ABSTRACT
Background
Breast cancer (BC) is a major global health concern. Although observational studies have reported an association between hypertension and BC risk, the causal nature of this relationship remains unclear.
Methods
We performed a univariate two-sample Mendelian randomization (MR) analysis to investigate the causal effect of genetically predicted hypertension on overall BC risk and its molecular subtypes. Summary-level genetic data for hypertension were obtained from the Africa Wits-INDEPTH Partnership for Genomic Research (AWI-Gen) study conducted in sub-Saharan Africa (n = 10,775). Single-nucleotide polymorphisms (SNPs) for exposure and outcome were harmonized before analysis. Causal estimates were primarily derived using the inverse-variance weighted (IVW) method with random effects, complemented by MR-Egger, weighted median, weighted mode, simple mode, and MR-robust adjusted profile score (RAPS) approaches. Sensitivity analyses assessed heterogeneity and horizontal pleiotropy, and reverse MR analyses evaluated potential causal effects of overall BC on hypertension. Additionally, colocalization analyses were conducted to determine whether hypertension- and BC-associated variants share common causal signals across genomic loci.
Results
After Bonferroni correction for multiple testing (p < 0.003), no statistically significant associations were observed between genetically predicted hypertension and overall BC or its molecular subtypes: overall BC (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 0.86–1.83, p = 0.23), estrogen receptor–positive BC (OR = 1.29, 95% CI: 0.81–2.06, p = 0.28), estrogen receptor–negative (ER−) BC (OR = 1.90, 95% CI: 1.06–3.41, p = 0.03), and triple-negative BC (OR = 1.98, 95% CI: 1.95–4.14, p = 0.07). The nominal association observed for ER− BC did not withstand correction for multiple testing. Colocalization analyses revealed generally low posterior probabilities for shared causal variants (PP.H4 < 0.5) across all BC subtypes. Findings were consistent across sensitivity analyses, and reverse MR provided no evidence of causality in the opposite direction.
Impact
This study represents the first MR and colocalization investigation of hypertension and BC risk in a sub-Saharan African population. Although no evidence of a direct genetic causal relationship was identified, the combined MR and colocalization findings suggest that previously reported associations may be driven by nongenetic metabolic or vascular mechanisms rather than shared inherited genetic determinants. Further studies in larger and more diverse populations are warranted to confirm these findings and explore underlying biological pathways.