Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in a middle-aged population with overweight and normal liver enzymes, and diagnostic accuracy of noninvasive proxies.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further testing. However, liver enzymes within the normal range do not exclude the presence of MASLD. We examined the prevalence of MASLD in a middle-aged population with overweight and normal liver enzymes. In addition, we examined the accuracy of 4 sets of noninvasive proxies for MASLD. We included 1017 participants from the Netherlands epidemiology of obesity cohort study with body mass index ≥25 kg/m2 and liver enzymes (asparate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase) within normal range. The diagnostic accuracy of biomarker scores (fatty liver index, liver fat score [LFS], STEATO-ELSA, and hepatic steatosis index) was determined against elevated hepatic triglyceride content measured by 1proton magnetic resonance spectroscopy. Participants (mean age 56 years, 49% women), had a median body mass index of 29.6 kg/m2 and a median hepatic triglyceride content of 4.4%. MASLD was present in 42% of participants and was more common in men than women, with respectively 47% and 36% being affected. The LFS showed the highest accuracy with an area under the curve of 0.72. We identified metabolic syndrome as the prime predictor for MASLD with an odds ratio of 2.95 (95% confidence interval 2.20-3.98). The prevalence of MASLD in middle-aged men and women with overweight and liver enzymes within the normal range is over 40%. LFS showed the highest accuracy to detect MASLD, but, overall, biomarker scores performed relatively poor. The presence of metabolic syndrome was the prime predictor of MASLD.

The association of plasma fatty acids with hand and knee osteoarthritis: the NEO study.

OBJECTIVE: To investigate the association of postprandial and fasting plasma saturated fatty acid (SFAs), monounsaturated fatty acid (MUFAs) and polyunsaturated fatty acid (PUFAs) concentrations with hand and knee osteoarthritis (OA). DESIGN: In the population-based NEO study clinical hand and knee OA were defined by the ACR classification criteria. Structural knee OA was defined on MRI. Hand and knee pain was determined by Australian/Canadian Hand Osteoarthritis Index (AUSCAN) and KOOS, respectively. Plasma was sampled fasted and 150 min after a standardized meal, and subsequently analysed using a nuclear magnetic resonance platform. Logistic regression analyses were used to investigate the association of total fatty acid, SFA, MUFA, total PUFA, omega-3 PUFA and omega-6 PUFA concentrations with clinical hand and knee OA, structural knee OA and hand and knee pain. Fatty acid concentrations were standardized (mean 0, SD 1). Analyses were stratified by sex and corrected for age, education, ethnicity and total body fat percentage. RESULTS: Of the 5,328 participants (mean age 56 years, 58% women) 7% was classified with hand OA, 10% with knee OA and 4% with concurrent hand and knee OA. In men, postprandial SFAs (OR (95% CI)) 1.23 (1.00; 1.50), total PUFAs 1.26 (1.00; 1.58) and omega-3 PUFAs 1.24 (1.01; 1.52) were associated with hand OA. SFAs and PUFAs were associated with structural, but not clinical knee OA. Association of fasting fatty acid concentrations were weaker than postprandial concentrations. CONCLUSION: Plasma postprandial SFA and PUFA levels were positively associated with clinical hand and structural knee OA in men, but not in women.

Avoiding selection bias in metabolomics studies: a tutorial.

BACKGROUND: Metabolomics techniques are increasingly applied in epidemiologic research. Many available assays are still relatively expensive and therefore measurements are often performed in small patient population studies such as case series or case-control designs with strong participant selection criteria. Subsequently, metabolomics data are frequently used to assess secondary associations for which the original study was not explicitly designed. Especially in these secondary analyses, there is a risk that the original selection criteria and the conditioning that takes place due to this selection are not properly accounted for which can lead to selection bias. AIM OF REVIEW: In this tutorial, we start with a brief theoretical introduction on the issue of selection bias. Subsequently, we demonstrate how selection bias can occur in metabolomics studies by means of an investigation into associations of metabolites with total body fat in a nested case-control study that was originally designed to study effects of elevated fasting glucose. KEY SCIENTIFIC CONCEPTS OF REVIEW: We demonstrate that standard analytical methods, such as stratification or adjustment in regression analyses, are not suited to deal with selection bias and may even induce the bias when analysing metabolite-phenotype relationships in selected groups. Finally, we show that inverse probability weighting, also known as survey weighting, can be used in some situations to make unbiased estimates of the outcomes.

