肪肝呈负相关。结论肥胖、胰岛素抵抗及脂质代谢紊乱是2型糖尿病并发脂肪肝的主要危险因素。     

Genetic risk of fatty liver disease and mortality in the general population: A Mendelian randomization study

Background & Aims

Fatty liver disease has been associated with higher all-cause as well as liver-related, ischemic heart disease (IHD)-related and extrahepatic cancer-related mortality in observational epidemiological studies. We tested the hypothesis that fatty liver disease is a causal risk factor for higher mortality.

Methods

We genotyped seven genetic variants known to be associated with fatty liver disease (in PNPLA3, TM6SF2, HSD17B13, MTARC1, MBOAT7, GCKR, and GPAM) in 110 913 individuals from the Danish general population. Hepatic steatosis was measured by hepatic computed tomography in n = 6965. Using a Mendelian randomization framework, we tested whether genetically proxied hepatic steatosis and/or elevated plasma alanine transaminase (ALT) was associated with liver-related mortality.

Results

During a median follow-up of 9.5 years, 16 119 individuals died. In observational analyses, baseline elevated plasma ALT was associated with higher all-cause (1.26-fold), liver-related (9-fold), and extrahepatic cancer-related (1.25-fold) mortality. In genetic analyses, the risk alleles in PNPLA3, TM6SF2, and HSD17B13 were individually associated with higher liver-related mortality. The largest effects were seen for the PNPLA3 and TM6SF2 risk alleles, for which homozygous carriers had 3-fold and 6-fold, respectively, higher liver-related mortality than non-carriers. None of the risk alleles, individually or combined into risk scores, were robustly associated with all-cause, IHD-related, or extrahepatic cancer-related mortality. In instrumental variable analyses, genetically proxied hepatic steatosis and higher plasma ALT were associated with liver-related mortality.

Conclusions

Human genetic data support that fatty liver disease is a causal driver of liver-related mortality.