rs11603023 (PHLDB1): Blood Lipid Levels Variant

Key takeaways

• This variant falls within one of 157 genetic locations linked to blood lipid levels identified in a study of nearly 190,000 individuals
• Lipid-associated loci like this one often overlap with associations for coronary artery disease, type 2 diabetes, blood pressure, and body mass index
• The alternative allele at rs11603023 reduces expression of nearby unannotated genes in whole blood, adipose (fat) tissue, and lung tissue
• The alternative allele increases PHLDB1 expression in cerebellar brain tissue and TREHP1 expression in pancreas and testis

What the research says A meta-analysis (a study pooling results across many cohorts) of 188,578 individuals identified 157 genomic loci associated with blood lipid levels, including low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol, at genome-wide significance (P < 5 x 10^-8); rs11603023, located near PHLDB1, falls within one of these identified loci. The study found that loci associated with blood lipids are often co-associated with cardiometabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. GTEx v11 eQTL (expression quantitative trait locus, a measure of how a genetic variant correlates with nearby gene activity) data from 953 donors shows the alternative allele at this position is associated with reduced expression of nearby unannotated genes across blood, fat, and lung, and with increased PHLDB1 expression in cerebellar brain tissue GTEx Portal.

Reported associations

• Blood lipids (LDL cholesterol, HDL cholesterol, triglycerides, total cholesterol): rs11603023 falls within one of 157 loci identified at P < 5 x 10^-8 across 188,578 individuals; the 62 newly identified loci as a group explained 1.6% of HDL variance, 2.1% of triglyceride variance, 2.4% of LDL variance, and 2.6% of total cholesterol variance in the Framingham offspring cohort
• Cardiometabolic and metabolic traits: The same study reports that blood lipid loci frequently co-associate with coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index

Evidence quality The primary association evidence comes from a meta-analysis of 188,578 individuals of primarily European ancestry, supplemented with data from East Asian, South Asian, and African ancestry cohorts, using both GWAS arrays and the Metabochip custom genotyping array. All reported associations meet the genome-wide significance threshold of P < 5 x 10^-8. The study notes that newly identified loci had generally smaller effect sizes than loci found in earlier GWAS. Variance explained figures (1.6% to 2.6%) describe the group of 62 newly identified loci collectively, not this locus individually, so the specific contribution of rs11603023 to lipid trait variance cannot be determined from the available source. No conflicting findings for this locus are reported in the provided study. The GTEx eQTL data are from GTEx v11 (953 donors) and represent statistically significant tissue-specific expression associations at FDR < 0.05, reflecting correlation rather than established causation.

Tissue-specific expression effects

• ENSG00000255422 (an unannotated gene near the locus): The alternative allele is associated with reduced expression in whole blood, subcutaneous adipose tissue, lung, and visceral adipose tissue GTEx Portal
• TREHP1: The alternative allele is associated with increased expression in pancreas and testis GTEx Portal
• ENSG00000287238 (an unannotated gene near the locus): The alternative allele is associated with reduced expression in tibial nerve GTEx Portal
• PHLDB1: The alternative allele is associated with increased expression in cerebellar brain hemisphere GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.