Interrelationship of the rs7903146 TCF7L2 gene variant with measures of glucose metabolism and adiposity: The NEO study.

BACKGROUND AND AIMS: We investigated the interrelationship of rs7903146-T in TCF7L2 with measures of glucose metabolism and measures of adiposity. METHODS AND RESULTS: This cross-sectional analysis was conducted in 5744 middle-aged participants (mean (standard deviation [SD]) age is 55.9 (6.0) years) from the Netherlands Epidemiology of Obesity (NEO) Study. Associations between rs7903146-T and Type 2 diabetes mellitus (T2D) were assessed with logistic regression. Additive (per-allele) associations with measures of glucose metabolism (e.g., fasting insulin) and adiposity (e.g., body mass index [BMI]) were examined with multivariable linear regression. In the total study population, rs7903146-T was associated with a higher risk of T2D (additive odds ratio: 1.42; 95% confidence interval: 1.17; 1.72), and specifically with T2D treated with insulin analogs (2.31 [1.19; 4.46]). After exclusion of participants treated with glucose-lowering medication, rs7903146-T was associated with lower mean insulin concentration (additive mean difference: -0.07 SD [-0.14; 0.00]), but not with higher mean glucose concentration (0.03 SD [-0.01; 0.07]). Furthermore, rs7903146-T was associated with, among other measures of adiposity, a lower mean BMI (-0.04 SD [-0.09; -0.00]), and a lower mean total body fat (-0.04 SD [-0.08; -0.00]). The association between rs7903146-T and T2D increased after adjustment for BMI (odds ratio: 1.51 [1.24; 1.86]); the association between rs7903146-T and fasting insulin diminished after adjustment (-0.05 SD [-0.11; 0.02]). CONCLUSION: rs7903146-T is associated with a decreased insulin concentration and increased risk of T2D with opposing effects of adjustment for adiposity.

Genetic variation in the obesity gene FTO is not associated with decreased fat oxidation: the NEO study.

BACKGROUND: The fat mass and obesity-associated (FTO) gene harbors the strongest common genetic variant associated with obesity. Recently, rs1421085-T to -C substitution mapped in FTO was shown to induce a developmental shift of human adipocytes from an energy-combusting beige to an energy-storing white phenotype in vitro. As browning of adipocytes selectively enhances fat oxidation (FatOx), we hypothesized that rs1421085-C in FTO is associated with deceased FatOx compared with carbohydrate oxidation (CarbOx) and an increased respiratory quotient (RQ). METHODS: In the Netherlands Epidemiology of Obesity study, a population-based cohort study of middle-aged individuals (45-65 years), anthropometry and genotyping was performed (n=5744), in addition to indirect calorimetry (n=1246). With linear regression analyses, we examined associations of rs1421085 genotype with FatOx, CarbOx and RQ. RESULTS: In the total study population, 36.7% carried the rs1421085-TT genotype, 47.6% rs1421085-CT and 15.7% rs1421085-CC. Mean (s.d.) age was 56 (6) years, mean (s.d.), body mass index (BMI) was 26.3 (4.4) kg m-2 and 56% of the total population were women. Measures of adiposity (difference, 95% confidence interval) were higher in CC carriers compared with that in rs1421085-TT carriers: BMI +0.56 (0.15, 0.98) kg m-2, waist circumference +1.25 (0.02, 2.49) cm and total body fat mass +1.21 (0.28, 2.14) kg. However, no differences in mean FatOx (+2.5 (-2.4, 7.4) mg min-1), CarbOx (-6.1 (-17.4, 5.2) mg min-1) or RQ (-0.01 (-0.02, 0.01)) were observed between the two genotypes. CONCLUSIONS: We observed no evidence for associations of rs1421085 in FTO with FatOx and RQ. This indicates that the rs1421085-C allele in FTO induces obesity likely via other pathways than via reduced FatOx.

[Personalized medicine: evolution or revolution?]. / 'Personalized medicine': evolutie of revolutie?

The principle that personal information is used to provide an individualized prognosis and therapy is an old maxim. Personalized medicine aims to add genetic and molecular information to routinely obtained clinical care data. Thus far, this additional information has not improved prognostic ability in many clinical conditions. Moreover, for most conditions, genetic or molecular knowledge that was used to guide therapeutic decisions has not been shown to improve the clinical outcome.

