Abstract 1340: Heterozygosity for a Mutation in the Extracellular Domain of SR-BI is Associated With High HDL Cholesterol Levels in a Family of Caucasian Descent
Background: Scavenger receptor class B type I (SR-BI) is a hepatic receptor for high-density lipoprotein (HDL). Although SR-BI knockout mice exhibit very high HDL cholesterol levels, the relevance of SR-BI for human HDL metabolism is not clear. The objective of this study was to address whether defects in SR-BI can underlie elevated HDL cholesterol levels in man.
Methods and results: The coding regions and intron-exon boundaries of the SR-BI gene were sequenced in 90 unrelated subjects with hyperalphalipoproteinemia (defined as plasma HDL cholesterol levels > 95th percentile for age and gender). In one index patient we identified heterozygosity for a point mutation resulting in the substitution of a proline for a serine residue at position 297 (P297S) in the extracellular domain of SR-BI. Of note, a proline residue at this position is highly conserved amongst vertebrates. A further 96 members of this patient’s family were recruited and genotyped. We carried out quantitative trait locus analyses with all heterozygous P297S carriers (n=14) and unaffected family members (n=83). Adjusted for kinship, the estimated allelic effect of P297S on HDL cholesterol levels was +0.4486 ± 0.116 mmol/L (p=0.00011). With additional adjustment for gender, age, body mass index, smoking habits and alcohol use, this association remained highly significant (allelic effect +0.3238 ± 0.109 mmol/L; p=0.0034). Furthermore, we compared the P297S carriers to 25 family controls, matched for age and gender. Carriers showed 37% increased HDL cholesterol levels (p=0.003) and a 17% increase in apolipoprotein A-1 (apoAI) levels (p=0.042) in absence of significant effects on total cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein B and apolipoprotein E levels.
Conclusion: In contrast to known deficiencies for apoAI, LCAT, ABCAI, and CETP, human SR-BI deficiency has thus far not been identified. Yet, this study suggests that SR-BI may be equally important in controlling HDL cholesterol levels in humans. Since we have not yet established the functionality of P297S, we have recently initiated further in vivo and in vitro studies which we hope to present in the near future.