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Obesity (Silver Spring, Md.) Dec 2023This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin...
OBJECTIVE
This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m ).
METHODS
Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms.
RESULTS
In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8).
CONCLUSIONS
Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity.
Topics: Adult; Humans; Body Mass Index; Finland; Longitudinal Studies; Obesity; Twins, Dizygotic; Twins, Monozygotic; Male; Female
PubMed: 37987187
DOI: 10.1002/oby.23906 -
MedRxiv : the Preprint Server For... Oct 2023Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of...
Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or "time controls" born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen's d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.
PubMed: 37961592
DOI: 10.1101/2023.10.23.23297381 -
International Journal of Molecular... Oct 2023The genetic and environmental determinants of serum propionylcarnitine concentrations (PC) remain largely unexplored. This study investigated the impact of genetic and...
Genetic and Lifestyle-Related Factors Influencing Serum Hyper-Propionylcarnitine Concentrations and Their Association with Metabolic Syndrome and Cardiovascular Disease Risk.
The genetic and environmental determinants of serum propionylcarnitine concentrations (PC) remain largely unexplored. This study investigated the impact of genetic and environmental factors on serum propionylcarnitine levels in middle-aged and elderly participants from the Ansan/Ansung cohort of the Korean Genome and Epidemiology Study. Our goal was to understand the role of PC on the risk of metabolic syndrome (MetS) leading to cardiovascular disease, particularly concerning branched-chain amino acid (BCAA) metabolism. We analyzed participants' demographic, lifestyle, and biochemical data with and without MetS. Serum metabolite concentrations, including carnitine, acylcarnitine, and amino acid concentrations, were measured, and the components of MetS were evaluated. Genetic variants associated with low and high PC were selected using genome-wide association studies after adjusting for MetS-related parameters. Further, genetic variants and lifestyle factors that interacted with the polygenic risk score (PRS) were analyzed. Participants with MetS were older and less educated, and their alcohol intake was higher than non-MetS participants. PC was significantly associated with the MetS risk and increased the serum levels of BCAAs and other amino acids. Higher PC positively correlated with MetS components, insulin resistance, and cardiovascular risk factors. Intake of calcium, sodium, and vitamin D were inversely associated with PC, but coffee consumption was positively linked to PC. Multiple C2 And Transmembrane Domain Containing-1 ()_rs4290997, Kinesin Family Member-7 ()_rs2350480, Coagulation Factor-II ()_rs2070850, Peroxisomal Biogenesis Factor-3 ()_rs223231, TBC1 Domain Family Member-22A ()_rs910543, and Phospholipase A2 Group-IV-C ()_rs7252136 interact with each other to have a threefold influence on PC. The PRS for the six-genetic variant model also interacted with age; the diet rich in beans, potato, and kimchi; and smoking status, influencing PC. In conclusion, elevated PC was associated with MetS and cardiovascular disease risk, suggesting their potential as disease biomarkers.
Topics: Middle Aged; Aged; Humans; Metabolic Syndrome; Genome-Wide Association Study; Cardiovascular Diseases; Risk Factors; Carnitine; Amino Acids; Life Style; Kinesins
PubMed: 37958793
DOI: 10.3390/ijms242115810 -
BMC Medicine Nov 2023Genetics play an important role in risk for cardiometabolic diseases-including type 2 diabetes, cardiovascular disease and obesity. Existing research has explored the...
BACKGROUND
Genetics play an important role in risk for cardiometabolic diseases-including type 2 diabetes, cardiovascular disease and obesity. Existing research has explored the clinical utility of genetic risk tools such as polygenic risk scores-and whether interventions communicating genetic risk information using these tools can impact on individuals' cognitive appraisals of disease risk and/or preventative health behaviours. Previous systematic reviews suggest mixed results. To expand current understanding and address knowledge gaps, we undertook an interpretive, reflexive method of evidence synthesis-questioning the theoretical basis behind current interventions that communicate genetic risk information and exploring how the effects of genetic risk tools can be fully harnessed for cardiometabolic diseases.
METHODS
We obtained 189 records from a combination of database, website and grey literature searches-supplemented with reference chaining and expert subject knowledge within the review team. Using pre-defined critical interpretive synthesis methods, quantitative and qualitative evidence was synthesised and critiqued alongside theoretical understanding from surrounding fields of behavioural and social sciences.