Increased amino acids levels and the risk of developing of hypertriglyceridemia in a 7-year follow-up.

BACKGROUND: Recently, five branched-chain and aromatic amino acids were shown to be associated with the risk of developing type 2 diabetes (T2D). AIM: We set out to examine whether amino acids are also associated with the development of hypertriglyceridemia. MATERIALS AND METHODS: We determined the serum amino acids concentrations of 1,125 individuals of the KORA S4 baseline study, for which follow-up data were available also at the KORA F4 7 years later. After exclusion for hypertriglyceridemia (defined as having a fasting triglyceride level above 1.70 mmol/L) and diabetes at baseline, 755 subjects remained for analyses. RESULTS: Increased levels of leucine, arginine, valine, proline, phenylalanine, isoleucine and lysine were significantly associated with an increased risk of hypertriglyceridemia. These associations remained significant when restricting to those individuals who did not develop T2D in the 7-year follow-up. The increase per standard deviation of amino acid level was between 26 and 40 %. CONCLUSIONS: Seven amino acids were associated with an increased risk of developing hypertriglyceridemia after 7 years. Further studies are necessary to elucidate the complex role of these amino acids in the pathogenesis of metabolic disorders.

A periconceptional energy-rich dietary pattern is associated with early fetal growth: the Generation R study.

OBJECTIVE: To identify periconceptional maternal dietary patterns associated with crown-rump length (CRL), estimated fetal weight (EFW) and birthweight. DESIGN: Population-based prospective birth cohort study. SETTING: Rotterdam, the Netherlands. PARTICIPANTS: For this study, 847 pregnant Dutch women were eligible. Women were included between 2001 and 2005. METHODS: Information on nutritional intake was collected by a semiquantitative food frequency questionnaire. For extracting dietary patterns, principal component factor analysis was used. Fetal growth was assessed using ultrasound measurements. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used. MAIN OUTCOME MEASURES: Crown-to-rump length, estimated fetal weight in second and third trimester and birthweight. RESULTS: An 'energy-rich dietary pattern' was identified, characterised by high intakes of bread, margarine and nuts. A significant association was shown between a high adherence to this dietary pattern (difference, mm: 2.15, 95% confidence interval 0.79-3.50) and CRL (linear trend analyses P = 0.015). No association was revealed between increasing adherence to this dietary pattern and EFW in second or third trimester, or birthweight. CONCLUSION: This study suggests that increasing adherence to an energy-rich dietary pattern is associated with increased CRL in the first trimester.

Fat mass and obesity-associated obesity-risk genotype is associated with lower foetal growth: an effect that is reversed in the offspring of smoking mothers.

Fat mass and obesity-associated (FTO) gene variants are associated with childhood and adult obesity; however, the influence of FTO polymorphisms on foetal growth is unknown. Associations between the FTO variant rs9939609 and the foetal growth trajectories, maternal pregnancy weight gain, anthropometric measures at birth and body mass index (BMI) at age 14 years were assessed in 1079 singleton-birth Australian Caucasians. Analyses were repeated in 3512 singleton-birth Dutch Caucasians. The rs9939609 obesity-risk AA genotype was associated with symmetrical intrauterine growth restriction; an effect reversed in mothers who smoked during pregnancy. The effect increased over time and was modified by maternal smoking for head circumference (P = 0.007), abdominal circumference (P = 0.007), femur length (P = 0.02) and estimated foetal weight (P = 0.001). The modification of the association between the AA genotype and birth anthropometrics by maternal smoking was consistent across birth weight (P = 0.01) and birth length (P = 0.04) and neonatal day 2 anthropometry. Consistent associations were replicated in the Generation R cohort. Maternal pregnancy weight gain matched the pattern of birth weight and was independent of placental weight. In adolescents, the AA genotype was associated with increased BMI-adjusted-for-age in males (P = 0.00009), but no effect was detected in females. A variant in the FTO gene influences foetal growth trajectories in the third trimester, early postnatal growth and adiposity in adolescence. Maternal smoking during pregnancy reversed the direction of association of rs9939609 on foetal growth, which was probably mediated by maternal energy intake. The detection of genetic variants associated with foetal growth has the potential to identify novel molecular mechanisms underlying growth and targeted early life intervention.

No association of obesity gene FTO with body composition at the age of 6 months. The Generation R Study.

