A tangled threesome: adiponectin, insulin sensitivity, and adiposity: can Mendelian randomization sort out causality?
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ABSTRACT:
SUBMITTER: Kizer JR
PROVIDER: S-EPMC3609579 | biostudies-literature | 2013 Apr
REPOSITORIES: biostudies-literature
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A tangled threesome: adiponectin, insulin sensitivity, and adiposity: can Mendelian randomization sort out causality?
Diabetes 20130401 4
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Project description:The adipocyte-secreted protein adiponectin is associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomization approach. In a sample of Swedish men aged 71 years (n = 942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity (M/I ratio) was measured by the euglycemic insulin clamp. We used three genetic variants in the ADIPOQ locus as instrumental variables (IVs) to estimate the potential causal effect of adiponectin on insulin sensitivity and compared these with results from conventional linear regression. The three ADIPOQ variants, rs17300539, rs3774261, and rs6444175, were strongly associated with serum adiponectin levels (all P ? 5.3 × 10(-9)) and were also significantly associated with M/I ratio in the expected direction (all P ? 0.022). IV analysis confirmed that genetically determined adiponectin increased insulin sensitivity (? = 0.47-0.81, all P ? 0.014) comparable with observational estimates (? = 0.50, all P(difference) ? 0.136). Adjustment for BMI and waist circumference partly explained the association of both genetically determined and observed adiponectin levels with insulin sensitivity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship partly mediated by reduced adiposity.
| S-EPMC3609596 | biostudies-literature
Project description:BackgroundAlthough the relationship between serum uric acid (SUA) and adiposity is well established, the direction of the causality is still unclear in the presence of conflicting evidences. We used a bidirectional Mendelian randomization approach to explore the nature and direction of causality between SUA and adiposity in a population-based study of Caucasians aged 35 to 75 years.Methods and findingsWe used, as instrumental variables, rs6855911 within the SUA gene SLC2A9 in one direction, and combinations of SNPs within the adiposity genes FTO, MC4R and TMEM18 in the other direction. Adiposity markers included weight, body mass index, waist circumference and fat mass. We applied a two-stage least squares regression: a regression of SUA/adiposity markers on our instruments in the first stage and a regression of the response of interest on the fitted values from the first stage regression in the second stage. SUA explained by the SLC2A9 instrument was not associated to fat mass (regression coefficient [95% confidence interval]: 0.05 [-0.10, 0.19] for fat mass) contrasting with the ordinary least square estimate (0.37 [0.34, 0.40]). By contrast, fat mass explained by genetic variants of the FTO, MC4R and TMEM18 genes was positively and significantly associated to SUA (0.31 [0.01, 0.62]), similar to the ordinary least square estimate (0.27 [0.25, 0.29]). Results were similar for the other adiposity markers.ConclusionsUsing a bidirectional Mendelian randomization approach in adult Caucasians, our findings suggest that elevated SUA is a consequence rather than a cause of adiposity.
| S-EPMC3378571 | biostudies-literature
Project description:BackgroundCross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose-response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects.Methods and findingsThe Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity. In observational analysis, a 3.3 kg/m² (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6×10⁻¹⁶), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7×10⁻²⁹), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0×10⁻⁴). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (∼5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI.ConclusionsOur results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation.
| S-EPMC3958348 | biostudies-literature
Project description:To examine associations of central adiposity, serum adiponectin and clamp-derived insulin sensitivity in a single longitudinal cohort from early adolescence to young adulthood.The cohort was examined three times at mean ages 15 years (n = 308), 19 years (n = 218) and 22 years (n = 163). Insulin sensitivity was measured with the euglycaemic hyperinsulinaemic clamp. Circulating adiponectin was measured by enzyme-linked immunosorbent assay. Computed tomography scans were used at mean age 22 to compute subcutaneous and visceral abdominal fat volume. Partial Pearson correlations and linear regression were used to examine cross-sectional associations at each examination.The moderate negative correlation between waist circumference and adiponectin was significant and essentially unchanged from mean age 15 (-0.32, P < 0.0001) to mean age 22 (-0.29, P < 0.002), whereas the negative correlation between waist circumference and insulin sensitivity and the positive correlation between adiponectin and insulin sensitivity increased steadily in magnitude to mean age 22 (-0.29, P = 0.0002; and 0.32, P < 0.0001, respectively). In regression models including both visceral and subcutaneous fat, only visceral fat was significantly associated with insulin sensitivity, while only subcutaneous fat was nearly significantly associated with adiponectin.This study shows that the significant negative relationship between waist circumference and adiponectin predated the development of significant relationships between insulin sensitivity and both waist circumference and adiponectin. It also shows that adiponectin is more closely related to subcutaneous fat and insulin sensitivity is more closely related to visceral fat in young adults.
