Investigation of Genetic Variation in Scavenger Receptor Class B, Member 1 (SCARB1) and Association with Serum Carotenoids

Objective: To investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD).<br/>Design: A cross-sectional study of healthy adults aged 20 to 70.<br/>Participants: We recruited 302 participants after local advertisement.<br/>Methods: We measured MPOD by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by high-performance liquid chromatography and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and Carotenoids in Age-Related Eye Disease Study (CAREDS) cohorts.<br/>Main Outcome Measures: Odds ratios for MPOD area, serum L and Z concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and gender.<br/>Results: After multiple regression analysis with adjustment for age, body mass index, gender, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, smoking, and dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P = 0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P = 2×10-4), an SNP in high linkage disequilibrium with rs11057841 (r2 = 0.93). No interactions by gender were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses.<br/>Conclusions: Our study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of age-related macular degeneration risk through combating the effects of oxidative stress within the retina.<br/>Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references. Ophthalmology 2013;120:1632–1640 © 2013 by the American Academy of Ophthalmology.

Ranakinestatin-PPF from the Skin Secretion of the Fukien Gold-Striped Pond Frog, Pelophylax plancyi fukienensis: A Prototype of a Novel Class of Bradykinin Bb>2b> Receptor Antagonist Peptide from Ranid Frogs

The defensive skin secretions of many amphibians are a rich source of bradykinins and bradykinin-related peptides (BRPs). Members of this peptide group are also common components of reptile and arthropod venoms due to their multiple biological functions that include induction of pain, effects on many smooth muscle types, and lowering systemic blood pressure. While most BRPs are bradykinin receptor agonists, some have curiously been found to be exquisite antagonists, such as the maximakinin gene-related peptide, kinestatin—a specific bradykinin Bb>2b>-receptor antagonist from the skin of the giant fire-bellied toad, Bombina maxima. Here, we describe the identification, structural and functional characterization of a heptadecapeptide (DYTIRTRLHQGLSRKIV), named ranakinestatin-PPF, from the skin of the Chinese ranid frog, Pelophylax plancyi fukienensis, representing a prototype of a novel class of bradykinin Bb>2b>-receptor specific antagonist. Using a preconstricted preparation of rat tail arterial smooth muscle, a single dose of 10⁻⁶ M of the peptide effectively inhibited the dose-dependent relaxation effect of bradykinin between 10⁻¹¹ M and 10⁻⁵ M and subsequently, this effect was pharmacologically-characterized using specific bradykinin Bb>1b>- (desArg-HOE140) and Bb>2b>-receptor (HOE140) antagonists; the data from which demonstrated that the antagonism of the novel peptide was mediated through Bb>2b>-receptors. Ranakinestatin—PPF—thus represents a prototype of an amphibian skin peptide family that functions as a bradykinin Bb>2b>-receptor antagonist herein demonstrated using mammalian vascular smooth muscle.

A Rare Loss-of-Function Variant in Scavenger Receptor Class B Type I (SCARB1) Raises HDL Cholesterol and Increases Risk of Coronary Disease

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL)<br/>cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a<br/>lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI<br/>knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased<br/>atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains<br/>unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328<br/>individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function<br/>variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene<br/>encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and<br/>abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells<br/>derived from induced pluripotent stem cells from the homozygous subject, and in mice.<br/>Large population-based studies revealed that subjects who are heterozygous carriers of<br/>the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have<br/>a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is<br/>statistically significant).