Association of the Lipoprotein Receptor <i>SCARB1</i> Common Missense Variant rs4238001 with Incident Coronary Heart Disease

<div><p>Background</p><p>Previous studies in mice and humans have implicated the lipoprotein receptor <i>SCARB1</i> in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of <i>SCARB1</i> missense single nucleotide polymorphism (SNP) rs4238001 with incident coronary heart disease (CHD).</p><p>Methods and Results</p><p>Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR]=1.49, 95% CI [1.04, 2.14], <i>P</i> = 0.028). Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events) and African Americans (total n = 5,962 with 355 CHD events) and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], <i>P</i> = 0.013), in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], <i>P</i> = 0.019), in males (HR of 1.29 with 95% CI [1.08, 1.54], <i>P</i> = 4.91x10^-3) and in White males (HR of 1.24 with 95% CI [1.03, 1.51], <i>P</i> = 0.026).</p><p>Conclusion</p><p><i>SCARB1</i> missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.</p></div

Characteristics of MESA participants across three ethnic groups.

<p>Data are presented as N (%) for binary measures or median [IQR] for continuous measure.</p><p>*Summary statistics are reported for the subset of individuals with data available for at least one of the clinical events.</p><p>†P-values are presented for statistical significance of the difference in values across race/ethnic groups according to a likelihood ratio test with 2 degrees of freedom.</p><p>Characteristics of MESA participants across three ethnic groups.</p

Effect estimates (log hazard ratio of CHD for rs4238001 effect allele T) and corresponding 95% confidence intervals shown for Model 1 (basic), Model 2 (extended), Model 3 (Model 2 + lipid medication) and Model 4 (NMR lipids).

<p>Analyses were conducted stratified by race/ethnic group and combined by meta- analysis, for all participants as well as stratified by sex (males or female).</p

Summary of genetic additive effects of rs4238001 allele T on HDL-C (log mg/dL), HDL particle number (nmol/L) and HDL particle size (log nm) under a basic model (Model 1).

<p>Analyses were conducted stratified by race/ethnic group and combined by meta-analysis, for all participants as well as stratified by sex (males or female).</p

Summary of estimated genetic additive effects of rs4238001 allele T on LDL-C (mg/dL), LDL particle number (nmol/L) and LDL particle size (log nm) under a basic regression model (Model 1).

<p>Analyses were conducted stratified by race/ethnic group and combined by meta-analysis, for all participants as well as stratified by sex (males or female).</p

Sputum culture positive by week in MGIT system, N = 25.

<p>All patients (100%) culture positive from pretreatment sputum specimen.</p

Clinical characteristics, patients treated for pulmonary multidrug-resistant tuberculosis (MDR-TB), N = 25.

<p>^aAt MDR-TB treatment initiation.</p><p>Clinical characteristics, patients treated for pulmonary multidrug-resistant tuberculosis (MDR-TB), N = 25.</p

Predictors of favorable interim treatment outcome using exact logistic regression.

<p>^aGreater change in time-to-positivity (TTP) reflects greater decrement in sputum bacterial burden.</p><p>Predictors of favorable interim treatment outcome using exact logistic regression.</p

Change in plasma drug activity measured at the time of estimated peak concentration (2hr) after 2 and 4 weeks of treatment.

<p>TDA = Tuberculosis drug activity, where values greater than 1.0 indicate <i>in vitro</i> killing of a patient’s plasma against their own <i>M</i>. <i>tuberculosis</i> isolate. p = 0.005 by paired sample t-test.</p

Additional file 1: of Genome-wide association study of subclinical interstitial lung disease in MESA

Online Data Supplement for “Genome-wide association study of subclinical interstitial lung disease in MESA”. (DOCX 14799 kb