FINDINGS
Existing interventions communicating genetic risk information focus predominantly on the "self", targeting individual-level cognitive appraisals, such as perceived risk and perceived behavioural control. This approach risks neglecting the role of contextual factors and upstream determinants that can reinforce individuals' interpretations of risk. It also assumes target populations to embody an "ascetic subject of compliance"-the idea of a patient who strives to comply diligently with professional medical advice, logically and rationally adopting any recommended lifestyle changes. We developed a synthesising argument-"beyond the ascetic subject of compliance"-grounded in three major limitations of this perspective: (1) difficulty applying existing theories/models to diverse populations, (2) the role of familial variables and (3) the need for a life course perspective.
CONCLUSIONS
Interventions communicating genetic risk information should account for wider influences that can affect individuals' responses to risk at different levels-including through interactions with their family systems, socio-cultural environments and wider health provision.
PROTOCOL REGISTRATION
PROSPERO CRD42021289269.
Topics: Humans; Diabetes Mellitus, Type 2; Risk Factors; Communication; Patient Compliance; Life Style
PubMed: 37953248
DOI: 10.1186/s12916-023-03150-9 -
BMC Medical Genomics Nov 2023Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic...
BACKGROUND
Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic variation captured in a polygenic risk score (PRS). In young adulthood, the 22q11.2 microdeletion conveys a 2-fold increased risk for mild-moderate hypertriglyceridemia. This study aimed to assess the role of the TG-PRS in individuals with this elevated baseline risk for mild-moderate hypertriglyceridemia.
METHODS
We studied a deeply phenotyped cohort of adults (n = 157, median age 34 years) with a 22q11.2 microdeletion and available genome sequencing, lipid level, and other clinical data. The association between a previously developed TG-PRS and TG levels was assessed using a multivariable regression model adjusting for effects of sex, BMI, and other covariates. We also constructed receiver operating characteristic (ROC) curves using logistic regression models to assess the ability of TG-PRS and significant clinical variables to predict mild-moderate hypertriglyceridemia status.
RESULTS
The TG-PRS was a significant predictor of TG-levels (p = 1.52E-04), along with male sex and BMI, in a multivariable model (p = 7.26E-05). The effect of TG-PRS appeared to be slightly stronger in individuals with obesity (BMI ≥ 30) (beta = 0.4617) than without (beta = 0.1778), in a model unadjusted for other covariates (p-interaction = 0.045). Among ROC curves constructed, the inclusion of TG-PRS, sex, and BMI as predictor variables produced the greatest area under the curve (0.749) for classifying those with mild-moderate hypertriglyceridemia, achieving an optimal sensitivity and specificity of 0.746 and 0.707, respectively.
CONCLUSIONS
These results demonstrate that in addition to significant effects of sex and BMI, genome-wide common variation captured in a PRS also contributes to the variable expression of the 22q11.2 microdeletion with respect to elevated TG levels.
Topics: Adult; Humans; Male; Young Adult; Risk Factors; Obesity; Cardiovascular Diseases; Hypertriglyceridemia; Triglycerides; Genome-Wide Association Study
PubMed: 37940981
DOI: 10.1186/s12920-023-01717-2 -
Frontiers in Nutrition 2023Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants...
INTRODUCTION
Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact with lifestyle factors was examined in 58,701 middle-aged Korean adults who participated in the Korean Genome and Epidemiology Study (KoGES).
METHODS
Participants were categorized into the Low-HDL (case; = 16,980) and Normal-HDL ( = 41,721) groups. The participants in the Low-HDL group were selected using the guideline-based cutoffs for hypo-HDL-C (<40 mg/dL for men and < 50 mg/dL for women) and included those taking medication for dyslipidemia. The genes associated with hypo-HDL-C were determined through a genome-wide association study (GWAS) in a city hospital-based cohort, and the results were validated in the Ansan/Anung study. The genetic variants for the single nucleotide polymorphism (SNP)-SNP interaction were selected using a generalized multifactor dimensionality reduction analysis, and the polygenic risk score (PRS) generated was evaluated for interaction with lifestyle parameters.
