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Kidney International Reports May 2024Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite... (Review)
Review
Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity. This narrative review explores contributors to within-family discordance in ADPKD severity. Cases of biallelic and digenic inheritance, where 2 rare pathogenic variants in cystogenic genes are coexistent in one family, account for a small proportion of within-family discordance. Genetic background, including cis and trans factors and the polygenic propensity for comorbid disease, also plays a role but has not yet been exhaustively quantified. Environmental exposures, including diet; smoking; alcohol, salt, and protein intake, and comorbid diseases, including obesity, diabetes, hypertension, kidney stones, dyslipidemia, and additional coexistent kidney diseases all contribute to ADPKD phenotypic variability among family members. Given that many of the factors contributing to phenotype variability are preventable, modifiable, or treatable, health care providers and patients need to be aware of these factors and address them in the treatment of ADPKD.
PubMed: 38707833
DOI: 10.1016/j.ekir.2024.01.053 -
The American Journal of Gastroenterology May 2024Excess weight is an established risk factor of colorectal cancer (CRC). However, evidence is lacking on how its impact varies by polygenic risk at different stages of...
INTRODUCTION
Excess weight is an established risk factor of colorectal cancer (CRC). However, evidence is lacking on how its impact varies by polygenic risk at different stages of colorectal carcinogenesis.
METHODS
We assessed the individual and joint associations of body mass index (BMI) and polygenic risk scores (PRSs) with findings of colorectal neoplasms among 4,784 participants of screening colonoscopy. Adjusted odds ratios (aORs) for excess weight derived by multiple logistic regression were converted to genetic risk equivalents (GREs) to quantify the impact of excess weight compared with genetic predisposition.
RESULTS
Overweight and obesity (BMI 25-<30 and ≥30 kg/m 2 ) were associated with increased risk of any colorectal neoplasm (aOR [95% confidence interval, CI] 1.26 [1.09-1.45] and 1.47 [1.24-1.75]). Obesity was associated with increased risk of advanced colorectal neoplasm (aOR [95% CI] 1.46 [1.16-1.84]). Dose-response relationships were seen for the PRS (stronger for advanced neoplasms than any neoplasms), with no interaction with BMI, suggesting multiplicative effects of both factors. Obese participants with a PRS in the highest tertile had a 2.3-fold (95% CI 1.7-3.1) and 2.9-fold (95% CI 1.9-4.3) increased risk of any colorectal neoplasm and advanced colorectal neoplasm, respectively. The aOR of obesity translated into a GRE of 38, meaning that its impact was estimated to be equivalent to the risk caused by 38 percentiles higher PRS for colorectal neoplasm.
DISCUSSION
Excess weight and polygenic risk are associated with increased risk of colorectal neoplasms in a multiplicative manner. Maintaining normal weight is estimated to have an equivalent effect as having 38 percentiles lower PRS.
PubMed: 38704818
DOI: 10.14309/ajg.0000000000002853 -
The American Journal of Clinical... Jun 2024Interplay between lifestyle risk scores (LRSs) and genetic risk scores (GRSs) on obesity and related chronic diseases are underinvestigated and necessary for...
BACKGROUND
Interplay between lifestyle risk scores (LRSs) and genetic risk scores (GRSs) on obesity and related chronic diseases are underinvestigated and necessary for understanding obesity causes and developing prevention strategies.
OBJECTIVES
This study aimed to investigate independent and joint associations and interactions of LRS and GRS with obesity prevalence and risks of diabetes, cardiovascular disease (CVD), and obesity-related cancer.
METHODS
In this cohort study of 444,957 UK Biobank participants [age: 56.5 ± 8.1 y; BMI (in kg/m): 27.4 ± 4.7], LRS included physical activity, dietary score, sedentary behavior, sleep duration, and smoking (range: 0-20, each factor had 5 levels). GRS was calculated based on 941 genetic variants related to BMI. Both scores were categorized into quintiles. Obesity (n = 106,301) was defined as baseline BMI ≥30. Incident diabetes (n = 16,311), CVD (n = 18,076), and obesity-related cancer (n = 17,325) were ascertained through linkage to registries over a median of 12-y follow-up.
