Age-Adjusted Phenome-Wide Analysis Identifies Liver Enzymes and Lipid Markers Associated with Prevalent Breast Cancer in the Qatar Biobank

Abstract

Most evidence linking phenotypic traits to breast cancer risk derives from Western populations, leaving a critical gap for the Middle East and North Africa region, where breast cancer presents at younger ages and where demographic, metabolic, and lifestyle profiles differ substantially. To address this, we conducted an exploratory phenome-wide association analysis within the Qatar Biobank, systematically screening 93 demographic, anthropometric, biochemical, lifestyle, and medical history variables among 96 women with physician-confirmed breast cancer and 471 healthy controls. A three-stage filtering pipeline: i) Benjamini–Hochberg-corrected significance, ii) Cliff''s Delta effect sizes, and iii) crude odds ratios, reduced 42 initial associations to 18 candidates, which were then evaluated using age-adjusted logistic regression with confounding quantified by percentage change in log-transformed odds ratios. Age was the dominant correlate of breast cancer status (OR = 1.10 per year, 95% CI: 1.08–1.13), and its adjustment fundamentally reshaped the association landscape: metabolic and anthropometric markers including glycated haemoglobin, body mass index, and waist circumference lost significance entirely, with effect attenuations exceeding 100% and reversal of effect direction, revealing these associations as artefacts of the 20-year median age gap between groups. In contrast, alanine aminotransferase, aspartate aminotransferase, total cholesterol, and LDL cholesterol remained statistically significant after adjustment for age. Multivariable models indicated that these four markers correspond to two mutually independent associations, hepatic and lipid, neither explained by adiposity or glycaemic status. Because all measurements were taken at a single visit after diagnosis had already occurred in the case group, these differences cannot be assigned a temporal direction and may reflect the consequences of disease, its treatment, or selective survival rather than pre-diagnostic biology. They are reported as exploratory cross-sectional correlates of prevalent breast cancer status requiring replication in an incident-case cohort, not as risk factors.