Investigating a Potential Causal Relationship Between Maternal Blood Pressure During Pregnancy and Future Offspring Cardiometabolic Health

Observational epidemiological studies have reported that higher maternal blood pressure (BP) during pregnancy is associated with increased future risk of offspring cardiometabolic disease. However, it is unclear whether this association represents a causal relationship through intrauterine mechanisms. We used a Mendelian randomization (MR) framework to examine the relationship between unweighted maternal genetic scores for systolic BP and diastolic BP and a range of cardiometabolic risk factors in the offspring of up to 29 708 genotyped mother-offspring pairs from the UKB study (UK Biobank) and the HUNT study (Trøndelag Health). We conducted similar analyses in up to 21 423 father-offspring pairs from the same cohorts. We confirmed that the BP-associated genetic variants from the general population sample also had similar effects on maternal BP during pregnancy in independent cohorts. We did not detect any association between maternal (or paternal) unweighted genetic scores and cardiometabolic offspring outcomes in the meta-analysis of UKB and HUNT after adjusting for offspring genotypes at the same loci. We find little evidence to support the notion that maternal BP is a major causal risk factor for adverse offspring cardiometabolic outcomes in later life.

The risk of venous thromboembolism attributed to established prothrombotic genotypes

Background: The proportion of venous thromboembolism (VTE) events that can be attributed to established prothrombotic genotypes has been scarcely investigated in the general population. We aimed to estimate the proportion of VTEs in the population that could be attributed to established prothrombotic genotypes using a population-based case-cohort. Methods: Cases with incident VTE (n=1,493) and a randomly sampled sub-cohort (n=13,069) were derived from the Tromsø Study (1994-2012) and the Nord-Trøndelag Health (HUNT) Study (1995-2008). DNA-samples were genotyped for 17 single nucleotide polymorphism (SNPs) associated with VTE. Hazard ratios with 95% confidence intervals (CIs) were estimated in Cox regression models. Population attributable fraction (PAF) with 95% bias-corrected CIs (based on 10,000 bootstrap samples) were estimated using a cumulative model where SNPs significantly associated with VTE were added one-by-one in ranked order of the individual PAFs. Results: Six SNPs were significantly associated with VTE (rs1799963 [Prothrombin], rs2066865 [FGG], rs6025 [FV Leiden], rs2289252 [F11], rs2036914 [F11] and rs8176719 [ABO]. The cumulative PAF for the six-SNP model was 45.3% (95% CI 19.7-71.6) for total VTE and 61.7% (95% CI 19.6-89.3) for unprovoked VTE. The PAF for prothrombotic genotypes was higher for DVT (52.9%) than for PE (33.8%), and higher for those aged <70 years (66.1%) than for those aged ≥70 years (24.9%). Conclusions: Our findings suggest that 45-62% of all VTE events in the population can be attributed to known prothrombotic genotypes. The PAF of established prothrombotic genotypes was higher in DVT than in PE, and higher in the young than in the elderly.

Cohort Profile Update: The HUNT Study, Norway

In the HUNT Study, all residents aged ≥20 years in the Nord-Trøndelag region, Norway have been invited to repeated surveys since 1984-86. The study data may be linked to local and national health registries. The HUNT4 survey in 2017-19 included 56 042 participants in Nord-Trøndelag and 107 711 participants in the neighboring Sør-Trøndelag region. The HUNT4 data enable more long-term follow-up, studies of life-course health trajectories, and within-family studies. New measures include body composition analysis using bioelectrical impedance; a one-week accelerometer recording; physical and cognitive testing in older adults; measurements of hemoglobin and blood cell counts, HbA1c and phosphatidylethanol; and genotyping. Researchers can apply for HUNT data access from HUNT Research Centre if they have obtained project approval from the Regional Committee for Medical and Health Research Ethics, see www.ntnu.edu/hunt/data.

Bone mineral density and risk of cardiovascular disease in men and women: the HUNT study

The association between bone mineral density (BMD) and cardiovascular disease (CVD) is not fully understood. We evaluated BMD as a risk factor for cardiovascular disease and specifically atrial fibrillation (AF), acute myocardial infarction (AMI), ischemic (IS) and hemorrhagic stroke (HS) and heart failure (HF) in men and women. This prospective population cohort utilized data on 22 857 adults from the second and third surveys of the HUNT Study in Norway free from CVD at baseline. BMD was measured using single and dual-energy X-ray absorptiometry in the non-dominant distal forearm and T-score was calculated. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from adjusted cox proportional hazards models. The analyses were sex-stratified, and models were adjusted for age, age-squared, BMI, physical activity, smoking status, alcohol use, and education level. Additionally, in women, we adjusted for estrogen use and postmenopause. During a mean follow-up of 13.6 ± 5.7 years, 2 928 individuals (12.8%) developed fatal or non-fatal CVD, 1 020 AF (4.5%), 1 172 AMI (5.1%), 1 389 IS (6.1%), 264 HS (1.1%), and 464 HF (2.0%). For every 1 unit decrease in BMD T-score the HR for any CVD was 1.01 (95% CI 0.98 to 1.04) in women and 0.99 (95% CI 0.94 to 1.03) in men. Point estimates for the four cardiovascular outcomes ranged from slightly protective (HR 0.95 for AF in men) to slightly deleterious (HR 1.12 for HS in men). We found no evidence of association of lower distal forearm BMD with CVD, AF, AMI, IS, HS, and HF.