Key result
The presence of a causative genetic variant was not an independent predictor of atherosclerotic cardiovascular disease in heterozygous familial hypercholesterolemia patients after adjusting for LDL-c levels (OR 1.708).
Why the study?
Heterozygous familial hypercholesterolemia increases premature ASCVD risk, but the effect of a causative genetic variant to predict ASCVD in patients undergoing treatment needed evaluation.
Does the presence of a causative genetic variant predict atherosclerotic cardiovascular disease in treated patients with heterozygous familial hypercholesterolemia?
Cohort (n=289)
No
Does the presence of a causative genetic variant predict atherosclerotic cardiovascular disease in treated patients with heterozygous familial hypercholesterolemia?
Odds Ratio: 1.708 (95% CI 0.899–3.242)
Absolute Event Rate: 27% vs 17.4%
p-value: p=0.102
In patients with heterozygous familial hypercholesterolemia under medical care, the presence of a causative genetic variant is not an independent predictor of ASCVD, whereas cumulative LDL-c levels play a definitive causal role.
LDL-c remains the dominant ASCVD risk driver in HeFH; leaves open whether genetic testing adds incremental value beyond lipids.
Background Heterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment. Materials and methods A retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study’s participants for the occurrence of ASCVD. Results A causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305–4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017–1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899–3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups ( p = 0.523). Conclusion In this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.
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Matta et al. (2023) conducted a cohort in Heterozygous familial hypercholesterolemia (n=289). Causative genetic variant vs. No causative genetic variant was evaluated on Occurrence of atherosclerotic cardiovascular disease (ASCVD) (OR 1.708, 95% CI 0.899-3.242, p=0.102). The presence of a causative genetic variant was not an independent predictor of atherosclerotic cardiovascular disease in heterozygous familial hypercholesterolemia patients after adjusting for LDL-c levels (OR 1.708).
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