Pregnancy hypertensive disorders linked to higher future risk of cardiovascular disease

24th February 2023

Pregnancy hypertensive disorders increase the longer term risk of cardiovascular diseases according to a results of a Mendelian analysis

Women who experience pregnancy hypertensive disorders such as preeclampsia have a higher risk of developing cardiovascular disorders in the future according to the findings of a Mendelian randomisation analysis by UK and Dutch researchers.

Hypertensive disorders during pregnancy affect 8% to 10% of all pregnant women and can lead to serious complications including mortality. In fact, one systematic analysis revealed how 14% of maternal deaths were due to hypertensive disorders. Moreover, observational evidence suggests that having a pregnancy-related hypertensive disorder increases the risk of cardiovascular events in later life. Nevertheless, observational data cannot be used to determine a causal relationship due to potential confounding. However, a better study design that can determine whether such a relationship is causal is the use of Mendelian randomisation (MR). This approach uses the genetic risk of disease as a proxy for the disease itself and can be used to mitigate the effect of confounding, as the MR estimate can be used to interpret the effect of the exposure, in this case pregnancy-related hypertensive diseases, on the outcome of interest (cardiovascular disease).

In the current study, researchers used estimates of genetic association obtained from genome-wide association data, to examine the association between gestational hypertension and preeclampsia and the risk of subsequently developing coronary artery disease, ischaemic stroke, heart failure and atrial fibrillation. The team also employed mediation analysis based on multivariable MR, to consider the impact of potential mediators e.g., body mass index, systolic blood pressure etc, on any identified associations.

Pregnancy hypertensive disorders and future cardiovascular risk

For any genetically predicted hypertensive disorder, there was an elevated risk of developing coronary artery disease (Odds ratio, OR = 1.24, 95% CI 1.08 – 1.43, p = 0.02). The risk was also elevated when considering gestational hypertension (OR = 1.08, p = 0.04), preeclampsia or eclampsia (OR = 1.06, p = 0.03) and ischaemic stroke (OR = 1.27, P < 0.001). However, the risks were non-significant for both gestational hypertension and preeclampsia and there were also non-significant for both heart failure and atrial fibrillation.

In the mediation analysis, there was a partial attenuation of the overall risk for CAD after adjusting for systolic blood pressure (adjusted OR = 1.10 vs 1.24) and the presence of type 2 diabetes (adjusted OR = 1.16 vs 1.24).

The authors concluded that given their findings, the presence of pregnancy-related hypertensive disorders should be considered as risk factors for cardiovascular disease.

Citation
Rayes B et al. Association of Hypertensive Disorders of Pregnancy With Future Cardiovascular Disease. JAMA Netw Open. 2023

Oesophageal cancer risk related to higher genetically predicted coffee consumption

1st September 2022

Oesophageal cancer risk is causally associated with genetically-predicted coffee consumption and this effect might be temperature-related

Oesophageal cancer risk is associated with genetically predicted coffee consumption even after adjustment for factors such as body mass index (BMI), smoking initiation and alcohol intake according to the findings of a Mendelian randomisation study by UK and Swedish researchers.

Coffee drinking has been found to have a wide range of health benefits including a reduced risk of cardiovascular disease and cancer.

Coffee contains a wide range of compounds, some of which including kahweol that has been reported to exert anti-cancer properties. Moreover, coffee has been associated with a significant decrease in the risk of colorectal cancer and colon cancer with a higher intake of the beverage also linked to a lower risk of prostate cancer.

Nevertheless, much of the data has been derived from epidemiological studies which can be subject to confounding and reverse causality, i.e., where the direction of causality between to factors is the opposite of what might be expected.

A Mendelian randomisation (MR) study is designed to avoid the problems due to confounding and reverse causality and assesses whether the genetically-predicted levels of a risk factor, for instance, coffee consumption, and a disease outcome, such as oesophageal cancer are associated.

Since genetic variants are present at birth, MR studies reduce the potential for reverse causality and confounding and are therefore more likely to generate a causal interpretation.

In the present study, researchers investigated the association of genetically-predicted coffee consumption and the risk of 22 different cancers which, for example, included those affecting the ovary, thyroid and bladder.

There were a total of 15 single nucleotide polymorphisms (SNPs) identified to be associated with coffee consumption although only 12 of these were used in the analysis. Most of the SNPs were in gene regions (one for example was near a locus linked to the smell/test perception of coffee) that were likely to affect coffee drinking behaviour or behaviour indirectly by altering the metabolism of caffeine.

