Adiposity-Related Heterogeneity in Patterns of Type 2 Diabetes Susceptibility Observed in Genome-Wide Association Data
Nicholas J. Timpson 1 2 ,
Cecilia M. Lindgren 1 3 ,
Michael N. Weedon 4 5 ,
...Joshua Randall 1 ,
Willem H. Ouwehand 6 7 ,
David P. Strachan 8 ,
N. William Rayner 1 3 ,
Mark Walker 9 ,
Graham A. Hitman 10 ,
Alex S.F. Doney 11 ,
Colin N.A. Palmer 12 ,
Andrew D. Morris 11 ,
Andrew T. Hattersley 4 5 ,
Eleftheria Zeggini 1 ,
Timothy M. Frayling 4 5 and
Mark I. McCarthy 1 3
1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
2 The Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Bristol University, Bristol, U.K
3 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
4 Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
5 Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
6 Department of Haematology, University of Cambridge, Cambridge, U.K
7 National Health Service Blood and Transplant, Cambridge Centre, Cambridge, U.K
8 Division of Community Health Services, St. George's University of London, London, U.K
9 Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
10 Centre for Diabetes and Metabolic Medicine, Barts, and The London, Royal London Hospital, Whitechapel, London, U.K
11 Diabetes Research Centre, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee,
Dundee, U.K
12 Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K
Corresponding author: Mark I. McCarthy, mark.mccarthy{at}drl.ox.ac.uk
Abstract
OBJECTIVE— This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns
of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes.
RESEARCH DESIGN AND METHODS— We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938
control subjects: 393,453 single-nucleotide polymorphisms SNPs) after stratifying case subjects (into “obese” and “nonobese”)
according to median BMI (30.2 kg/m 2 ). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in
type 2 diabetes association signal was sought in additional samples.
RESULTS— In the “obese-type 2 diabetes” scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk RR 1.49 95% CI 1.34–1.66, P = 1.3 × 10 −13 ), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 1.09–1.35, P = 0.001). This situation was reversed in the “nonobese” scan, with FTO association undetectable (RR 1.07 0.97–1.19, P = 0.19) and TCF7L2 predominant (RR 1.53 1.37–1.71, P = 1.3 × 10 −14 ). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity
( FTO : P DIFF = 1.4 × 10 −7 ; TCF7L2 : P DIFF = 4.0 × 10 −6 ). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and
18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for
effect size heterogeneity for the SLC30A8 locus alone (RR obese 1.08 1.01–1.15; RR nonobese 1.18 1.10–1.27: P DIFF = 0.04).
CONCLUSIONS— This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations
in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within
type 2 diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 3 December 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted November 19, 2008.
Received July 7, 2008.
DIABETES
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of ...this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5, with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
To identify the clinical and genetic factors that explain why the rate of diabetes progression is highly variable between individuals following diagnosis of type 2 diabetes.
We studied 5,250 patients ...with type 2 diabetes using comprehensive electronic medical records in Tayside, Scotland, from 1992 onward. We investigated the association of clinical, biochemical, and genetic factors with the risk of progression of type 2 diabetes from diagnosis to the requirement of insulin treatment (defined as insulin treatment or HbA1c ≥8.5% 69 mmol/mol treated with two or more noninsulin therapies).
Risk of progression was associated with both low and high BMI. In an analysis stratified by BMI and HbA1c at diagnosis, faster progression was independently associated with younger age at diagnosis, higher log triacylglyceride (TG) concentrations (hazard ratio HR 1.28 per mmol/L 95% CI 1.15-1.42) and lower HDL concentrations (HR 0.70 per mmol/L 95% CI 0.55-0.87). A high Genetic Risk Score derived from 61 diabetes risk variants was associated with a younger age at diagnosis and a younger age when starting insulin but was not associated with the progression rate from diabetes to the requirement of insulin treatment.
Increased TG and low HDL levels are independently associated with increased rate of progression of diabetes. The genetic factors that predispose to diabetes are different from those that cause rapid progression of diabetes, suggesting a difference in biological process that needs further investigation.
Objective:
Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol ...consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.
Methods:
To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.
Results:
The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level (“consumption” and “problems,” rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.
Conclusions:
This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis ...that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory ...volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Aims/hypothesis
The aim of the study was to examine the association between lipoprotein-associated phospholipase A
2
(Lp-PLA
2
) activity levels and incident diabetic retinopathy and change in ...retinopathy grade.
Methods
This was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (
n
= 1364) by stratified Lp-PLA
2
activity levels (in quartiles). The same analysis was performed for transitions to more severe grades.
Results
The hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA
2
activity compared with the lowest. Higher Lp-PLA
2
activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA
2
activity compared with the lowest, respectively.
Conclusions/interpretation
Higher Lp-PLA
2
levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA
2.
Objectives:
The G8 is a well-validated screening test for older cancer patients. The current study was undertaken to determine whether the G8 is predictive of short-term post-operative outcomes after ...head and neck cancer (HNC) surgery.
Methods:
Consecutive patients aged 65 years or more and referred for a preoperative assessment by a speech-language pathologist were consecutively screened by clinicians at 2 academic medical centers using the G8. The G8 was used to screen for vulnerability prior to surgery. Patients were deemed vulnerable if they had a total G8 score ≤14 according to published guidelines. Data were also collected on demographic characteristics, tumor staging, post-operative course, and tracheostomy and feeding tube (FT) status.
