Key result
Unexplained familial hypercholesterolaemia links to an excess of rare variants across ~18 novel genes.
Why the study?
Mutations in LDLR, APOB, and PCSK9 explain 80% of definite familial hypercholesterolaemia cases, but the genetic cause in mutation-negative patients remains unclear.
Case-Control (n=2,051)
p-value: p=<4.3×10(-4)
BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. METHODS AND RESULTS: Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out. CONCLUSIONS: No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.
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Futema et al. (2014) conducted a case-control in Familial hypercholesterolaemia (n=2,051). Rare or novel genetic variants vs. Absence of these rare or novel genetic variants (controls) was evaluated on Excess of functional rare or novel variants (gene-based burden test) (p=<4.3×10(-4)). Whole exome sequencing of unexplained familial hypercholesterolaemia cases found no single major novel locus, but identified an excess of novel variants in 18 genes, primarily CH25H and INSIG2.
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