Hypertension is a major risk factor for cardiovascular and renal diseases. Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) linked to hypertension. Specifically, the rs17249754 polymorphism in the ATP2B1 gene is implicated in blood pressure (BP) regulation. The A allele is hypothesized to confer protection by influencing Ca2+ ion handling in vascular smooth muscle cells.This study analyzed the association between ATP2B1 rs17249754 and BP, focusing on interactions with smoking and alcohol consumption in a cohort.A total of 65,535 participants from the Genome and Epidemiology Study were included. Genotyping, quality control, phasing, and imputation were performed using standard protocols. The target polymorphism, ATP2B1 rs17249754, was extracted using PLINK. Linear regression evaluated the associations with systolic and diastolic BP, stratified by lifestyle factors and adjusted for covariates.Linear regression analyses, adjusted for covariates such as sex, age, BMI, and lifestyle factors, revealed that individuals with the AA genotype exhibited significantly lower systolic (SBP) and diastolic blood pressure (DBP) compared to GA or GG genotypes. Lifestyle factors strongly influenced these genetic effects. Among smokers, current smokers with the AA genotype showed SBP reduction compared to GA or GG genotypes. Similar associations were observed among non-drinkers and current drinkers.The ATP2B1 rs17249754 polymorphism regulates calcium homeostasis via PMCA1, reducing vascular smooth muscle contraction and BP. Smoking and alcohol consumption might disrupt calcium regulation and increase oxidative stress, which could exacerbate BP dysregulation, particularly in GA or GG genotypes. Smoking cessation and reduced alcohol intake may help mitigate these effects, possibly allowing the A allele to play a protective role.This study emphasizes the interplay between genetic and environmental factors in BP regulation, supporting the integration of genetic markers with lifestyle interventions for personalized hypertension management.