Familial hypercholesterolemia polygenic risk
My genetic test for familial hypercholesterolemia (FH) came back negative, but my LDL is very high. Could the cause still be genetic?
Yes. Researchers at Amrita School of Medicine in Kochi studied 151 South Asian patients with clinical FH and untreated LDL ≥190 mg/dL. Traditional genetic testing found a clearly pathogenic or likely pathogenic mutation in only 18 of 151 patients, just 12%. When they looked at polygenic risk scores, the patients without a single identifiable FH mutation had the highest polygenic LDL risk. With the best integrated models, about 73–74% of FH patients fell into the top two genetic-risk quintiles. Severe inherited high cholesterol does not always come from one abnormal gene such as LDLR, APOB or PCSK9. In some people, many common genetic variants act together to substantially raise LDL. Polygenic risk scores are not yet ready for routine screening, but this research could help explain some of the “missing genetic risk” for premature heart disease in South Asians. Bottom line: a negative FH gene test does not rule out an inherited cause. If your LDL is very high, or you have a strong family history, keep treating it seriously and work with your doctor. Reference: Abraham N, Menon R, Pavithran PV, Udhwani L, Bassi A, Samson PL, et al. Validated Polygenic Risk Scores Complement Monogenic Testing in South Asian Patients With Familial Hypercholesterolemia. JACC: Asia. 2026;6(8 Part 1):1597–1600. doi:10.1016/j.jacasi.2026.06.007