The brain insulin receptor gene network and associations with frailty index.

OBJECTIVE: To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in frailty across follow-up. METHODS: This longitudinal study included 1605 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network, which measure genetic variation in the function of the insulin receptor, were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Frailty was assessed in at baseline in 2001-2004, 2011-2013 and 2017-2018 by applying a deficit accumulation-based frailty index. Analyses were carried out by applying linear mixed models and logistical regression models adjusted for adult socioeconomic status, birthweight, smoking and their interactions with age. RESULTS: The FI levels of women were 1.19%-points (95% CI 0.12-2.26, P = 0.029) higher than in men. Both categorical and continuous hePRS-IR in women were associated with higher FI levels than in men at baseline (P < 0.05). In women with high hePRS-IR, the rate of change was steeper with increasing age compared to those with low or moderate hePRS-IR (P < 0.05). No associations were detected between mePRS-IR and frailty at baseline, nor between mePRS-IR and the increase in mean FI levels per year in either sex (P > 0.43). CONCLUSIONS: Higher variation in the function of the insulin receptor gene network in the hippocampus is associated with increasing frailty in women. This could potentially offer novel targets for future drug development aimed at frailty and ageing.

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

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.

The relationship between health-related quality of life and melancholic depressive symptoms is modified by brain insulin receptor gene network.

To investigate whether expression-based polygenic risk scores for the insulin receptor gene network (ePRS-IRs) modifiy the association between type of depressive symptoms and health-related quality of life (HRQoL). This cross-sectional study includes 1558 individuals from the Helsinki Birth Cohort Study. Between 2001 and 2004, the Short Form-36 questionnaire was employed to assess mental and physical components of HRQoL and Beck Depression Inventory (BDI) to assess depressive symptoms. Depressive symptoms were categorized into minimal (BDI < 10), non-melancholic and melancholic types of depression. The ePRS-IRs were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions of the brain. General linear regression models adjusted for age, sex, population stratification, lifestyle factors and body mass index were applied to analyze the data. Both types of depressive symptoms were associated with lower HRQoL (p < 0.0001). HePRS-IR modified the association between the types of depression and mental HRQoL (p for interaction = 0.005). Melancholic type of depressive symptoms was associated with higher mental HRQoL compared to the non-melancholic symptoms among individuals with low hePRS-IR (adjusted mean 4.1, 95% CI 0.7-7.4, p = 0.018). However, no such difference was evident in moderate or high hePRS-IR groups as higher hePRS-IR was associated with lower mental HRQoL (B = - 3.4, 95% CI - 5.6 to - 1.2) in individuals with melancholic type of depressive symptoms. No direct associations were detected between the ePRS-IRs and type of depressive symptoms or HRQoL. Variations in the glucose-insulin metabolism can lower HRQoL in individuals with melancholic depressive symptoms.

Impaired glucose regulation, depressive symptoms, and health-related quality of life.

INTRODUCTION: This study aims to investigate whether the associations between impaired glucose regulation and health-related quality of life are modified by severity or type of depressive symptoms. RESEARCH DESIGN AND METHODS: For this cross-sectional study, we included 1939 individuals (mean age 61.5 years) from the Helsinki Birth Cohort Study. Between 2001 and 2004, a standard 2-hour 75 g oral glucose tolerance test was applied to define normoglycemia, pre-diabetes, and newly diagnosed diabetes. Information on previously diagnosed diabetes was collected from national registers and questionnaires. Pre-diabetes was defined as having either impaired fasting glucose or impaired glucose tolerance. The Mental and Physical Component Scores of health-related quality of life were assessed with Short Form-36. Beck's Depression Inventory was employed to investigate the severity of depressive symptoms and to define minimal (depression score <10), non-melancholic, and melancholic types of depression. We analyzed data with general linear models adjusted for sex, age, lifestyle factors, comorbidities, and body mass index. RESULTS: Glucose regulation subgroups, especially previously known diabetes, were associated with lower Physical Component Score (p=0.001) and higher depression score (p=0.015), but not with the Mental Component Score (p=0.189). Non-melancholic depression was associated with lower Physical and Mental Component Scores compared with those with depression score <10 and melancholic depression (p<0.001), independently of glucose regulation status (p for glucose regulation status by depression type interaction >0.54). CONCLUSIONS: Non-melancholic type of depression and previously known diabetes are independently associated with lower health-related quality of life. This should be appraised in long-term treatment of diabetes and when treating non-melancholic depressive symptoms to maintain a higher health-related quality of life.

Unexpectedly High Prevalence of Common Variable Immunodeficiency in Finland.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. Prevalence varies greatly between countries and studies. Most diagnostic criteria include hypogammaglobulinemia and impaired vaccine response. AIM: To evaluate the minimum prevalence as well as the clinical and immunological phenotypes of CVID in Southern Finland. METHODS: We performed a cross-sectional study to assess all adult CVID patients followed up in three hospital districts in Southern and South-Eastern Finland between April 2007 and August 2015. CVID diagnosis was based, with a minor modification, on the ESID/PAGID criteria for primary CVID. Antipolysaccharide responses to Pneumovax® were defined as impaired only if 50% or more of the serotypes did not reach a level of 0.35 µg/mL after vaccination. We further characterized the patients' B cell phenotypes and complications associated with CVID. RESULTS: In total, 9 patients were excluded due to potential secondary causes before diagnosis. ESID/PAGID criteria were met by 132 patients (males 52%), of whom, 106 had "probable" and 26 "possible CVID." Based on the population statistics in the three hospital districts, the minimum adult prevalence per 100,000 inhabitants in Finland for all CVID ("probable CVID," respectively) patients was 6.9 (5.5). In the highest prevalence district (Helsinki and Uusimaa), the prevalence was 7.7 (6.1). CVID patients suffer from frequent complications. Ten patients died during follow-up. Of probable CVID patients, 73% had more than one clinical phenotype. Intriguingly, gradual B cell loss from peripheral blood during follow-up was seen in as many as 16% of "probable CVID" patients. Patients with possible CVID displayed somewhat milder clinical and laboratory phenotypes than probable CVID patients. We also confirm that large granular lymphocyte lymphoproliferation is a CVID-associated complication. CONCLUSION: The prevalence of CVID in Finland appears the highest recorded, likely reflecting the genetic isolation and potential founder effects in the Finnish population. Studies to discover potential gene variants responsible for the high prevalence in Finland thus seem warranted. Increased awareness of CVID among physicians would likely lead to earlier diagnosis and improved quality of care.