Dataset Information

Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

ABSTRACT:

Background

Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke.

Methods

We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (N_cases=51,929, N_cntrl=39,980) and subsequent arterial ischemic stroke (AIS) N_cases=45,120, N_cntrl=46,789) after first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (pQTLs) to determine the effect of 1,463 plasma protein abundances on subsequent MACE using Mendelian randomization (MR).

Results

Two variants were significantly associated with subsequent cardiovascular events: rs76472767 (OR=0.75, 95% CI = 0.64-0.85, p= 3.69×10^-08) with subsequent AIS and rs13294166 (OR=1.52, 95% CI = 1.37-1.67, p=3.77×10^-08) with subsequent MACE. Using MR, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 (effect OR= 0.77, 95% CI = 0.66-0.88, adj. p=0.05), and TNFRSF14 (effect OR=1.42, 95% CI = 1.24-1.60, adj. p=0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation.

Conclusions

We found evidence that two proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets.

SUBMITTER: Elmore A

PROVIDER: S-EPMC10863017 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Elmore Andrew A Adhikari Nimish N Hartley April E AE Javier Aparicio Hugo H Posner Dan C DC Hemani Gibran G Tilling Kate K Gaunt Tom R TR Wilson Peter P Casas J P JP Michael Gaziano John J Smith George Davey GD Paternoster Lavinia L Cho Kelly K Peloso Gina M GM

medRxiv : the preprint server for health sciences 20240201

<h4>Background</h4>Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke.<h4>Methods</h4>We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (N<sub>cases</sub>=51,929, N<sub>cntrl</sub>= ...[more]

PMID: 38352469

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Project description:BackgroundObservational studies link moderate alcohol consumption to reduced risk of cardiometabolic diseases, including coronary heart disease (CHD) and type 2 diabetes mellitus (T2D). Mendelian randomization (MR) studies suggest that these associations are due to confounding. We present observed and genetically proxied associations between alcohol consumption and the incidence of CHD and T2D among African Americans (AA), European Americans (EA), and Hispanic Americans (HA) from the Million Veteran Program.MethodsWe conducted two retrospective, nested case-control studies of 33,053 CHD and 28,278 T2D cases matched to five controls each at the time of the event (index date). We used the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) score closest in time prior to the index date to estimate alcohol exposure. Models were adjusted for smoking, body mass index (BMI), chronic kidney disease, rheumatoid arthritis, and the use of statins or antihypertensive medications. MR analyses used either a single variant in ADH1B or a genetic score (GS) as instrumental variables.ResultsObservational analysis showed a U-shaped association of alcohol consumption with CHD and T2D risk. However, in MR analyses, neither ADH1B genotype-predicted (in 36,465 AAs, 146,464 EAs, and 11,342 HAs) nor GS-predicted (in EAs) alcohol consumption was associated with CHD risk. Similarly, T2D was not associated with alcohol consumption predicted either by ADH1B genotype (in 42,008 AAs, 109,351 EAs, and 13,538 HAs) or GS (in EAs). Multivariable MR analyses that adjusted for the effects of blood pressure and smoking also showed no association between alcohol consumption and cardiometabolic diseases.ConclusionsWe replicate prior observational studies that show a U-shaped association between alcohol consumption and cardiometabolic diseases, but MR findings show no causal association between these traits. This is largely consistent with previous MR analyses in EAs and expands the literature by providing similar findings in AA and HA populations.

Project description:BackgroundThere is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans. Furthermore, it is unclear whether primarily drinking beer, wine, or liquor is associated with a difference in stroke risk.MethodsThe study included 185,323 Million Veteran Program participants who self-reported alcohol consumption on the Lifestyle Survey. Moderate consumption was defined as 1-2 drinks/day and beverage preference of beer, wine or liquor was defined if ≥ 50% of total drinks consumed were from a single type of beverage. Strokes were defined using ICD-9 and ICD-10 codes from the participants' electronic health record.ResultsThe mean (sd) age of the sample was 64 (13) years and 11% were women. We observed 4,339 (94% ischemic; 6% hemorrhagic) strokes over a median follow-up of 5.2 years. In Cox models adjusted for age, sex, race, education, income, body mass index, smoking, exercise, diet, cholesterol, prevalent diabetes, prevalent hypertension, lipid-lowering medication, antihypertensive medication, and diabetes medication, moderate alcohol consumption (1-2 drinks/day) was associated with a 22% lower risk of total stroke compared with never drinking [Hazards ratio (HR) 95% confidence interval (CI): 0.78 (0.67, 0.92)]. When stratifying by stroke type, we observed a similar protective association with moderate consumption and ischemic stroke [HR (95% CI): 0.76 (0.65, 0.90)], but a non-statistically significant higher risk of hemorrhagic stroke [HR (95% CI): 1.29 (0.64, 2.61)]. We did not observe a difference in ischemic or hemorrhagic stroke risk among those who preferred beer, liquor or wine vs. no beverage preference. When stratifying by prior number of hospital visits (≤ 15, 16-33, 34-64, ≥ 65) as a proxy for health status, we observed attenuation of the protective association with greater number of visits [HR (95% CI): 0.87 (0.63, 1.19) for ≥ 65 visits vs. 0.80 (0.59, 1.08) for ≤ 15 visits].ConclusionsWe observed a lower risk of ischemic stroke, but not hemorrhagic stroke with moderate alcohol consumption and did not observe substantial differences in risk by beverage preference among a sample of U.S. Veterans. Healthy user bias of moderate alcohol consumption may be driving some of the observed protective association.

Dataset Information

Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Background

Methods

Results

Conclusions

Publications

Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

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