Diabetes Metab J.  2024 Sep;48(5):960-970. 10.4093/dmj.2023.0039.

Biologically Informed Polygenic Scores for Brain Insulin Receptor Network Are Associated with Cardiometabolic Risk Markers and Diabetes in Women

• Selenius JS
• Silveira PP
• Bonsdorff Mv
• Lahti J
• Koistinen H
• Koistinen R
• Seppälä M
• Eriksson JG
• Wasenius NS

• KMID: 2559005
• DOI: http://doi.org/10.4093/dmj.2023.0039

Abstract

Background
To investigate associations between variations in the co-expression-based brain insulin receptor polygenic score and cardiometabolic risk factors and diabetes mellitus.
Methods
This cross-sectional study included 1,573 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Cardiometabolic markers included body composition, waist circumference, circulating lipids, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 1 and 3 (IGFBP-1 and -3). Glucose and insulin levels were measured during a standardized 2-hour 75 g oral glucose tolerance test and impaired glucose regulation status was defined by the World Health Organization 2019 criteria. Analyzes were adjusted for population stratification, age, smoking, alcohol consumption, socioeconomic status, chronic diseases, birth weight, and leisure-time physical activity.
Results
Multinomial logistic regression indicated that one standard deviation increase in hePRS-IR was associated with increased risk of diabetes mellitus in all participants (adjusted relative risk ratio, 1.17; 95% confidence interval, 1.01 to 1.35). In women, higher hePRS-IR was associated with greater waist circumference and higher body fat percentage, levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, insulin, and IGFBP-1 (all P≤0.02). The mePRS-IR was associated with decreased IGF-1 level in women (P=0.02). No associations were detected in men and studied outcomes.
Conclusion
hePRS-IR is associated with sex-specific differences in cardiometabolic risk factor profiles including impaired glucose regulation, abnormal metabolic markers, and unfavorable body composition in women.

Keyword

Cardiometabolic risk factors; Diabetes mellitus; Lipid metabolism

Figure

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  Fig. 1. Relative risk ratios of the (A) polygenic risk score for the hippocampal-insulin receptor (hePRS-IR) and (B) polygenic risk score for the mesocorticolimbic-insulin receptor (mePRS-IR) and glucose regulation status in all participants, men and women. Analyses are adjusted for age, population stratification, smoking, alcohol consumtion, socioeconomic status, presence of chronic diseases, birth weight, and leisure-time physical activity. RRR, relative risk ratio; CI, confidence interval.

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