BACKGROUND: High levels of lipoprotein(a) [Lp(a)] are a causal risk factor for cardiovascular disease. Lp(a) levels are primarily determined genetically, around 90%. Although Lp(a) remains a risk factor for cardiovascular disease, little is known about how individuals with genetically elevated levels of Lp(a) respond to exercise training. Purpose: This research investigates whether the cardiometabolic responses to exercise differs based on LPA genotype. METHODS: We measured LPA genotype (SNP rs3798220) and phenotypes in 670 Black and White participants of the HERITAGE Family Study who completed 20 weeks of exercise training. Phenotypes were measured before and after training, including body composition, cardiopulmonary exercise tests, lipid panels, inflammatory markers, and measures of glucose homeostasis. Student’s t-tests and general linear models were used to determine whether mean training-induced changes in phenotypes differed between LPA genotypes. P<0.05 was used to determine significance. RESULTS: At baseline, individuals with genetically predicted high levels of Lp(a) (rs3798220 CT genotype, n=24) had a generally worse cardiometabolic profile (e.g., higher concentration of triglycerides, apoB, and small LDL) compared to the TT genotype (n=646). For several phenotypes both LPA genotypes experienced similar improvements in response to training, including increases in VO2max and HDL-C and decreases in submaximal exercise blood pressure (all p<0.05 for within group changes). However, the rs3798220 CT genotype group experienced some training responses in an unexpected direction, including significant increases in resting blood pressure (+3.0 (6.6) mmHg SBP; +3.0 (6.1) mmHg DBP), fasting glucose (+0.3 (0.4) mmol/L), and LDL-C (+7.8 (15.5) mg/dL) that were not observed in the TT genotype. CONCLUSIONS: LPA genotype reflects a subset of the population with higher lifetime CVD risk that may experience unfavorable cardiometabolic responses to exercise training for select phenotypes. These findings may have important clinical implications, as individuals with genetically predicted high Lp(a) levels should still exercise for its many other beneficial effects. However, these individuals may need to focus on dietary and pharmacological interventions to maximally reduce CVD risk. Larger studies with measured Lp(a) levels are needed to validate these genetic findings.

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