Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.

Background

Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.

Methods and Findings

The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p<0.001) than men (2.3: 2.0–2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p<0.001) in men and 2.7 (2.2–3.4, p<0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.

Conclusions

Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.

Please see later in the article for the Editors' Summary

Editors' Summary

Background. People with diabetes are more likely to have cardiovascular disease such as heart attacks and strokes. They also have a higher risk of dying prematurely from any cause. Controlling blood sugar (glucose), blood pressure, and cholesterol can help reduce these risks. Some people with type 1 diabetes can achieve tight blood glucose control through a strict regimen that includes a carefully calculated diet, frequent physical activity, regular blood glucose testing several times a day, and multiple daily doses of insulin. Other drugs can reduce blood pressure and cholesterol levels. Keeping one's weight in the normal range and not smoking are important ways in which all people, including those with type 1 diabetes can reduce their risks of heart disease and premature death.

Why Was This Study Done? Researchers and doctors have known for almost two decades what patients with type 1 diabetes can do to minimize the complications from the disease and thereby reduce their risks for cardiovascular disease and early death. So for some time now, patients should have been treated and counseled accordingly. This study was done to evaluate the current risks for have cardiovascular disease and premature death amongst people living with type 1 diabetes in a high-income country (Scotland).

What Did the Researchers Do and Find? From a national register of all people with type 1 diabetes in Scotland, the researchers selected those who were older than 20 years and alive at any time from January 2005 to May 2008. This included about 19,000 people who had been diagnosed with type 1 diabetes before 2005. Another 2,600 were diagnosed between 2005 and 2008. They also obtained data on heart attacks and strokes in these patients from hospital records and on deaths from the natural death register. To obtain a good picture of the current relative risks, they compared the patients with type 1 diabetes with the non-diabetic general Scottish population with regard to the risk of heart attacks/strokes and death from all causes. They also collected information on how well the people with diabetes controlled their blood glucose, on their weight, and whether they smoked.

They found that the current risks compared with the general Scottish population are quite a bit lower than those of people with type 1 diabetes in earlier decades. However, people with type 1 diabetes in Scotland still have much higher (more than twice) the risk of heart attacks, strokes, or premature death than the general population. Moreover, the researchers found a high number of deaths in younger people with diabetes from coma—caused by either too much blood sugar (hyperglycemia) or too little (hypoglycemia). Severe hyperglycemia and hypoglycemia happen when blood glucose control is poor. When the scientists looked at test results for HbA1c levels (a test that is done once or twice a year to see how well patients controlled their blood sugar over the previous 3 months) for all patients, they found that the majority of them did not come close to controlling their blood glucose within the recommended range.

When the researchers compared body mass index (a measure of weight that takes height into account) and smoking between the people with type 1 diabetes and the general population, they found similar proportions of smokers and overweight or obese people.

What Do these Findings Mean? The results represent a snapshot of the recent situation regarding complications from type 1 diabetes in the Scottish population. The results suggest that within this population, strategies over the past two decades to reduce complications from type 1 diabetes that cause cardiovascular disease and death are working, in principle. However, there is much need for further improvement. This includes the urgent need to understand why so few people with type 1 diabetes achieve good control of their blood sugar, and what can be done to improve this situation. It is also important to put more effort into keeping people with diabetes from taking up smoking or getting them to quit, as well as preventing them from getting overweight or promoting weight reduction, because this could further reduce the risks of cardiovascular disease and premature death.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001321

National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on heart disease and diabetes, on general complications of diabetes, and on the HbA1c test (on this site and some others called A1C test) that measures control of blood sugar over the past 3 months

Diabetes.co.uk provides general information on type 1 diabetes, its complications, and what people with the disease can do to reduce their risks

The Canadian Diabetes Association offers a cardiovascular risk self-assessment tool and other relevant information

The American Diabetes Association has information on the benefits and challenges of tight blood sugar control and how it is tested

The Juvenile Diabetes Research Foundation funds research to prevent, cure, and treat type 1 diabetes

Diabetes UK provides extensive information on diabetes for patients, carers, and clinicians

OBJECTIVE

People with type 1 diabetes have increased risk of hospital admission compared with those without diabetes. We hypothesized that HbA1c would be an important indicator of risk of hospital admission.