The researchers tested the association using data from the UK Biobank and also tested these for replication in the FinnGen consortium. The results were then adjusted for differences in genetically-predicted body mass index, smoking and alcohol consumption.

The effect sizes of the associations between genetically-predicted coffee consumption and cancer risk were scaled to a 50% increase in coffee consumption.

Oesophageal cancer risk and coffee consumption

Using a sample of 367,561 European participants, 59,647 had one of the 22 site-specific cancers. However, genetically-predicted coffee consumption was not associated with the risk of any cancer in the main analysis (odds ratio, OR = 1.05, 95% CI 0.98 – 1.14, p = 0.183) even after adjustment for BMI, smoking and alcohol intake.

But when the team looked at digestive system cancers overall, there was an increased risk (OR = 1.28, 95% CI 1.09 – 1.51, P = 0.003) and which remained significant after adjustment for BMI, smoking initiation and alcohol consumption.

This higher risk was largely driven by oesophageal cancer (OR = 2.79, 95% CI 1.73 – 4.50) in the Biobank and remained after adjustment for the effect of BMI, smoking and alcohol intake. In the FinnGen consortium, genetically predicted coffee consumption was associated with a non-significant increase in oesophageal cancer (OR = 2.01, 95% CI 0.57 – 7.05, p = 0.27) and which was attenuated after adjustment for BMI.

Coffee consumption was also associated with an increased risk of multiple myeloma in the Biobank data (OR = 2.25) even after adjustment and a reduced risk of ovarian cancer.

Interestingly, when the researchers looked at coffee consumption and individual’s preferences for drinking, they found that a preference for drinking warm (OR = 2.74) and hot (OR = 5.45) coffee was also significantly associated with a higher risk of oesophageal cancer but, surprisingly, not for very hot.

In a further subgroup analysis based on self-reported coffee intake, the risk of oesophageal cancer was similar among those drinking 1 – 3 cups/day compared with those who did not drink coffee and which the authors suggested might be due to consumption of tea.

The authors concluded that their study found evidence that coffee consumption was causally associated with a risk of oesophageal cancer and that there was some evidence that this was related to a temperature effect.

Citation
Carter P et al. Coffee consumption and cancer risk: a Mendelian randomisation study Clin. Nutr 2022

Elevated lipoprotein A levels positively associated with higher risk of prostate cancer

4th February 2022

Elevated lipoprotein A levels have been found to be associated with an increased risk of total, advanced and early age onset prostate cancer

A study by researchers from the Department of Epidemiology and Biostatistics, Imperial College, London has revealed a positive association between lipoprotein A concentrations and the risk of total, advanced and early age onset prostate cancer.

Prostate cancer is the second most common cancer diagnosis in men and the fifth leading cause of death worldwide. The GLOBOCAN 2018 data revealed how prostate cancer accounted for 7.1% of all incident cancers and 3.8% of all deaths. Moreover, there is some degree of biological heterogeneity with prostate cancer such that while there are several traditional risk factors including, age, ethnicity, family history, smoking, alcohol consumption, vasectomy and diet, the risk are different for more advanced disease. For instance, with more aggressive prostate cancer, the risk factors have mirrored those associated with cardiovascular disease such as obesity, dyslipidaemia, glucose intolerance, metabolic syndrome, unhealthy dietary habits or caloric excess, lack of physical activity and inflammation. Nevertheless, there remains much uncertainty over the precise relationship between cardiovascular risk factors and prostate cancer. For instance, though dyslipidaemia, as characterised for example, by elevated cholesterol levels, is a potential risk factor, a meta-analysis of 14 studies concluded that blood total cholesterol, HDL and LDL levels were not associated with the risk of either overall prostate cancer or high-grade prostate cancer. Furthermore, treatment for hyperlipidaemia, especially with the use of statins found that although there was no evidence that cholesterol lowering is beneficial for the prevention of low-grade or localised prostate cancer, there did appear to be an association between statin use and a reduced risk of advanced or high-grade prostate cancer. Much of the evidence for the relationship between prostate cancer and lipids comes from observational studies and one approach to control for the various confounders present in such analyses, is the use of Mendelian randomisation. In fact, one such Mendelian randomisation study assessing whether circulating lipids causally influence prostate cancer risk, concluded that there was some weak evidence to suggest that higher LDL and triglyceride levels increase aggressive prostate cancer risk.