RESULTS
The LRS and GRS were independently positively associated with all outcomes. Additive interactions of LRS and GRS were observed for all outcomes (P < 0.021). Comparing the top with bottom LRS quintile, prevalence differences (95% CIs) for obesity were 17.8% (15.9%, 19.7%) in the top GRS quintile and 10.7% (8.3%, 13.1%) in the bottom GRS quintile; for diabetes, CVD, and obesity-related cancer, incidence rate differences associated with per SD increase in LRS were greater in the top than that in the bottom GRS quintile. Participants from top quintiles of both LRS and GRS had 6.16-fold, 3.81-fold, 1.56-fold, and 1.44-fold higher odds/risks of obesity, diabetes, CVD, and obesity-related cancer, respectively, than those from bottom quintiles of both scores.
CONCLUSIONS
Higher LRS was associated with higher obesity prevalence and risks of related chronic diseases regardless of GRS, highlighting the broad benefits of healthy lifestyles. Additive gene-lifestyle interactions emphasize the public health importance of lifestyle interventions among people with high genetic risks.
Topics: Humans; Obesity; United Kingdom; Middle Aged; Female; Prospective Studies; Male; Life Style; Chronic Disease; Biological Specimen Banks; Risk Factors; Cardiovascular Diseases; Genetic Predisposition to Disease; Cohort Studies; Aged; Neoplasms; Adult; Body Mass Index; Diabetes Mellitus; UK Biobank
PubMed: 38677521
DOI: 10.1016/j.ajcnut.2024.04.025 -
Calcified Tissue International Jun 2024Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from:...
Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/A) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/A stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/A mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300 mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/A mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to β-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in β-cell mass suggest that KK/A mice in this study are modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/A mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/A mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/A mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/A mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/A mice was likely due to overall bone quality being compromised.
Topics: Animals; Diabetes Mellitus, Type 2; Mice; Female; Disease Models, Animal; Male; Mutation; Obesity; Bone and Bones; Mice, Obese; Bone Density
PubMed: 38642089
DOI: 10.1007/s00223-024-01216-1 -
Nature Genetics May 2024We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl...
We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.
Topics: Humans; Liver Cirrhosis; Genome-Wide Association Study; Genetic Predisposition to Disease; Liver Neoplasms; Carcinoma, Hepatocellular; Alanine Transaminase; Polymorphism, Single Nucleotide; Male; Lipase; Female; gamma-Glutamyltransferase; Membrane Proteins; Cohort Studies; Case-Control Studies; Multifactorial Inheritance; Risk Factors; Genetic Variation
PubMed: 38632349
DOI: 10.1038/s41588-024-01720-y -
Journal of Endocrinological... Apr 2024Dyslipidemia plays a pivotal role in increasing cardiovascular risk. In clinical practice the misleading association between altered lipid profile and obesity is common,...
PURPOSE
Dyslipidemia plays a pivotal role in increasing cardiovascular risk. In clinical practice the misleading association between altered lipid profile and obesity is common, therefore genetically inherited dyslipidemias may not completely be addressed among patients with overweight. Thus, we aim to investigate the influence of overweight and obesity on the lipid phenotype in a cohort of patients with different forms of dyslipidemia.
METHODS
A retrospective analysis was conducted on patients with dyslipidemia from 2015 to 2022. Patients were stratified in familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), non-familial hyperlipidemia or polygenic hypercholesterolemia (PH). Clinical characteristics and lipid profile were evaluated.
RESULTS
Of the total of 798 patients, 361 were affected by non-familial hyperlipidemia (45.2%), while FCHL, FH and PH was described in 19.9%, 14.0% and 20.9% of patients, respectively. Overweight prevalence was higher in FCHL and non-familial hyperlipidemia patients than FH and PH patients. Subjects with overweight and obesity were independently associated with lower levels of high-density lipoprotein cholesterol (HDL-C) compared to patients with normal weight (52.4 and 46.0 vs 58.1, respectively; p < 0.0001); levels of triglycerides (TG) and non-HDL-C were higher in patients with overweight and obesity than patients with normal weight (257.3 and 290.9 vs 194.8, and 221.5 and 219.6 vs 210.1, p < 0.0001 and p = 0.01, respectively), while no differences were observed between patients with overweight and obesity.