RESEARCH DESIGN AND METHODS

The Scottish Care Information–Diabetes Collaboration, a dynamic national register of diagnosed cases of diabetes in Scotland, was linked to national data on admissions. We identified 24,750 people with type 1 diabetes during January 2005 to December 2007. We assessed the relationship between deciles of mean HbA1c and hospital admissions in people with type 1 diabetes adjusting for patient characteristics.

RESULTS

There were 3,229 hospital admissions. Of the admissions, 8.1% of people had mean HbA1c <7.0% (53 mmol/mol) and 16.3% had HbA1c <7.5% (58 mmol/mol). The lowest odds of admission were associated with HbA1c 7.7–8.7% (61–72 mmol/mol). When compared with this decile, a J-shaped relationship existed between HbA1c and admission. The highest HbA1c decile (10.8–18.4%/95–178 mmol/mol) showed significantly higher odds ratio (95% CI) for any admission (2.80, 2.51–3.12); the lowest HbA1c decile (4.4–7.1%/25–54 mmol/mol) showed an increase in odds of admission of 1.29 (1.10–1.51). The highest HbA1c decile experienced significantly higher odds of diabetes-related (3.31, 2.94–3.72) and diabetes ketoacidosis admissions (10.18, 7.96–13.01).

CONCLUSIONS

People with type 1 diabetes with highest and lowest mean HbA1c values were associated with increased odds of admission. People with high HbA1c (>10.8%/95 mmol/mol) were at particularly high risk. There is the need to develop effective interventions to reduce this risk.

We surveyed gene–gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E−08) and a Bonferroni corrected threshold (P=1.1E−12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E−08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E−08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

OBJECTIVE

The study objective was to describe the effect of socioeconomic status (SES) on mortality among people with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We used a population-based national electronic diabetes database for 35- to 84-year-olds in Scotland for 2001–2007 linked to mortality records. SES was derived from an area-based measure with Q5 and Q1 representing the most deprived and affluent quintiles, respectively. Poisson regression was used to estimate relative risks (RRs) for mortality among people with type 2 diabetes compared with the population without diabetes stratified by age (35–64 and 65–84 years), sex, duration of diabetes (<2 and ≥2 years), and SES.

RESULTS

Complete data were available for 210,994 eligible individuals (99.4%), and there were 33,842 deaths. Absolute mortality from all causes among people with type 2 diabetes increased with increasing age and socioeconomic deprivation and was higher for men than women. RR for mortality associated with type 2 diabetes was highest for women aged 35–64 years in Q1 with diabetes duration <2 years at 4.83 (95% CI 3.15–7.40) and lowest for men aged 65–84 years in Q5 with diabetes duration ≥2 years at 1.13 (1.03–1.24).

CONCLUSIONS

SES modifies the association between type 2 diabetes and mortality so that RR for mortality is lower among more deprived populations. Age, sex, and duration of diabetes also interact with type 2 diabetes to influence RR of mortality. Differences in prevalence of comorbidities may explain these findings.

The genetic structure of human populations is important in population genetics, forensics and medicine. Using genome-wide scans and individuals with all four grandparents born in the same settlement, we here demonstrate remarkable geographical structure across 8–30 km in three different parts of rural Europe. After excluding close kin and inbreeding, village of origin could still be predicted correctly on the basis of genetic data for 89–100% of individuals.

Background

Fibrin fragment D-dimer is one of several peptides produced when cross-linked fibrin is degraded by plasmin, and is the most widely-used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

Methods and Results

A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21,052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ~2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (p-value 6.4×10−52) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (p-value 2.4×10−14) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (p-value 2.9×10−18) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099, 0.096, and 0.061 unit difference, respectively, in natural-log transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for non-synonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

Conclusions

Three genes were associated with fibrin D-dimer levels, of which the F3 association was the strongest and has not been previously reported.

Genome analysis provides a powerful approach to test for evidence of genetic variation within and between geographical regions and local populations. Copy number variants which comprise insertions, deletions and duplications of genomic sequence provide one such convenient and informative source. Here, we investigate copy number variants from genome wide scans of single nucleotide polymorphisms in three European population isolates, the island of Vis in Croatia, the islands of Orkney in Scotland and the South Tyrol in Italy. We show that whereas the overall copy number variant frequencies are similar between populations, their distribution is highly specific to the population of origin, a finding which is supported by evidence for increased kinship correlation for specific copy number variants within populations.

