High density lipoprotein cholesterol (HDL-C) levels are thought to protect against cardiovascular disease. This may or may not be true in certain populations. The Rodriguez-Oquendo lab is studying the genetic link between healthy HDL cholesterol, heart disease, and infertility in women. This work suggests that variations within the SCARB1 (scavenger receptor class B type I) gene, connected to increased HDL levels, are associated with heart disease risk as well as hormonal and fertility problems in women. The goal of the research discoveries is the development of methods to diagnose and, ultimately, treat heart disease and improve a woman’s ability to conceive.
Project 1: Determine the causal pathway of the SCARB1 rs10846744 variant to cardiovascular disease
We previously reported a statistically significant association of SCARB1 intronic single nucleotide polymorphism (SNP) rs10846744 with common carotid intimal-medial artery thickness in each of the 4 Multi-Ethnic Study of Atherosclerosis racial/ethnic groups (white, Chinese, black, and Hispanic).
Methods and Results
Using an expanded sample of 7936 Multi-Ethnic Study of Atherosclerosis participants, phenotyped for measures of subclinical atherosclerosis, incident myocardial infarction, and cardiovascular disease, and genotyped through the SNP Health Association Resource project, we have now examined the genetic association of these phenotypes with 126 genotyped and imputed SCARB1 SNPs. We also performed stratified analyses to examine whether SCARB1 SNP effects differed by sex. Our analysis of the full Multi-Ethnic Study of Atherosclerosis cohort provides strong evidence for the association of rs10846744 with common carotid intimal-medial thickness (P=1.04E-4 in combined analysis of all 4 Multi-Ethnic Study of Atherosclerosis racial/ethnic groups). In sex-stratified analysis, we observed statistically significant association of rs10846744 with incident cardiovascular disease events in males (P=0.01). Examining analytical results from the Myocardial Infarction Genetics Consortium for replication, we observed further support for the association of rs10846744 with myocardial infarction.
The SCARB1 SNP, rs10846744, exerts a major effect on subclinical atherosclerosis and incident cardiovascular disease in humans.
Project 2: Determine the mechanisms of the SCARB1 gene polymorphisms on human female fertility
The goal of this study was to evaluate the association of SCARB1 single nucleotide polymorphisms (SNPs) and fertility outcomes in women undergoing IVF.
Between November 2007 and March 2010, granulosa cells and follicular fluid were collected from women undergoing IVF. Five SCARB1 SNPs were sequenced and progesterone levels were measured in the follicular fluid. Fertility measurements were defined as the presence of gestational sac(s) and fetal heartbeat(s).
The study group consisted of 274 women (mean age of 36.4 ± 4.6 years). The racial/ethnic composition was 55% Caucasian (n = 152), 25% African-American (n = 68), 12% Asian (n = 34), 5% Hispanic, (n = 14) and 2% other (n = 6). There was a significant difference in the genotype frequencies of the SCARB1 SNPs across the groups. Subjects who were homozygous for the minor allele in the rs5888 SNP had higher follicular progesterone levels than those who were homozygous for the major allele (P = 0.03). In the Caucasian group, carriers of the minor A allele of the rs4238001 SNP had lower follicular progesterone levels compared with homozygous carriers of the major G allele (P = 0.04). In this group, follicular progesterone levels were highly predictive of the rs4238001 SNP (P = 0.03). In the entire cohort, minor allele carriers of rs4238001 did not have any viable fetuses at Day 42 following embryo transfers (P = 0.04). In the African-American group in particular, there was also an association between rs10846744 and gestational sac(s) (P = 0.006), and fetal heartbeat(s) (P = 0.005).
In part, SCARB1 rs4238001 and rs10846744 SNPs may contribute to human female infertility.