BACKGROUND: Genome-wide association studies on body mass index (BMI) have identified an FTO polymorphism (rs9939609) as having the strongest effect. AIM: We examined the effect of FTO genotype on body composition at the age of 6 months using skinfold thickness measurements and dual energy X-ray absorptiometry (DXA). MATERIAL/SUBJECTS AND METHODS: This study was embedded in a population-based prospective cohort study from early fetal life onwards. FTO genotype was related to anthropometric measurements (weight and height), subcutaneous fat mass measured by skinfold thickness, and total, truncal, and peripheral fat mass and lean mass measured by DXA. Analyses for skinfold thickness and DXA were performed in 695 and 216 children, respectively. RESULTS: Genotype frequency was TT 40.3%, TA 45.5%, and AA 14.2%. No significant differences between FTO genotypes were found in weight, height or BMI. Furthermore, FTO genotype was not associated with any skinfold thickness. Finally, no associations between FTO genotype and body composition measures (fat and lean mass) assessed by DXA were found. CONCLUSIONS: We observed no association between this FTO polymorphism and body composition at the age of 6 months. Longer follow-up studies are necessary to examine at which age and by which mechanisms FTO genotype starts to influence fat mass and body composition.

Abdominal fat in children measured by ultrasound and computed tomography.

The prevalence of childhood obesity is increasing rapidly. Visceral fat plays an important role in the pathogenesis of metabolic and cardiovascular diseases. Currently, computed tomography (CT) is broadly seen as the most accurate method of determining the amount of visceral fat. The main objective was to examine whether measures of abdominal visceral fat can be determined by ultrasound in children and whether CT can be replaced by ultrasound for this purpose. To assess whether preperitoneal fat thickness and area are good approximations of visceral fat at the umbilical level, we first retrospectively examined 47 CT scans of nonobese children (body mass index <30kg/m(2); median age 7.9 y [95% range 1.2 to 16.2]). Correlation coefficients between visceral and preperitoneal fat thickness and area were 0.58 (p<0.001) and 0.76 (p<0.001), respectively. Then, to assess how preperitoneal and subcutaneous fat thicknesses and areas measured by ultrasound compare with these parameters in CT, we examined 34 nonobese children (median age 9.5 [95% range 0.3 to 17.0]) by ultrasound and CT. Ultrasound measurements of preperitoneal and subcutaneous fat were correlated with CT measurements, with correlation coefficients ranging from 0.75-0.97 (all p<0.001). Systematic differences of up to 24.0cm(2) for preperitoneal fat area (95% confidence interval -29.9 to 77.9cm(2)) were observed when analyzing the results described by the Bland-Altman method. Our findings suggest that preperitoneal fat can be used as an approximation for visceral fat in children and that measuring abdominal fat with ultrasound in children is a valid method for epidemiological and clinical studies. However, the exact agreement between the ultrasound and CT scan was limited, which indicates that ultrasound should be used carefully for obtaining exact fat distribution measurements in individual children.

Tracking and determinants of subcutaneous fat mass in early childhood: the Generation R Study.

OBJECTIVES: To examine the development and tracking of subcutaneous fat mass in the first 2 years of life and to examine which parental, fetal and postnatal characteristics are associated with subcutaneous fat mass. DESIGN: This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. Subcutaneous fat mass was measured by skinfold thickness (biceps, triceps, suprailiacal, subscapular) at the ages of 1.5, 6 and 24 months in 1012 children. Information about parental, fetal and postnatal growth characteristics was collected by physical and fetal ultrasound examinations and questionnaires. RESULTS: Normal values of subcutaneous fat mass are presented. Total subcutaneous fat mass was higher in girls than in boys at the age of 24 months (P=0.01). Subjects in the lowest and highest quartiles at the age of 6 months tended to keep their position in the same quartile at the age of 24 months (odds ratios 1.86 (95% confidence interval (CI) 1.3, 2.7)) and 1.84 (95% CI: 1.3, 2.6), respectively). Maternal height and weight, paternal weight, fetal weight at 30 weeks, birth weight and weight at the age of 6 weeks were each inversely associated with subcutaneous fat mass at the age of 24 months after adjustment for current weight at 24 months. CONCLUSION: This study shows for the first time that subcutaneous fat mass tends to track in the first 2 years of life. Furthermore, the results suggest that an adverse fetal environment and growth are associated with increased subcutaneous fat mass at the age of 24 months. Further studies are needed to examine whether these associations persist in later life.