Background

Many medical disorders of public health importance are complex diseases caused by multiple genetic, environmental and lifestyle factors. Recent technological advances have made it possible to analyse the genetic variants that predispose to complex diseases. Reliable detection of these variants requires genome-wide association studies in sufficiently large numbers of cases and controls. This approach is often hampered by difficulties in collecting appropriate control samples. The Generation Scotland: Donor DNA Databank (GS:3D) aims to help solve this problem by providing a resource of control DNA and plasma samples accessible for research.

Methods

GS:3D participants were recruited from volunteer blood donors attending Scottish National Blood Transfusion Service (SNBTS) clinics across Scotland. All participants gave full written consent for GS:3D to take spare blood from their normal donation. Participants also supplied demographic data by completing a short questionnaire.

Results

Over five thousand complete sets of samples, data and consent forms were collected. DNA and plasma were extracted and stored. The data and samples were unlinked from their original SNBTS identifier number. The plasma, DNA and demographic data are available for research. New data obtained from analysis of the resource will be fed back to GS:3D and will be made available to other researchers as appropriate.

Conclusions

Recruitment of blood donors is an efficient and cost-effective way of collecting thousands of control samples. Because the collection is large, subsets of controls can be selected, based on age range, gender, and ethnic or geographic origin. The GS:3D resource should reduce time and expense for investigators who would otherwise have had to recruit their own controls.

Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size.

Objective: Our objective was to establish the health status of adults with CAH.

Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom.

Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18–69) years.

Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts.

Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.

Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.

Adult patients with congenital adrenal hyperplasia (CAH) have poor subjective health status and only a minority of CAH adults receives regular review by endocrine specialists.

OBJECTIVE

To test the hypotheses that decreased insulin-mediated glucose disposal in muscle is associated with a reduced muscle microvascular exchange capacity (Kf) and that 6 months of high-dose statin therapy would improve microvascular function in people with central obesity.

RESEARCH DESIGN AND METHODS

We assessed skeletal muscle microvascular function, visceral fat mass, physical activity levels, fitness, and insulin sensitivity in skeletal muscle in 22 female and 17 male volunteers with central obesity whose age (mean ± SD) was 51 ± 9 years. We tested the effect of atorvastatin (40 mg daily) on muscle microvascular function in a randomized, double-blind, placebo-controlled trial lasting 6 months.

RESULTS

Kf was negatively associated with a measure of glycemia (A1C; r = −0.44, P = 0.006) and positively associated with insulin sensitivity (the ratio of insulin-stimulated glucose effectiveness, or M value, to the mean insulin concentration, or I value; r = 0.39, P = 0.02). In regression modeling, A1C, visceral fat mass, and M:I explained 38% of the variance in Kf (in a linear regression model with Kf as the outcome [R2 = 0.38, P = 0.005]). M:I was associated with Kf independently of visceral fat mass (B coefficient 3.13 [95% CI 0.22–6.02], P = 0.036). Although 6 months' treatment with atorvastatin decreased LDL cholesterol by 51% (P < 0.001) and plasma high-sensitivity C-reactive protein by 75% (P = 0.02), microvascular function was unchanged.

CONCLUSIONS

Decreased insulin-mediated glucose uptake in skeletal muscle is associated with impaired muscle microvascular exchange capacity (Kf), independently of visceral fat mass. Muscle microvascular function is not improved by 6 months of high-dose statin treatment, despite marked statin-mediated improvements in lipid metabolism and decreased inflammation.

Background

We set out to identify common genetic determinants of the length of RR and QT intervals in 2,325 individuals from isolated European populations.

Methods and Results

We analyzed heart rate at rest, measured as RR interval, and length of corrected QT interval for association to 318,237 SNPs. RR interval was associated to common variants within GPR133, a G-Protein Coupled Receptor (rs885389, P = 3.9 × 10-8). QT interval was associated to the earlier reported NOS1AP gene (rs2880058, P = 2.00 × 10-10) and to a region on chromosome 13 (rs2478333, P = 4.34 × 10-8), which is 100 kb from the closest known transcript LOC730174 and has previously not been associated with length of QT interval.

