Allelic variation in the promoter region of the LDL receptor gene: analysis of an African-specific variant in the FP2 cis-acting regulatory element

DNA samples of 2303 individuals from nine different population groups were screened for variant −175g→t in the promoter region of the low-density lipoprotein receptor (LDLR) gene. The −175g→t variant detected at carrier frequencies of 3–10% in different African population groups was absent in the Caucasian and Asian (Chinese) individuals studied. In contrast to previous findings in Black South Africans where this polymorphism predominated in patients with familial hypercholesterolaemia (FH), it occurred at a significantly lower frequency in hypercholesterolaemics from the recently admixed Coloured population of South Africa compared with population-matched controls (P<0.0001). Haplotype and mutation analysis excluded the likelihood that this finding is due to association with a specific disease-related mutation in FH patients, although reversal of the positive association with FH observed in the Black population may, at least in part, be due to admixture linkage disequilibrium. Transient transfection studies in HepG2 cells demonstrated that the −175t allele is associated with a non-significant decrease (∼7%) of LDLR transcription in the absence of sterols. The data presented in this study raise the possibility that the −175g→t polymorphism may have subtle effects that become clinically important within certain genetic and/or environmental contexts.