rs11789603 (ABCA1): HDL and Lipoprotein Variant

Key takeaways

• rs11789603 is a variant in the ABCA1 gene, a locus connected to HDL cholesterol and lipoprotein regulation in large-scale genetic studies
• Trans-ancestral metabolomic genome-wide studies across approximately 450,000 UK Biobank participants identified 29,824 locus-metabolite associations for 249 lipoprotein and small-molecule phenotypes
• HDL cholesterol is one of seven core components of metabolic syndrome, studied in populations of up to 4.9 million individuals
• Lipoprotein subclasses are linked to multiple conditions beyond cardiovascular disease, including age-related macular degeneration
• The provided source studies do not contain variant-specific association statistics or effect sizes for rs11789603

What the research says A trans-ancestral metabolomic genome-wide association study in approximately 450,000 UK Biobank participants identified 29,824 locus-metabolite associations mapping to 753 genomic regions for 249 phenotypes including 14 lipoprotein subclasses spanning extra-large VLDL to small HDL particles, with genetic effects largely consistent between men and women and across British White European (n = 434,646), British African (n = 6,573), and British Central/South Asian (n = 8,796) ancestries. The largest multivariate metabolic syndrome genome-wide analysis to date (observed n = 4,947,860 in European-ancestry populations) identified 1,307 associated genetic loci, estimated metabolic syndrome heritability at 0.10 to 0.30, and found individual component heritability ranging from 0.26 for type 2 diabetes to 0.61 for hypertension, with HDL cholesterol among the seven core components modeled. A three-tiered analysis of 72,376 UK Biobank donors identified 84 metabolic markers associated with age-related macular degeneration (AMD), of which lipoprotein subclasses comprised 39%, and found 19 metabolites including very small VLDL subclasses with likely causal roles in AMD pathology via Mendelian randomization.

Reported associations

• HDL cholesterol and lipoprotein subclasses: Trans-ancestral metabolomic GWAS in approximately 450,000 participants profiled 14 lipoprotein subclasses and associated characteristics; the Global Lipids Genetics Consortium separately identified 380 independent variants associated with HDL cholesterol in European-ancestry populations; genetic effects at these loci were largely consistent across major ancestral groups
• Metabolic syndrome: Multivariate MetS GWAS (observed n = 4,947,860) identified 1,307 associated loci enriched primarily in brain tissue; MetS heritability was estimated at 0.10 to 0.30, with HDL cholesterol among seven core metabolic components alongside BMI, waist circumference, type 2 diabetes, fasting glucose, hypertension, and triglycerides
• Age-related macular degeneration: Lipoprotein subclasses comprised 39% of 84 AMD-associated metabolic markers among 72,376 UK Biobank donors; among 19 metabolites with likely causal roles in AMD, depletion of circulating very small VLDL particles was proposed as a primary candidate mechanism
• Lipid-modifying therapy metabolomics: Drug-target Mendelian randomization in up to 115,082 UK Biobank participants showed that CETP inhibition (which raises HDL cholesterol) and statin therapy (which lowers LDL cholesterol) produced markedly different metabolomic signatures; triglyceride-targeting therapies strongly lowered glycoprotein acetyls (an inflammation marker) while LDL-targeting therapies had little effect on this marker
• Circulating fatty acids: GWAS of 19 fatty acid traits in up to 239,268 European-ancestry UK Biobank participants identified 215 independent loci for PUFA-related traits, 163 for MUFA-related traits, and 119 for SFA-related traits; 35% of these loci colocalized with molecular QTL signals for at least one of six molecular phenotypes examined

Evidence quality The source studies are large and methodologically rigorous. The metabolomic GWAS applied a stringent metabolome-adjusted genome-wide significance threshold (P < 2.0 x 10-10) and conducted trans-ancestral meta-analyses. The MetS GWAS used genomic structural equation modeling to capture shared genetic architecture across components, and the AMD study incorporated three-tiered Mendelian randomization to distinguish associative from likely causal metabolite effects. A study of sex differences in cardiometabolic traits conducted sex-specific GWAS in 161,906 females and 141,980 males in UK Biobank, finding sex differences in heritability for nearly half of traits examined and significant sex-differential SNP effects for 72.62% of traits. However, none of the provided study excerpts report specific association statistics, effect sizes, or p-values for rs11789603 itself. The associations listed above reflect findings from studies of lipoprotein and metabolic phenotypes broadly and do not constitute confirmed variant-level associations for this SNP. Direct evidence for rs11789603 is not available from the provided source material.

Lifestyle considerations No lifestyle considerations on file for this variant.