Conclusion

Our results suggested association between RR interval and GPR133 and confirmed association between QT interval and NOS1AP.

Genome-wide association studies (GWAS) have identified 38 larger genetic regions affecting classical blood lipid levels without adjusting for important environmental influences. We modeled diet and physical activity in a GWAS in order to identify novel loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. The Swedish (SE) EUROSPAN cohort (NSE = 656) was screened for candidate genes and the non-Swedish (NS) EUROSPAN cohorts (NNS = 3,282) were used for replication. In total, 3 SNPs were associated in the Swedish sample and were replicated in the non-Swedish cohorts. While SNP rs1532624 was a replication of the previously published association between CETP and HDL cholesterol, the other two were novel findings. For the latter SNPs, the p-value for association was substantially improved by inclusion of environmental covariates: SNP rs5400 (pSE,unadjusted = 3.6×10−5, pSE,adjusted = 2.2×10−6, pNS,unadjusted = 0.047) in the SLC2A2 (Glucose transporter type 2) and rs2000999 (pSE,unadjusted = 1.1×10−3, pSE,adjusted = 3.8×10−4, pNS,unadjusted = 0.035) in the HP gene (Haptoglobin-related protein precursor). Both showed evidence of association with total cholesterol. These results demonstrate that inclusion of important environmental factors in the analysis model can reveal new genetic susceptibility loci.

Author Summary

In this article we report a genome-wide association study on cholesterol levels in the human blood. We used a Swedish cohort to select genetic polymorphisms that showed the strongest association with cholesterol levels adjusted for diet and physical activity. We replicated several genetic loci in other European cohorts. This approach extends present genome-wide association studies on lipid levels, which did not take these lifestyle factors into account, to improve statistical results and discover novel genes. In our analysis, we could identify two genetic loci in the SLC2A2 (Glucose transporter type 2) and the HP (Haptoglobin-related protein precursor) gene whose effects on total cholesterol have not been reported yet. The results show that inclusion of important environmental factors in the analysis model can reveal new insights into genetic determinants of clinical parameters relevant for metabolic and cardiovascular disease.

Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

Author Summary

Studies investigating the extent to which genetics influences human characteristics such as height have concentrated mainly on common variants of genes, where having one or two copies of a given variant influences the trait or risk of disease. This study explores whether a different type of genetic variant might also be important. We investigate the role of recessive genetic variants, where two identical copies of a variant are required to have an effect. By measuring genome-wide homozygosity—the phenomenon of inheriting two identical copies at a given point of the genome—in 35,000 individuals from 21 European populations, and by comparing this to individual height, we found that the more homozygous the genome, the shorter the individual. The offspring of first cousins (who have increased homozygosity) were predicted to be up to 3 cm shorter on average than the offspring of unrelated parents. Height is influenced by the combined effect of many recessive variants dispersed across the genome. This may also be true for other human characteristics and diseases, opening up a new way to understand how genetic variation influences our health.

Background

Non alcoholic fatty liver disease (NAFLD) is associated with increased risk of type 2 diabetes and chronic liver disease but identifying patients who have NAFLD without resorting to expensive imaging tests is challenging. In order to help identify people for imaging investigation of the liver who are at high risk of NAFLD, our aim was to: a) identify easily measured risk factors at baseline that were independently associated with incident fatty liver at follow up, and then b) to test the diagnostic performance of thresholds of these factors at baseline, to predict or to exclude incident fatty liver at follow up.

Methods

2589 people with absence of fatty liver on ultrasound examination at baseline were re-examined after a mean of 4.4 years in a Korean occupational cohort study. Multi-variable logistic regression analyses were used to identify baseline factors that were independently associated with incident fatty liver at follow up. The diagnostic performance of thresholds of these baseline factors to identify people with incident fatty liver at follow-up was assessed using receiver operating characteristic (ROC) curves.

Results

430 incident cases of fatty liver were identified. Several factors were independently associated with incident fatty liver: increased triglyceride (per mmol/l increase) OR 1.378 [95%CIs 1.179, 1.611], p < 0.0001; glucose (per mmol/l increase) OR 1.215 [95%CIs 1.042, 1.416], p = 0.013; waist (per cm increase) OR 1.078 [95%CIs 1.057, 1.099], p < 0.001; ALT (per IU/L increase) OR 1.009 [95%CIs 1.002, 1.017], p = 0.016; and platelets (per 1x109/L increase) OR 1.004 [1.001, 1.006], p = 0.001; were each independently associated with incident fatty liver. Binary thresholds of the five factors were applied and the area under the ROC curve for incident fatty liver was 0.75 (95%CI 0.72–0.78) for the combination of all five factors above these thresholds.