CONCLUSION
While dyslipidemias can be influenced by various factors, an important determinant may lie in genetics, frequently acting as an underlying cause of altered lipid profiles, even in cases of overweight conditions.
PubMed: 38605186
DOI: 10.1007/s40618-024-02368-5 -
American Journal of Preventive... Jun 2024Triglycerides play a crucial role in the efficient storage of energy in the body. Mild and moderate hypertriglyceridemia (HTG) is a heterogeneous disorder with...
Triglycerides play a crucial role in the efficient storage of energy in the body. Mild and moderate hypertriglyceridemia (HTG) is a heterogeneous disorder with significant association with atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, ischemic stroke, and peripheral artery disease and represents an important component of the residual ASCVD risk in statin treated patients despite optimal low-density lipoprotein cholesterol reduction. Individuals with severe HTG (>1,000 mg/dL) rarely develop atherosclerosis but have an incremental incidence of acute pancreatitis with significant morbidity and mortality. HTG can occur from a combination of genetic (both mono and polygenic) and environmental factors including poor diet, low physical activity, obesity, medications, and diseases like insulin resistance and other endocrine pathologies. HTG represents a potential target for ASCVD risk and pancreatitis risk reduction, however data on ASCVD reduction by treating HTG is still lacking and HTG-associated acute pancreatitis occurs too rarely to effectively demonstrate treatment benefit. In this review, we address the key aspects of HTG pathophysiology and examine the mechanisms and background of current and emerging therapies in the management of HTG.
PubMed: 38584606
DOI: 10.1016/j.ajpc.2024.100648 -
Nature Genetics Apr 2024Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence...
Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.
Topics: Adult; Humans; Adaptor Proteins, Signal Transducing; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Induced Pluripotent Stem Cells; Liver Diseases; Nerve Tissue Proteins; Obesity; Proteomics
PubMed: 38575728
DOI: 10.1038/s41588-024-01694-x -
Psychological Medicine Apr 2024Attention-deficit hyperactivity disorder (ADHD) is often comorbid with other medical conditions in adult patients. However, ADHD is extremely underdiagnosed in adults...
Associations between attention-deficit hyperactivity disorder genetic liability and ICD-10 medical conditions in adults: utilizing electronic health records in a Phenome-Wide Association Study.
BACKGROUND
Attention-deficit hyperactivity disorder (ADHD) is often comorbid with other medical conditions in adult patients. However, ADHD is extremely underdiagnosed in adults and little is known about the medical comorbidities in undiagnosed adult individuals with high ADHD liability. In this study we investigated associations between ADHD genetic liability and electronic health record (EHR)-based ICD-10 diagnoses across all diagnostic categories, in individuals without ADHD diagnosis history.
METHODS
We used data from the Estonian Biobank cohort ( = 111 261) and generated polygenic risk scores (PRS) for ADHD (PRS) based on the ADHD genome-wide association study. We performed a phenome-wide association study (PheWAS) to test for associations between standardized PRS and 1515 EHR-based ICD-10 diagnoses in the full and sex-stratified sample. We compared the observed significant ICD-10 associations to associations with (1) ADHD diagnosis and (2) questionnaire-based high ADHD risk analyses.
RESULTS
After Bonferroni correction ( = 3.3 × 10) we identified 80 medical conditions associated with PRS. The strongest evidence was seen with chronic obstructive pulmonary disease (OR 1.15, CI 1.11-1.18), obesity (OR 1.13, CI 1.11-1.15), and type 2 diabetes (OR 1.11, CI 1.09-1.14). Sex-stratified analysis generally showed similar associations in males and females. Out of all identified associations, 40% and 78% were also observed using ADHD diagnosis or questionnaire-based ADHD, respectively, as the predictor.
CONCLUSIONS
Overall our findings indicate that ADHD genetic liability is associated with an increased risk of a substantial number of medical conditions in undiagnosed individuals. These results highlight the need for timely detection and improved management of ADHD symptoms in adults.
PubMed: 38563284
DOI: 10.1017/S0033291724000606 -
Journal of Clinical Medicine Feb 2024Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can... (Review)
Review
Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.
PubMed: 38546831
DOI: 10.3390/jcm13051347