Large-Scale Gene-Smoking Interactions and Fine Mapping Study Identifies Multiple Novel Blood Pressure Loci in over 1...

Area of Science:

• Genetics
• Cardiovascular Disease
• Environmental Health

Background:

• Cigarette smoking is a significant factor affecting blood pressure (BP).
• Understanding gene-smoking interactions is crucial for identifying novel genetic loci and biological pathways involved in BP regulation.
• Previous research has explored genetic influences on BP, but gene-environment interactions, particularly with smoking, require further investigation.

Purpose of the Study:

• To conduct a large-scale genome-wide association meta-analysis to identify genetic variants associated with BP, considering interactions with smoking.
• To explore how smoking status, intensity (cigarettes per day), and duration (pack years) modify the genetic effects on BP.
• To develop and apply a novel fine-mapping method (SuSiEgxe) to prioritize causal variants and uncover biological pathways for smoking-associated BP regulation.

Main Methods:

• Genome-wide association meta-analysis of systolic BP, diastolic BP, and pulse pressure in over 1.18 million individuals across five ancestry groups.
• Analysis of interactions between genetic variants and smoking exposures (smoking status, cigarettes per day, pack years).
• Development and application of SuSiEgxe, a fine-mapping tool utilizing gene-environment interaction summary statistics.

Main Results:

• Identified twelve novel loci for BP at genome-wide significance (P < 5 × 10^-9).
• Highlighted biological processes including tight junction integrity, mitochondrial health, vascular relaxation, and endothelial function.
• Discovered that smoking modifies the genetic effects of six variants on BP, with fine-mapped loci implicating immune-related pathways.

Conclusions:

• This study significantly expands the understanding of genetic loci influencing BP and their interaction with smoking.
• The findings provide novel insights into the biological mechanisms underlying smoking-associated BP regulation, particularly highlighting immune-related pathways.
• The developed SuSiEgxe method offers a valuable tool for future gene-environment interaction studies.