Conclusion

Simple risk factors that overlap considerably with risk factors for type 2 diabetes allow identification of people at high risk of incident fatty liver at who use of hepatic imaging could be targeted.

OBJECTIVE

To investigate the independent contributions of waist circumference, physical activity, and sedentary behavior on glycemia in South Asians living in Scotland.

RESEARCH DESIGN AND METHODS

Participants were 1,228 (523 men and 705 women) adults of Indian or Pakistani origin screened for the Prevention of Type 2 Diabetes and Obesity in South Asians (PODOSA) trial. All undertook an oral glucose tolerance test, had physical activity and sitting time assessed by International Physical Activity Questionnaire, and had waist circumference measured.

RESULTS

Mean ± SD age and waist circumference were 49.8 ± 10.1 years and 99.2 ± 10.2 cm, respectively. One hundred ninety-one participants had impaired fasting glycemia or impaired glucose tolerance, and 97 had possible type 2 diabetes. In multivariate regression analysis, age (0.012 mmol ⋅ L−1 ⋅ year−1 [95% CI 0.006–0.017]) and waist circumference (0.018 mmol ⋅ L−1 ⋅ cm−1 [0.012–0.024]) were significantly independently associated with fasting glucose concentration, and age (0.032 mmol ⋅ L−1 ⋅ year−1 [0.016–0.049]), waist (0.057 mmol ⋅ L−1 ⋅ cm−1 [0.040–0.074]), and sitting time (0.097 mmol ⋅ L−1 ⋅ h−1 ⋅ day−1 [0.036–0.158]) were significantly independently associated with 2-h glucose concentration. Vigorous activity time had a borderline significant association with 2-h glucose concentration (−0.819 mmol ⋅ L−1 ⋅ h−1 ⋅ day−1 [−1.672 to 0.034]) in the multivariate model.

CONCLUSIONS

These data highlight an important relationship between sitting time and 2-h glucose levels in U.K. South Asians, independent of physical activity and waist circumference. Although the data are cross-sectional and thus do not permit firm conclusions about causality to be drawn, the results suggest that further study investigating the effects of sitting time on glycemia and other aspects of metabolic risk in South Asian populations is warranted.

QRS interval on the electrocardiogram reflects ventricular depolarization and conduction time, and is a risk factor for mortality, sudden death, and heart failure. We performed a genome-wide association meta-analysis in 40,407 European-descent individuals from 14 studies, with further genotyping in 7170 additional Europeans, and identified 22 loci associated with QRS duration (P < 5 × 10−8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors, and calcium-handling proteins, but also point to novel biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a gene at our most significant locus, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10−204) and 10 loci for sphingolipids (smallest P-value = 3.10×10−57). After a correction for multiple comparisons (P-value<2.2×10−9), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.

Author Summary

Phospho- and sphingolipids are integral to membrane formation and are involved in crucial cellular functions such as signalling, membrane fluidity, membrane protein trafficking, neurotransmission, and receptor trafficking. In addition to severe monogenic diseases resulting from defective phospho- and sphingolipid function and metabolism, the evidence suggests that variations in these lipid levels at the population level are involved in the determination of cardiovascular and neurologic traits and subsequent disease. We took advantage of modern laboratory methods, including microarray-based genotyping and electrospray ionization tandem mass spectrometry, to hunt for genetic variation influencing the levels of more than 350 phospho- and sphingolipid phenotypes. We identified nine novel loci, in addition to confirming a number of previously described loci. Several other genetic regions provided substantial evidence of their involvement in these traits. All of these loci are strong candidates for further research in the field of lipid biology and are likely to yield considerable insights into the complex metabolic pathways underlying circulating phospho- and sphingolipid levels. Understanding these mechanisms might help to illuminate factors leading to the development of common cardiovascular and neurological diseases and might provide molecular targets for the development of new therapies.

