rs10282088 (IGFBP1/IGFBP3): Blood Pressure Locus

Key takeaways

• rs10282088, near the IGFBP1 and IGFBP3 genes (proteins that bind and regulate insulin-like growth factors in the bloodstream), was identified as a novel blood pressure locus in a study of over 750,000 individuals.
• The variant shows horizontal pleiotropy, meaning it appears to influence both systolic and diastolic blood pressure through independent biological pathways rather than one trait causing the other.
• Including pleiotropic blood pressure variants from this study in a composite genetic risk score improved cardiovascular disease prediction by up to 2.01-fold.
• Replication was performed in a separate multiethnic cohort of nearly 320,000 participants from the Million Veteran Program.
• Specific effect sizes for this variant alone are not reported in the available evidence, and evidence at the single-locus level remains preliminary.

What the research says A genome-wide horizontal pleiotropy analysis of blood pressure traits drew on summary statistics from up to 757,601 European-ancestry individuals across the UK Biobank (UKB) and International Consortium for Blood Pressure (ICBP), with replication in 318,891 multiethnic participants from the Million Veteran Program (MVP). The variant was identified in this work; across the full analysis, 118 novel blood pressure horizontal pleiotropic variants spanning 18 novel loci were replicated in MVP, while an additional 219 novel signals were identified in a combined meta-analysis without further independent replication. A composite genetic risk score built from pleiotropic variants captured 1.11 to 3.26 times more heritability for blood pressure traits than standard polygenic scores, and increased Nagelkerke R-squared (a measure of variance explained by the score) for hypertension by 1.09-fold and for cardiovascular disease by 2.01-fold.

Reported associations

• Systolic blood pressure: This locus was identified as part of a set of novel horizontal pleiotropic blood pressure variants in a meta-analysis of up to 757,601 European-ancestry individuals from UKB-ICBP, with replication in MVP.
• Diastolic blood pressure: The analysis examined systolic and diastolic blood pressure jointly; variants captured under horizontal pleiotropy, including those at this region, appear to have independent effects on both traits rather than one trait mediating the other.
• Pulse pressure: Pulse pressure (defined as systolic minus diastolic blood pressure) was a third phenotype examined in the same discovery GWAS.
• Hypertension genetic risk score: A composite polygenic score built with pleiotropic blood pressure variants from this study increased Nagelkerke R-squared for hypertension by 1.09-fold compared to standard polygenic scores; the separate contribution of this locus to that improvement is not reported.
• Cardiovascular disease genetic risk score: The same composite score increased Nagelkerke R-squared for cardiovascular disease by 2.01-fold; the specific contribution of this locus alone is not separately reported.

Evidence quality The discovery analysis used a large sample (up to 757,601 European-ancestry individuals from UKB-ICBP), and independent replication was performed in 318,891 multiethnic participants from MVP. Within the overall study, 118 novel horizontal pleiotropic blood pressure variants were replicated; an additional 219 novel signals identified in a combined UKB-ICBP plus MVP meta-analysis did not have a further independent replication step. The available evidence does not specify whether rs10282088 falls into the replicated subset or the non-independently-replicated subset. No individual-level effect sizes (beta coefficients or odds ratios) are reported for the variant alone. The analysis focuses on a methodologically specific subset of blood pressure genetics (horizontal pleiotropy), and this locus has not been assessed in dedicated follow-up studies. Evidence for this individual locus is therefore preliminary.

Lifestyle considerations No lifestyle considerations on file for this variant.