High apolipoprotein B (apoB) levels may be associated with a reduced lifespan and an increase in the risk for heart disease, stroke, and type 2 diabetes (T2D), according to a study in Lancet Healthy Longevity.

Investigators analyzed the effects of genetically predicted higher elevations in apoB and self-reported outcomes in first-degree relatives of participants from the UK Biobank database for 12 diseases, including heart disease, stroke, hypertension, and Alzheimer’s disease. (In this study, for apoB measures, 1 SD elevated lipoprotein trait = 0.24g/L).

A median of 400,304 participants reported information on prevalent diseases in first-degree relatives; 180,472 (39.7%) participants reported that their mothers were still alive and 103,919 (23.1%) reported that their fathers were still alive. Among deceased parents, the mean age at death was 75.7 years (SD 13.3) in mothers and 70.9 years (SD 13.1) in fathers.


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Genetically elevated apoB was associated with a lower relative odds that an individual’s parents were alive (fathers: odds ratio [OR] 0.94; 95% CI, 0.92-0.97; mothers: OR 0.97; 95% CI, 0.96-0.99). Fathers were estimated to die 0.89 years earlier (95% CI, 0.63-1.16; false discovery rate [FDR]-adjusted P = 4.0 × 10¹⁰), corresponding to a mean of 10.7 months of life lost per 1 SD higher apoB in offspring, and mothers 0.48 years earlier (95% CI, 0.25-0.71; FDR-adjusted P = 1.7 × 10⁴) mean, 5.8 months of life lost per 1 SD higher apoB in offspring.

The findings were replicated regarding age of death and parental vital status in conventional 2-sample mendelian randomization. ApoB was associated with reduced survival, and the effect was stronger when low-density lipoprotein (LDL) cholesterol and triglycerides were included in the multivariable mendelian randomization.

An increase in apoB by 1 SD was associated with lower relative odds of surviving to the 90th centile of lifespan (OR 0.38; 95% CI, 0.22-0.65) in the multivariable mendelian randomization.

The protective effect of LDL cholesterol against T2D increased (0.34 per 1 SD higher LDL cholesterol, 0.21-0.54), and a strong positive association was found between apoB and T2D risk (2.32 per 1 SD higher apoB, 1.49-3.61) in the multivariable mendelian randomization.

In univariable mendelian randomization, an increased risk of heart disease was found for all first-degree relatives of individuals with genetically elevated apoB (fathers: OR 1.20; 95% CI, 1.16-1.25; FDR-adjusted P = 1.9 × 10²¹; mothers: OR 1.14; CI, 1.09-1.19; FDR-adjusted P = 5.4 × 10⁹). Mothers of offspring who had genetically elevated apoB had an increased risk of stroke (OR 1.05; CI, 1.02-1.08; FDR-adjusted P = 4.2 × 10⁴).

The investigators noted that they couldn’t conclude that apoB directly causes outcomes in first-degree relatives because genetically increased apoB is an approximation to unconfounded estimates within first-degree relatives. In addition, they added, the effect estimates generated by the genetic instruments had been attenuated through regression dilution because first-degree relatives share 50% of their DNA.

Researchers did say their findings supported apoB “as being the major lipoprotein entity implicated in the aetiology of coronary heart disease and stroke” and that “higher apoB decreases lifespan and increases the risk of type 2 diabetes.” In summary, the researchers concluded their findings “highlight the crucial role of apoB in causing cardiometabolic disease, which collectively shortens the lifespan.”

Disclosure: Some of the study authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Richardson TG, Wang Q, Sanderson E, et al. Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relatives. Lancet Healthy Longev. 2021;2(6):e317-e326. doi:10.1016/S2666-7568(21)00086-6