Background

Despite the growing emphasis on the inclusion of ethnic minority patients in research, there is little published on the recruitment of these populations especially to randomised, community based, lifestyle intervention trials in the UK.

Methods

We share our experience of recruitment to screening in the PODOSA (Prevention of Diabetes and Obesity in South Asians) trial, which screened 1319 recruits (target 1800) for trial eligibility. A multi-pronged recruitment approach was used. Enrolment via the National Health Service included direct referrals from health care professionals and written invitations via general practices. Recruitment within the community was carried out by both the research team and through our partnerships with local South Asian groups and organisations. Participants were encouraged to refer friends and family throughout the recruitment period.

Results

Health care professionals referred only 55 potential participants. The response to written invitations via general practitioners was 5.2%, lower than reported in other general populations. Community orientated, personal approaches for recruitment were comparatively effective yielding 1728 referrals (82%) to the screening stage.

Conclusions

The PODOSA experience shows that a community orientated, personal approach for recruiting South Asian ethnic minority populations can be successful in a trial setting. We recommend that consideration is given to cover recruitment costs associated with community engagement and other personalised approaches. Researchers should consider prioritising approaches that minimise interference with professionals' work and, particularly in the current economic climate, keep costs to a minimum. The lessons learned in PODOSA should contribute to future community based trials in South Asians.

Trial Registration

Current Controlled Trials ISRCTN25729565

Genome-wide association (GWA) studies have identified a number of loci underlying variation in human serum uric acid (SUA) levels with the SLC2A9 gene having the largest effect identified so far. Gene-gene interactions (epistasis) are largely unexplored in these GWA studies. We performed a full pair-wise genome scan in the Italian MICROS population (n = 1201) to characterise epistasis signals in SUA levels. In the resultant epistasis profile, no SNP pairs reached the Bonferroni adjusted threshold for the pair-wise genome-wide significance. However, SLC2A9 was found interacting with multiple loci across the genome, with NFIA - SLC2A9 and SLC2A9 - ESRRAP2 being significant based on a threshold derived for interactions between GWA significant SNPs and the genome and jointly explaining 8.0% of the phenotypic variance in SUA levels (3.4% by interaction components). Epistasis signal replication in a CROATIAN population (n = 1772) was limited at the SNP level but improved dramatically at the gene ontology level. In addition, gene ontology terms enriched by the epistasis signals in each population support links between SUA levels and neurological disorders. We conclude that GWA epistasis analysis is useful despite relatively low power in small isolated populations.

Over half of all proteins are glycosylated, and alterations in glycosylation have been observed in numerous physiological and pathological processes. Attached glycans significantly affect protein function; but, contrary to polypeptides, they are not directly encoded by genes, and the complex processes that regulate their assembly are poorly understood. A novel approach combining genome-wide association and high-throughput glycomics analysis of 2,705 individuals in three population cohorts showed that common variants in the Hepatocyte Nuclear Factor 1α (HNF1α) and fucosyltransferase genes FUT6 and FUT8 influence N-glycan levels in human plasma. We show that HNF1α and its downstream target HNF4α regulate the expression of key fucosyltransferase and fucose biosynthesis genes. Moreover, we show that HNF1α is both necessary and sufficient to drive the expression of these genes in hepatic cells. These results reveal a new role for HNF1α as a master transcriptional regulator of multiple stages in the fucosylation process. This mechanism has implications for the regulation of immunity, embryonic development, and protein folding, as well as for our understanding of the molecular mechanisms underlying cancer, coronary heart disease, and metabolic and inflammatory disorders.

Author Summary

By combining recently developed high-throughput glycan analysis with genome-wide association study, we performed the first comprehensive analysis of common genetic polymorphisms that affect protein glycosylation. Over half of all proteins are glycosylated; but, due to difficulties in glycan analysis and the absence of a genetic template for their synthesis, knowledge about the complex processes that regulate glycan assembly is still limited. We demonstrated that HNF1α regulates the expression of key fucosyltransferase and fucose biosynthesis genes and acts as a master regulator of plasma protein fucosylation. Proper protein fucosylation is essential in numerous processes including inflammation, cancer, and coronary heart disease, thus the identification of a master regulator of plasma protein fucosylation has important implications for understanding both normal biological functions and disease processes.

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 (FEV1) and the ratio of FEV1 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 ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 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.