| S-EPMC3418404 | biostudies-literature
Project description:Polymyositis is a prominent subgroup of idiopathic inflammatory myopathy, considered to have an autoimmune etiology. However, research exploring the condition between immunocytes and polymyositis remains limited, indicating the need for further investigation to unravel these intricate associations. We employed bidirectional Mendelian randomization (MR) analysis to ascertain causality between 731 immunocytes and polymyositis. We also compared the positive immunocytes with dermatomyositis. Our primary analytical method was inverse variance weighted, supplemented by 4 other MR techniques. Additionally, Cochran Q test was performed to assess heterogeneity, MR-Egger to appraise pleiotropy, and MR-PRESSO to identify and eliminate potential outliers. Furthermore, the leave-one-out test evaluated the impact of each instrumental variable (IV) on the causal effect. The inverse variance weighted results revealed that 10 immunocytes exert a protective effect against polymyositis (P < .05, OR < 1), while 16 immunocytes are connected with an elevated risk of the disease (P < .05, OR > 1). In reverse MR, polymyositis was found to decrease the levels of 2 immune cells (P < .05, OR < 1) and elevate the expression of 5 immune cell phenotypes (P < .05, OR > 1). A complex correlation was found between polymyositis and the immunocyte phenotypes CD8, CD33dim, HLA-DR, CD11b, and CD45. Additionally, it was discovered that 15 types of immune cells share a causal relationship between polymyositis and dermatomyositis. All analyses demonstrated no heterogeneity or horizontal pleiotropy (P > .05). Our study provides compelling evidence regarding the intricate causal relationships between immunocytes and polymyositis. Polymyositis and dermatomyositis share common immunocytes' regulatory mechanisms. CD8, CD33dim, HLA-DR, CD11b, and CD45 may represent potential immune cell markers for polymyositis. These findings hold implications for planning prognosis and therapeutic strategies for polymyositis, offering novel insights for drug development.
| S-EPMC11521033 | biostudies-literature
Project description:Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes. MR studies can be straightforward; for example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease. However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret. In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C-reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease). Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol). We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations. In doing so, we hope to contribute towards more reliable evaluations of MR findings.
| S-EPMC5600813 | biostudies-literature
Project description:BackgroundNumerous observational studies have suggested a correlation between sarcopenia and depression, but the nature of this relationship requires further investigation.MethodsThis study employed bidirectional Mendelian randomization to explore this connection. Data from genome-wide association studies were used, encompassing measures of sarcopenia and mental factors, including depression and emotional states. The initial analysis concentrated on the impact of depression on sarcopenia, and then it examined the reverse relationship. The same methodology was applied to emotional data for validation.ResultsThe results indicated a reciprocal causation between sarcopenia and depression, even when emotional state data were considered. Various emotions can impact sarcopenia, and in turn, sarcopenia can affect emotions, except subjective well-being. These findings highlight a cyclic deterioration between sarcopenia and depression, with a link to negative emotions and a partially ameliorative effect of subjective well-being on sarcopenia.ConclusionsIn summary, this study sheds light on the interplay between psychiatric factors and sarcopenia, offering insights into intervention and prevention strategies.
| S-EPMC11319753 | biostudies-literature
Project description:It is reported that overweight may lead to accelerated aging. However, there is still a lack of evidence on the causal effect of overweight and aging. We collected genetic variants associated with overweight, age proxy indicators (telomere length, frailty index and facial aging), etc., from genome-wide association studies datasets. Then we performed MR analyses to explore associations between overweight and age proxy indicators. MR analyses were primarily conducted using the inverse variance weighted method, followed by various sensitivity and validation analyses. MR analyses indicated that there were significant associations of overweight on telomere length, frailty index, and facial aging (β = -0.018, 95% CI = -0.033 to -0.003, p = 0.0162; β = 0.055, 95% CI = 0.030-0.079, p < 0.0001; β = 0.029, 95% CI = 0.013-0.046, p = 0.0005 respectively). Overweight also had a significant negative causality with longevity expectancy (90th survival percentile, β = -0.220, 95% CI = -0.323 to -0.118, p < 0.0001; 99th survival percentile, β = -0.389, 95% CI = -0.652 to -0.126, p = 0.0038). Moreover, the findings tend to favor causal links between body fat mass/body fat percentage on aging proxy indicators, but not body fat-free mass. This study provides evidence of the causality between overweight and accelerated aging (telomere length decreased, frailty index increased, facial aging increased) and lower longevity expectancy. Accordingly, the potential significance of weight control and treatment of overweight in combating accelerated aging need to be emphasized.