Results:
Ninety patients were consecutively screened during the study period. Using the G8, 64% of the patients were deemed vulnerable. Vulnerable patients differed significantly from non-vulnerable patients with regard to age, health, tumor stage, and baseline dysphagia, and underwent more extensive surgery. Postoperatively, vulnerable patients had a significantly longer hospital length of stay (LOS; 10.17 vs 5.50 days, respectively, P < .001), were less likely to discharge home (76% vs 94%, P = .044), and were more likely to be FT dependent for over a month (54% vs 21%, P = .006) compared to non-vulnerable patients. In regression models, controlling for T-stage and surgical variables, the G8 independently predicted 2 post-operative outcomes of interest, namely LOS and FT dependency.
Conclusions:
The G8 may be a useful screening tool for identifying older adults at risk of a protracted postoperative medical course after HNC surgery. Future research should aim to identify the optimal screening protocol and how this information can be incorporated into clinical pathways to enhance the post-operative outcomes of older HNC patients.
•LSVT LOUD® decreased voice handicap.•LSVT LOUD® improved communicative participation and communicative effectiveness.•There was a strong correlation between patient- and partner-ratings.•The ...Communicative Participation Item Bank was sensitive to treatment changes.•LSVT LOUD® may reduce social isolation risk by facilitating social participation.
Lee Silverman Voice Treatment (LSVT LOUD®), an intensive 4-week program of voice therapy, is regarded as the most well-researched, efficacious treatment for hypokinetic dysarthria in individuals with Parkinson’s disease (PD). Although numerous studies have published acoustic and perceptual findings, there is comparatively little information about the impact of LSVT LOUD® on functional communication outcomes.
This prospective, longitudinal study investigated the impact of treatment on daily communication in 25 individuals with PD. Three validated communication measures (the Voice Handicap Index, the Communicative Effectiveness Scale, and the Communicative Participation Item Bank) were given before and after treatment and again 4–8 weeks and 3–6 months following treatment. Communication partners were also asked to rate communication effectiveness at all four timepoints.
Significant improvements were found for all three self-reported scales which remained above baseline across all post-treatment timepoints. In addition, self-reported communicative effectiveness was significantly correlated with the assessments of communication partners. Particular benefits were reported for more complex communicative activities such as asking questions, giving detailed information, communicating in noisy situations, and speaking in groups.
Overall, the findings suggested that LSVT LOUD® promotes an increased sense of personal control over the communication difficulties resulting from PD by decreasing voice handicap and improving communication effectiveness and communicative participation. For individuals with PD, LSVT LOUD® may reduce the risk of social isolation by improving communication and facilitating social participation.
As a result of this activity, the participant will be able to (1) describe the impact of PD on voice and communication, (2) discuss how these characteristics may be associated with more global measures of functional communication and particularly communicative participation, (3) explain which aspects of functional communication were affected by LSVT LOUD® as assessed by study participants and their communication partners.
Despite the high incidence of sarcopenia in the orthopaedic community, studies evaluating the influence of sarcopenia following primary total knee arthroplasty (TKA) are limited. Therefore, the ...purpose of this study is to determine if sarcopenic patients undergoing primary TKA have higher rates of (1) in-hospital lengths of stay (LOS); (2) medical complications; (3) implant-related complications; (4) fall risk; (5) lower extremity fracture risk; and (6) costs of care. Sarcopenia patients were matched to controls in a 1:5 ratio according to age, sex, and medical comorbidities. The query yielded 90,438 patients with (
= 15,073) and without (
= 75,365) sarcopenia undergoing primary TKA. Primary outcomes analyzed included: in-hospital LOS, 90-day medical complications, 2-year implant-related complications, fall risk, lower extremity fracture risk, and costs of care. A
-value of less than 0.05 was considered statistically significant. Patients with sarcopenia undergoing primary TKA had greater in-hospital LOS (4 vs. 3 days,
< 0.0001). Sarcopenic patients were also found to have increased incidence and odds of 90-day medical complications (2.9 vs. 1.1%; odds ratio OR = 2.83,
< 0.0001), falls (0.9 vs. 0.3%; OR = 3.54,
< 0.0001), lower extremity fractures (1.0 vs. 0.2%; OR = 5.54,
< 0.0001), and reoperation (0.9 vs. 0.5%; OR = 1.87,
< 0.0001). Additionally, sarcopenic patients had greater 2-year implant-related complications (4.3 vs. 2.4%; OR = 1.80,
< 0.0001), as well as day of surgery ($52,900 vs. 48,248,
< 0.0001), and 90-day ($68,303 vs. $57,671,
< 0.0001) costs compared with controls. This analysis of over 90,000 patients demonstrates that patients with sarcopenia undergoing primary TKA have greater in-hospital LOS, increased odds of 90-day medical complications, falls, lower extremity fractures, and reoperations. Additionally, sarcopenia was associated with greater 2-year implant-related complications, day of surgery costs, and 90-day costs. The study is useful as it can allow orthopaedic surgeons to properly educate these patients of the potential complications which may occur following their surgery.
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