LIPA Variants in Genome-Wide Association Studies of Coronary Artery Diseases

Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver

“…We also note that mutations in four of the complex phenotype-causing genes, LIPA (MIM: 613497), LIPC (MIM: 151670), GPIHBP1 (MIM: 612757), and IRF8 (MIM: 601565), have been implicated in related Mendelian diseases, [90][91][92][93] and 50% of the trait-relevant genes that have murine models were reported to display similar phenotype in the model organism as well (Mouse Genome Database; Table S11). Lastly, while LIPA, PLTP (MIM: 172425), and SLC39A8 (MIM: 608732) have been previously suggested to affect their associated phenotypes through protein altering mutations, [94][95][96] our findings are in line with those of Wild et al 97 and Hess et al, 98 suggesting that genotypedependent changes in their gene expression levels also contribute to the complex trait pathogenesis.…”

HDL and Reverse Cholesterol Transport

“…Lysosomal acid lipase (LAL), encoded by the LIPA gene in humans, is responsible for the hydrolysis of LD-associated CE to generate free cholesterol for efflux 45 . Genome-wide association studies have identified several loss of function mutations in LIPA as causative of Wolman disease, cholesterol ester storage disease (CESD) and coronary artery disease (CAD) 48 .…”

Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies

“…A recent study by Morris et al . [33∎∎] with editorial comments [34] has begun to tackle these intriguing questions. Overexpression of LAL in COS7 cell lines showed that the risk allele (C) at rs1051338, a coding variant in high linkage disequilibrium with the GWAS single-nucleotide polymorphisms (SNPs), encoding a nonsynonymous threonine to proline change (Thr16Pro) within the signal peptide of LAL, may impair LAL protein translocation from the endoplasmic reticulum resulting in proteosomal degradation and reduced LAL protein and activity [33∎∎].…”

“…These data are highly suggestive, but not yet definitive for rs1051338 being ‘the’ causal variant at the LIPA GWAS locus [34]. First, this study did not address the published and surprising eQTL data of higher LIPA mRNA levels in risk allele carriers if the rs1051338 coding variant is indeed causal for CHD and associated with lower LAL activity; second, a relative small sample size in this study may not provide sufficient statistical evidence for the detection of the modest effects as expected for a common variant associated with complex trait.…”

“…First, this study did not address the published and surprising eQTL data of higher LIPA mRNA levels in risk allele carriers if the rs1051338 coding variant is indeed causal for CHD and associated with lower LAL activity; second, a relative small sample size in this study may not provide sufficient statistical evidence for the detection of the modest effects as expected for a common variant associated with complex trait. Last, the data also do not address other linked SNP at the LIPA locus, including those noncoding SNPs of similar allele frequency yet showing stronger association with increased risk of CHD and also with higher mRNA expression in eQTL studies [34].…”