β-glucocerebrosidase gene locus as a link for Gaucher's disease and familial hypo-α-lipoproteinaemia

Background Gaucher's disease is the most common lysosomal storage disorder, caused by deficiency of glucocerebrosidase resulting from homozygosity for any of several mutations of the glucocerebrosidase gene locus. Affected people have decreased concentrations of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). We assessed the association between mutations in the glucocerebrosidase locus and hypo-α-lipoproteinaemia. Methods We studied 258 people from 43 unrelated Spanish families. 57 participants were affected, 137 were nonaffected carriers, and 64 were non-carriers. We determined glucocerebrosidase genotypes and measured plasmid lipids, apolipoproteins A-I, B, and E, and leucocyte glucocerebrosidase activity. Findings The most common glucocerebrosidase mutations were N370S (45%), L444P (23%), and G377S (5%). Deletions and recombinants accounted for another 5%, and point mutations in exons 5, 6, 9, and 10 were present in 12%. Affected participants had lower LDL-C and HDL-C concentrations than non-affected carriers (p<0·001) and non-carriers (p<0·001). HDL-C values were also significantly different between the non-affected carriers and non-carriers. Mutations at this locus may account for as much as 19·5% of the genetic variability in HDL-C in the population studied. Interpretation Heterozygosity for these mutations at the glucocerebrosidase locus does not result in clinical expression of Gaucher's disease but can decrease HDL-C concentrations. Given the high frequency of these mutations, the glucocerebrosidase locus might lead to familial low α-lipoproteinaemia in up to 2% of the general population and be one of the most common known genetic causes of HDL-C.