| S-EPMC10410004 | biostudies-literature
Project description:BackgroundWhile growing evidence suggests a relationship between migraine and cardiovascular disease, the genetic evidence for a causal relationship between migraine and cardiovascular disease is still scarce. Investigating the causal association between migraine and cardiovascular disease is vital.MethodsWe carried out a bidirectional Mendelian randomization (MR) study including discovery samples and replication samples using publicly available genome-wide association study (GWAS) summary datasets and stringent screening instrumental variables. Four different MR techniques-Inverse variance weighted (IVW), MR ‒Egger, weighted median, and weighted mode-as well as various sensitivity analyses-Cochran's Q, IVW radial, leave-one-out (LOO), and MR-PRESSO-were utilized to investigate the causal relationship between cardiovascular disease and migraine.ResultsThe protective causal effects of genetically predicted migraine on coronary artery disease (OR, 0.881; 95% CI 0.790-0.982; p = 0.023) and ischemic stroke (OR, 0.912; 95% CI 0.854-0.974; p = 0.006) were detected in forward MR analysis but not in any other cardiovascular disease. Consistently, we also discovered protective causal effects of coronary atherosclerosis (OR, 0.865; 95% CI 0.797-0.940; p = 0.001) and myocardial infarction (OR, 0.798; 95% CI 0.668-0.952; p = 0.012) on migraine in reverse MR analysis.ConclusionWe found a potential protective effect of migraine on coronary artery disease and ischemic stroke and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine. We emphasised epidemiological and genetic differences and the need for long-term safety monitoring of migraine medications and future research to improve cardiovascular outcomes in migraine patients.
| S-EPMC11321219 | biostudies-literature
Project description:Background & aimsThe pathogenesis of hypertension involves a diverse range of genetic, environmental, hemodynamic, and more causative factors. Recent evidence points to an association between the gut microbiome and hypertension. Given that the microbiota is in part determined by host genetics, we used the two-sample Mendelian randomization (MR) analysis to address the bidirectional causal link between gut microbiota and hypertension.MethodsWe selected genetic variants (P < 1 × 10-5) for gut microbiota (n = 18,340) from the MiBioGen study. Genetic association estimates for hypertension were extracted from genome-wide association study (GWAS) summary statistics on 54,358 cases and 408,652 controls. Seven complementary MR methods were implemented, including the inverse-variance weighted (IVW) method, followed by sensitivity analyses to verify the robustness of the results. Reverse-direction MR analyses were further conducted to probe if there was a reverse causative relationship. Bidirectional MR analysis then examines a modulation of gut microbiota composition by hypertension.ResultsAt the genus level, our MR estimates from gut microbiome to hypertension showed that there were 5 protective factors Allisonella, Parabacteroide, Phascolarctobacterium, Senegalimassilia, and unknowngenus (id.1000000073), while 6 genera Clostridiuminnocuum, Eubacteriumcoprostanoligenes, Eubacteriumfissicatena, Anaerostipes, LachnospiraceaeFCS020, and unknowngenus (id.2041) are risk factors. The Alcaligenaceae and ClostridialesvadinBB60 were detrimental and beneficial at the family level, respectively. In contrast, the MR results of hypertension-gut flora showed hypertensive states can lead to an increased abundance of Eubacteriumxylanophilum, Eisenbergiella, and Lachnospiraceae and a lower abundance of Alistipes, Bilophila, Butyricimonas, and Phascolarctobacterium.ConclusionAltered gut microbiota is a causal factor in the development of hypertension, and hypertension causes imbalances in the intestinal flora. Substantial research is still needed to find the key gut flora and explore the specific mechanisms of their effects so that new biomarkers can be found for blood pressure control.
| S-EPMC10192878 | biostudies-literature