RESULTS
The participants with hypo-HDL-C showed a 1.45 and 1.36-fold higher association with myocardial infarction and stroke, respectively. The High-PRS with four SNPs, namely _rs3741297, _rs708272, _rs180327, and _rs588136, and that with the 11q23.3 haplotype were positively associated with hypo-HDL-C by about 3 times, which was a 2.4-fold higher association than the PRS of 24 SNP with < 5×10. The risk alleles of _rs708272 and _rs588136 were linked to increased expression in the heart and decreased in the brain, respectively. The selected SNPs were linked to the reverse cholesterol transport pathway, triglyceride-rich lipoprotein particle remodeling pathway, cholesterol storage, and macrophage-derived foam cell differentiation regulation. The PRS of the 4-SNP model interacted with energy intake and smoking status, while that of the haplotype interacted with a glycemic index of the diet, sulfur microbial diet, and smoking status.
DISCUSSION
Adults with a genetic risk for hypo-HDL-C need to modulate their diet and smoking status to reduce their risk.
PubMed: 37860035
DOI: 10.3389/fnut.2023.1244185 -
Current Obesity Reports Dec 2023Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review... (Review)
Review
PURPOSE OF REVIEW
Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review highlights current research and its challenges in genetics and epigenetics of obesity.
RECENT FINDINGS
Recent progress in genetics of polygenic traits, particularly represented by genome-wide association studies, led to the discovery of hundreds of genetic variants associated with obesity, which allows constructing polygenic risk scores (PGS). In addition, epigenome-wide association studies helped identifying novel targets and methylation sites being important in the pathophysiology of obesity and which are essential for the generation of methylation risk scores (MRS). Despite their great potential for predicting the individual risk for obesity, the use of PGS and MRS remains challenging. Future research will likely discover more loci being involved in obesity, which will contribute to better understanding of the complex etiology of human obesity. The ultimate goal from a clinical perspective will be generating highly robust and accurate prediction scores allowing clinicians to predict obesity as well as individual responses to body weight loss-specific life-style interventions.
Topics: Humans; DNA Methylation; Genome-Wide Association Study; Epigenesis, Genetic; Obesity; Phenotype; Genetic Risk Score
PubMed: 37819541
DOI: 10.1007/s13679-023-00526-z -
MedRxiv : the Preprint Server For... Sep 2023We assessed whether adding early life exposures to a model based on polygenic risk score (PRS) improves prediction of obesity risk. We used a birth cohort with data at...
We assessed whether adding early life exposures to a model based on polygenic risk score (PRS) improves prediction of obesity risk. We used a birth cohort with data at birth and BMI and waist circumference (WC) measured at age 32. The PRS was composed of SNPs identified in GWAS for BMI. Linear and logistic models were used to explore associations with obesity-related phenotypes. Improvement in prediction was assessed using measures of model discrimination (AUC), and net reclassification improvement (NRI). One SD change in PRS was associated with a significant increase in BMI and WC. These associations were slightly attenuated (13.7%-14.2%) with the addition of early life exposures to the model. Also, higher maternal pre-pregnancy BMI was associated with increase in offspring BMI and WC (p<0.001). For prediction obesity (BMI ≥ 30), the addition of early life exposures to the PRS model significantly increase the AUC from 0.69 to 0.73. At an obesity risk threshold of 15%, the addition of early life exposures to the PRS model provided a significant improvement in reclassification of obesity (NRI, 0.147; 95% CI 0.068-0.225). We conclude that inclusion of early life exposures to a model based on PRS improves obesity risk prediction in an Israeli population-sample.
PubMed: 37732179
DOI: 10.1101/2023.09.05.23295076 -
The Journal of Clinical Endocrinology... Jan 2024Polycystic ovary syndrome (PCOS) has historically been conceptualized as a disorder of the reproductive system in women. However, offspring of women with PCOS begin to...
CONTEXT
Polycystic ovary syndrome (PCOS) has historically been conceptualized as a disorder of the reproductive system in women. However, offspring of women with PCOS begin to show metabolic features of PCOS in childhood, suggestive of childhood manifestations.
OBJECTIVE
To identify childhood manifestations of genetic risk for PCOS.
