Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034(11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45-6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99-3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07-2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28-0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25-2.21]) and Asian (1.51 [1.28-1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34-3.15]).

OBJECTIVELipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat.RESEARCH DESIGN AND METHODSTo investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10).RESULTSAbdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.CONCLUSIONSEnlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

OBJECTIVE-Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.RESEARCH DESIGN AND METHODS-We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations. There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, ␥-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P Ͻ 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10 -1.25]; P ϭ 3 ϫ 10 Ϫ6 ). RESULTS-EachCONCLUSIONS-FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of Ͼ12,000 individuals were needed to detect associations at P Ͻ 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions. Diabetes 57:1419-1426, 2008T he global prevalence of obesity and overweight (defined by a BMI Ն30 and Ն25 kg/m 2 , respectively) is increasing rapidly (1). Obesity and overweight are key risk factors for type 2 diabetes (2). Although recent increases in obesity reflect lifestyle changes, genetic factors are also important in predisposing some individuals to obesity.Common variation in the FTO (fat mass-and obesityassociated) gene is associated with higher BMI and the risk of obesity in populations of European and Hispanic ancestry (3-5). Each copy of the A allele at rs9939609 is associated with a 0.10-SD (95% CI 0.08 -0.12) higher BMI, equivalent to an increase of ϳ0.4 kg/m 2 , and a 1.31-fold (1.23-1.39) higher odds of obesity (3). A study of 5,243 children showed that the effect is almost exclusively mediated by differences in fat mass (3). The FTO variant is also associated with higher odds of type 2 diabetes (per allele odds ratio [OR] ϳ1.25; P ϭ 5 ϫ 10 Ϫ8 ), although this effect can be entirely explained by differences in BMI between case and control subjects (3,6 -9).The association between FTO genotype and type 2 diabetes suggests that the FTO alleles that raise adiposity have adverse metabolic consequences. However, the question of which metabolic phenotypes and to what degree they are altered has not been tested in large numbers. Obesity is associated with insulin resistance, nonalcoholic fatty liver disease, hyperglycemia, hypertension, and dyslipidemia in the general population (10). These associations continue throughout the BMI range and are often seen as e...

Here we report the first complete sequence and gene map of a human major histocompatibility complex (MHC), a region on chromosome 6 which is essential to the immune system. When it was discovered over 50 years ago the region was thought to specify histocompatibility genes, but their nature has been resolved only in the last two decades. Although many of the 224 identified gene loci (128 predicted to be expressed) are still of unknown function, we estimate that about 40% of the expressed genes have immune system function. Over 50% of the MHC has been sequenced twice, in different haplotypes, giving insight into the extraordinary polymorphism and evolution of this region. Several genes, particularly of the MHC class II and III regions, can be traced by sequence similarity and synteny to over 700 million years ago, clearly predating the emergence of the adaptive immune system some 400 million years ago. The sequence is expected to be invaluable for the identification of many common disease loci. In the past, the search for these loci has been hampered by the complexity of high gene density and linkage disequilibrium.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

