Abstract
BACKGROUND: Cholestatic liver disease disproportionately affects South Asians, yet they remain underrepresented in genomic studies. This recall study aimed to recall volunteers from a British South Asian genetic cohort that were considered to be at high risk of cholestatic liver disease based on their genotype or phenotype. METHODS: Cases were defined as participants with rare (minor allele frequency <1%) heterozygous loss of function (LoF) variants in ABCB4 and ABCB11 (genotype re-call) or with a previous intrahepatic cholestasis of pregnancy (ICP) diagnosis (ICD10 O26.6). Cases were matched 1:1 to controls. A detailed medical and family history was taken along with fasting anthropometric and transient elastography (TE) measurements and blood samples. RESULTS: Out of 22 eligible volunteers, 9 (41%) participate in the recall (8/9 genotype and 1/9 phenotype recall). Among the recalled cases there are 5 ABCB4 LoF, 3 ABCB11 LoF, and 1 ICP phenotype. Of these, 5/9 (55.6%) exhibit findings suggestive of liver involvement (genotype re-call). Specifically, 2/5 (50%) have increased liver stiffness on TE with one also demonstrating abnormal liver blood tests. 2/5(40%) report at least 2 cholestatic symptoms and an additional 1/5 (20%) demonstrates abnormal liver blood tests without increased liver stiffness. CONCLUSIONS: This study shows findings suggestive of liver involvement in 55.6% of volunteers, underscoring the potential of rare heterozygous ABCB4/11 variants as markers for identifying individuals at high risk of developing cholestatic liver disease. Consequently, individuals at higher genetic risk benefit from monitoring, personalised treatment and prevention strategies for cholestatic liver disease.