METHODS
We calculated a PCOS polygenic risk score (PRS) for 12 350 girls and boys in 4 pediatric cohorts-ALSPAC (UK), COPSAC (Denmark), Project Viva (USA), and The HOLBÆK Study (Denmark). We tested for association of the PRS with PCOS-related phenotypes throughout childhood and with age at pubarche and age at peak height velocity and meta-analyzed effects across cohorts using fixed-effect models.
RESULTS
Higher PRS for PCOS was associated with higher body mass index in midchildhood (0.05 kg/m2 increase per 1 SD of PRS, 95% CI 0.03, 0.07, P = 3 × 10-5) and higher risk of obesity in early childhood (OR 1.34, 95% CI 1.13, 1.59, P = .0009); both persisted through late adolescence (P all ≤.03). Higher PCOS PRS was associated with earlier age at pubarche (0.85-month decrease per 1 SD of PRS, 95% CI -1.44, -0.26, P = .005) and younger age at peak height velocity (0.64-month decrease per 1 SD of PRS, 95% CI -0.94, -0.33, P = 4 × 10-5).
CONCLUSION
Genetic risk factors for PCOS are associated with alterations in metabolic, growth, and developmental traits in childhood. Thus, PCOS may not simply be a condition that affects women of reproductive age but, rather, a possible manifestation of an underlying condition that affects both sexes starting in early life.
Topics: Child, Preschool; Male; Adolescent; Humans; Female; Child; Polycystic Ovary Syndrome; Risk Factors; Obesity; Body Mass Index; Genetic Predisposition to Disease; Genetic Risk Score
PubMed: 37690116
DOI: 10.1210/clinem/dgad533 -
Nutrients Sep 2023Hypothyroidism is a prevalent endocrine disorder and is associated with a variety of metabolic disturbances. This study aimed to investigate the polygenic variants...
Hypothyroidism is a prevalent endocrine disorder and is associated with a variety of metabolic disturbances. This study aimed to investigate the polygenic variants associated with hypothyroidism risk and the interaction of polygenic risk scores (PRS) with dietary patterns in influencing disease risk in 56,664 participants aged >40 in a hospital-based cohort. The participants were classified as having hypothyroidism (n = 870) diagnosed by a physician and no hypothyroidism (n = 55,794). Genetic variants associated with hypothyroidism were identified using a genome-wide association study (GWAS). Genetic variants interacting with each other were selected using a generalized multifactor dimensionality reduction analysis, and the PRS generated was evaluated for interaction with lifestyle parameters. Coffee, alcohol, meat intake, and a Korean balanced diet were inversely associated with hypothyroidism risk, as were selenium, copper, and manganese intakes. White blood cell (WBC) counts and serum alkaline phosphatase and triglyceride concentrations were positively associated with hypothyroidism risk, as were osteoporosis and thyroid cancer. The GMDR analysis generated a three-single nucleotide polymorphism (SNP) model comprising dual oxidase-1 ()_rs1648314; thyroid-stimulating hormone receptor ()_rs75664963; and major histocompatibility complex, class-II, DQ Alpha-1 ()_rs17426593. The PRS derived from the three- and seven-SNP models were associated with a 2.11- and 2.32-fold increase in hypothyroidism risk, respectively. Furthermore, the PRS from the three-SNP model showed interactions with WBC counts, wherein the positive association with hypothyroidism risk was more pronounced in participants with low WBC counts than those with high WBC counts (≥4 × 10 /L). Dietary patterns, such as the plant-based diet (PBD) and the Western-style diet (WSD), along with smoking status, exhibited interactions with the PRS, influencing hypothyroidism risk. In participants with a high PRS, those in the high-PBD, low-WSD, and smoker groups had a higher proportion of hypothyroidism than those in the low-PBD, high-WSD, and non-smoker groups. In conclusion, genetic variants related to immunity and thyroid hormone secretion were linked to hypothyroidism risk, and their PRS interacted with PBD and WSD intake and smoking status. These results contribute to a better understanding of hypothyroidism and its prevention strategies for precision medicine intervention.
Topics: Humans; Cohort Studies; Genome-Wide Association Study; Hypothyroidism; Life Style; Risk Factors
PubMed: 37686882
DOI: 10.3390/nu15173850