De novo lipogenesis (DNL) is paradoxically up-regulated by its end product, saturated fatty acids (SAFAs). We tested the hypothesis that SAFA-induced up-regulation of DNL reflects coordinate up-regulation of elongation and desaturation pathways for disposal of SAFAs and production of monounsaturated fatty acids to protect cells from SAFA toxicity. Human preadipocytes were differentiated in vitro for 14 days with [U-13 C]palmitate (0 -200 M) to distinguish exogenous fatty acids from those synthesized by DNL. Exogenous palmitate up-regulated DNL (p < 0.001) concomitantly with SCD and elongation (each p < 0.001). Adipocytes from some donors were intolerant to high palmitate concentrations (400 M). Palmitate-intolerant cells showed lower TG accumulation. They had lower expression of SCD mRNA and less monounsaturated fatty acids in TG, emphasizing the importance of desaturation for dealing with exogenous SAFAs. There was greater [U-13 C]palmitate incorporation in phospholipids. SCD knockdown with small interfering RNA caused down-regulation of DNL and of expression of DNLrelated genes, with reduced membrane fluidity (p < 0.02) and insulin sensitivity (p < 0.01), compared with scrambled small interfering RNA controls. There was preferential channeling of DNL-derived versus exogenous palmitate into elongation and of DNL-derived versus exogenous stearate into desaturation. DNL may not act primarily to increase fat stores but may serve as a key regulator, in tandem with elongation and desaturation, to maintain cell membrane fluidity and insulin sensitivity within the human adipocyte.In many cell types, including pancreatic ␤-cells and endothelial cells, the saturated fatty acid (SAFA) 2 palmitate can have adverse effects on cell function, including endoplasmic reticulum stress and apoptosis (1-4). Palmitate-induced apoptosis can be rescued by the monounsaturated fatty acids (MUFAs) palmitoleate (16:1 n-7) and oleate (18:1 n-9), preventing apoptosis and increasing fatty acid storage as triglyceride (TG) (5, 6). Additionally, the adverse effects of an overabundance of saturated fatty acids have been well documented in humans (7,8).De novo lipogenesis (DNL) is the formation of lipids from nonfat precursors such as glucose and produces the SAFAs myristate (14:0, a minor end product) and palmitate (16:0, the main end product). Palmitate and stearate (18:0) are substrates for stearoyl-CoA desaturase (SCD, or ⌬-9 desaturase), which acts to convert these SAFAs to MUFAs palmitoleate and oleate, respectively. In the liver, the pathways of DNL and fatty acid desaturation by SCD appear to be coordinately regulated (9). Therefore, it would seem that SCD plays a crucial role in maintaining the intracellular equilibrium of SAFAs and MUFAs. However, the literature surrounding the role of SCD in cell function and disease is conflicting.Paradoxically, SAFAs have been shown to up-regulate lipogenesis. Early studies in rats showed palmitate to stimulate glucose incorporation into TG fatty acids (10, 11). Several studies of high fat feeding ...

Background/Objectives:Fat distribution is a strong and independent predictor of type 2 diabetes (T2D) and cardiovascular disease (CVD) and is usually determined using conventional anthropometry in epidemiological studies. Dual-energy X-ray absorptiometry (DXA) can measure total and regional adiposity more accurately. Nonetheless, whether DXA provides more precise estimates of cardiovascular risk in relation to total and regional adiposity is not known. We determined the strength of the associations between DXA- and conventional anthropometry determined fat distribution and T2D and CVD risk markers.Subjects/Methods:Waist (WC) and hip circumference (HC) and DXA was used to measure total and regional adiposity in 4950 (2119 men) participants aged 29–55 years from the Oxford Biobank without pre-existing T2D or CVD. Cross-sectional associations were compared between WC and HC vs. DXA-determined regional adiposity (all z-score normalised) with impaired fasting glucose, hypertriglyceridemia, hypertension and insulin resistance (IR).Results:Following adjustment for total adiposity, upper body adiposity measurements showed consistently increased risk of T2D and CVD risk markers except for abdominal subcutaneous fat in both sexes, and arm fat in men, which showed protective associations. Among upper adiposity depots, visceral fat mass showed stronger odds ratios (OR) ranging from 1.69 to 3.64 compared with WC 1.07–1.83. Among lower adiposity depots, HC showed modest protection for IR in both sexes (men: OR 0.80 (95% confidence interval 0.67, 0.96); women: 0.69 (0.56, 0.86)), whereas gynoid fat and in particular leg fat showed consistent and strong protective effects for all outcomes in both men and women. The differential effect of body fat distribution on CVD and T2D were more pronounced at higher levels of total adiposity.Conclusions:Compared with DXA, conventional anthropometry underestimates the associations of regional adiposity with T2D and CVD risk markers. After correcting for overall adiposity, greater subcutaneous fat mass in particular in the lower body is protective relative to greater android or visceral adipose tissue mass.