For the present study, the UK researchers sought to determine whether genetically predicted lipid traits were associated with the overall risk of prostate cancer. They used data from the UK Biobank and looked for associations between not only cholesterol, HDL and LDL levels and prostate cancer but also with other lipid sub-fractions including lipoprotein A, apolipoprotein A and B.

Lipoprotein A and prostate cancer

Univariate analysis revealed that HLD and LDL cholesterol levels, triglycerides and apolipoprotein A and B concentrations were not associated with total prostate cancer risk. There was also no significant association between these sub-fractions and advanced prostate cancer. However, the analysis did reveal that elevated lipoprotein A levels were associated with advanced prostate cancer (odds ratio, OR = 1.03, 95% CI 1.0 – 1.06, p = 0.046) and with an increased risk of early onset prostate cancer (OR = 1.25, 95% CI 1.107 – 1.42, p < 0.001). Using multivariate analysis, the authors found that lipoprotein A levels were associated with total (OR = 1.068, p = 0.034), advanced (OR = 1.07, p = 0.055) and early onset prostate cancer (OR = 1.15, p = 0.028).

The authors concluded that their data indicated a positive association between lipoprotein A levels and the risk of total, advanced and early onset prostate cancer. In addition, they suggested that screening for high lipoprotein A levels, could be used to identify high-risk groups for prostate cancer.

Citation
Ioannidou A et al. The relationship between lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study PLoS Med 2022

Dual analytical approach reveals causal link between smoking and outcomes in COVID-19

1st October 2021

A dual analytical approach combining observational and Mendelian randomisation data suggests smoking linked to worse outcomes in COVID-19.

Throughout the COVID-19 pandemic, several important risk factors for more severe disease have become apparent including male sex, increased age and cardiovascular co-morbidities. Whether or not being a current smoker affects COVID-19 outcomes is less clear with some analyses indicating a higher risk of worse outcomes, whereas others reviews suggest a reduced risk . One solution to untangling this ambiguity is the adoption of a dual analytical approach to data analysis, for example, by comparing the results from observational studies with those from a Mendelian randomisation study. In a Mendelian randomisation (MR) study, the underlying assumption is that a genetic variant influences only the variable of interest and since genetic variants are randomly allocated at birth, MR is less susceptible to confounding which is a problem in observational studies. Genetic analysis can be used to identify variants associated with particular traits. For example, tobacco and alcohol use are known to have heritable behaviours and in one study, researchers identified 566 genetic variants in 406 loci associated with multiple stages of tobacco use, e.g., initiation, cessation, and heaviness (i.e., the number of cigarettes smoked per day).

Using a dual analytical approach to examine the relationship between smoking and outcomes in COVID-19, a team from the Nuffield Department of Primary Care Health Sciences, University of Oxford, UK, turned to data held within the UK Biobank. The researchers separately explored the relationship between smoking and COVID-19 using findings from both observational studies and Mendelian randomisation. For the MR study, researchers used established genetic proxies for smoking initiation and smoking heaviness (i.e., the number of cigarettes smoked per day). The results were analysed using multivariate logistic regression analysis adjusted for several variables including age, sex, ethnicity and several co-morbidities.

Findings

For the observational analysis, there were 421,469 individuals with a median age of 68.6 years (55.1% female). Current smokers were found to have an overall higher risk of hospitalisation (adjusted odds ratio, aOR = 1.80, 95% CI 1.26 – 2.29) and mortality (aOR = 4.89, 95% CI 3.41 – 7.0).

Similarly, in the Mendelian randomisation analysis, genetic propensity to initiate smoking was associated with a higher risk of hospitalisation (aOR = 1.60, 95% CI 1.13 – 2.27), but not mortality (aOR = 1.35, 95% CI 0.82 – 2.22, p = 0.23). For genetically predicted higher number of cigarettes smoked per day, the risk of hospitalisation was also higher (aOR = 5.08, 95% CI 2.04 – 12.66) and risk of death (aOR = 10.02, 95% CI 2.53 – 39.72).

Discussing their findings, the authors said that this was the first study to adopt a dual analytical approach to assess the relationship between smoking and outcomes from COVID-19. They concluded that the congruence between the two methods indicated that a lifelong predisposition to smoking and smoking heaviness supported a causal effect (found in the observational analysis) of smoking on COVID-19 severity.

Citation

Clift AK et al. Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort. Thorax 2021