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Background : Monogenic familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentrations due to monogenic mutations in  LDLR ,  APOB ,  PCSK9 , and  APOE . Some mutation-negative patients have a polygenic cause for elevated LDL-C due to a burden of common LDL-C-raising alleles, as demonstrated in people of White British (WB) ancestry using a 12-single nucleotide polymorphism (SNP) score. This score has yet to be evaluated in people of South Asian (SA), and Black and Caribbean (BC) ethnicities.   Objectives : 1) Compare the LDL-C and 12-SNP score distributions across the three major ethnic groups in the United Kingdom: WB, SA, and BC individuals; 2) compare the association of the 12-SNP score with LDL-C in these groups; 3) evaluate ethnicity-specific and WB 12-SNP score decile cut-off values, applied to SA and BC ethnicities, in predicting LDL-C concentrations and hypercholesterolaemia (LDL-C&amp;gt;4.9 mmol/L).   Methods : The United Kingdom Biobank cohort was used to analyse the LDL-C (adjusted for statin use) and 12-SNP score distributions in self-reported WB ( n  = 353,166), SA ( n  = 7,016), and BC ( n  = 7,082) participants. To evaluate WB and ethnicity-specific 12-SNP score deciles, the total dataset was split 50:50 into a training and testing dataset. Regression analyses (logistic and linear) were used to analyse hypercholesterolaemia (LDL-C&amp;gt;4.9 mmol/L) and LDL-C.   Findings : The mean (±SD) measured LDL-C differed significantly between the ethnic groups and was highest in WB [3.73 (±0.85) mmol/L], followed by SA [3.57 (±0.86) mmol/L,  p  &amp;lt; 2.2 × 10 −16 ], and BC [3.42 (±0.90) mmol/L] participants ( p  &amp;lt; 2.2 × 10 −16 ). There were significant differences in the mean (±SD) 12-SNP score between WB [0.90 (±0.23)] and BC [0.72 (±0.25),  p  &amp;lt; 2.2 × 10 −16 ], and WB and SA participants [0.86 (±0.19),  p  &amp;lt; 2.2 × 10 −16 ]. In all three ethnic groups the 12-SNP score was associated with measured LDL-C [ R  2  (95% CI): WB = 0.067 (0.065–0.069), BC = 0.080 (0.063–0.097), SA = 0.027 (0.016–0.038)]. The odds ratio and the area under the curve for hypercholesterolaemia were not statistically different when applying ethnicity-specific or WB deciles in all ethnic groups.   Interpretation : We provide information on the differences in LDL-C and the 12-SNP score distributions in self-reported WB, SA, and BC individuals of the United Kingdom Biobank. We report the association between the 12-SNP score and LDL-C in these ethnic groups. We evaluate the performance of ethnicity-specific and WB 12-SNP score deciles in predicting LDL-C and hypercholesterolaemia.

frontiers in genetics

LDL-C Concentrations and the 12-SNP LDL-C Score for Polygenic Hypercholesterolaemia in Self-Reported South Asian, Black and Caribbean Participants of the UK Biobank