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Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC.MethodsA GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls.ResultsMR-UC was associated with more extensive disease (P = 2.7 × 10−6) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10−16) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10−6).ConclusionsA SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC. (Inflamm Bowel Dis 2010)

Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities. We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed. We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

Nonadherence to cardiovascular medications such as statins is a common, important problem. Clinicians currently rely on intuition to identify medication nonadherence. The visit-to-visit variability (VVV) of low-density lipoprotein (LDL) cholesterol might represent an opportunity to identify statin nonadherence with greater accuracy. We examined the clinical and pharmacy data from 782 members of the Boston Medical Center Health Plan, seen at either the Boston Medical Center or its affiliated community health centers, who were taking statins and had ≥3 LDL cholesterol measurements from 2008 to 2011. The LDL cholesterol VVV (defined by the within-patient SD) was categorized into quintiles. Multivariate logistic regression models were generated with statin nonadherence (defined by the standard 80% pharmacy refill-based medication possession ratio threshold) as the dependent variable. The proportion of statin nonadherence increased across the quintiles of LDL cholesterol VVV (64.3%, 71.2%, 89.2%, 92.3%, 91.7%). Higher quintiles of LDL cholesterol VVV had a strong positive association with statin nonadherence, with an adjusted odds ratio of 3.4 (95% confidence interval 1.7 to 7.1) in the highest versus lowest quintile of LDL cholesterol VVV. The age- and gender-adjusted model had poor discrimination (C-statistic 0.62, 95% confidence interval 0.57 to 0.67), but the final adjusted model (age, gender, race, mean LDL cholesterol) demonstrated good discrimination (C-statistic 0.75, 95% confidence interval 0.71 to 0.79) between the adherent and nonadherent patients. In conclusion, the VVV of LDL cholesterol demonstrated a strong association with statin nonadherence in a clinic setting. Furthermore, a VVV of LDL cholesterol-based model had good discrimination characteristics for statin nonadherence. Research is needed to validate and generalize these findings to other populations and biomarkers.

Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited. We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor β1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years. Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 μg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor β1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk. In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.

BACKGROUND Diabetes may be an independent risk factor for atrial fibrillation. However, results from prior studies are in conflict, and no study has examined diabetes duration or glycemic control. OBJECTIVE To examine the association of diabetes with risk of atrial fibrillation and to describe risk according to diabetes duration and glycemic control. DESIGN A population-based case-control study. PARTICIPANTS Within a large, integrated healthcare delivery system, we identified 1,410 people with newly-recognized atrial fibrillation from ICD-9 codes and validated cases by review of medical records. 2,203 controls without atrial fibrillation were selected from enrollment lists, stratified on age, sex, hypertension, and calendar year. MAIN MEASURES Information on atrial fibrillation, diabetes and other characteristics came from medical records. Diabetes was defined based on physician diagnoses recorded in the medical record, and pharmacologically treated diabetes was defined as receiving antihyperglycemic medications. Information about hemoglobin A1c levels came from computerized laboratory data. KEY RESULTS Among people with atrial fibrillation, 252/1410 (17.9%) had pharmacologically treated diabetes compared to 311/2203 (14.1%) of controls. The adjusted OR for atrial fibrillation was 1.40 (95% CI 1.15-1.71) for people with treated diabetes compared to those without diabetes. Among those with treated diabetes, the risk of developing atrial fibrillation was 3% higher for each additional year of diabetes duration (95% CI 1-6%). Compared to people without diabetes, the adjusted OR for people with treated diabetes with average hemoglobin A1c ≤7 was 1.06 (95% CI 0.74-1.51); for A1c >7 but ≤8, 1.48 (1.09-2.01); for A1c >8 but ≤9, 1.46 (1.02-2.08); and for A1c >9, 1.96 (1.22–3.14). CONCLUSIONS Diabetes was associated with higher risk of developing atrial fibrillation, and risk was higher with longer duration of treated diabetes and worse glycemic control. Future research should identify and test approaches to reduce the risk of atrial fibrillation in people with diabetes.

Caroline Fox and colleagues report results of a genome-wide association study to identify common variants associated with indices of renal function. They show that variants at UMOD , a gene previously implicated in rare monogenic forms of kidney disease, are associated with risk of chronic kidney disease in the general population. Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity 1 . We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m 2 ) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations ( P < 5 × 10 −8 ) with CKD at the UMOD locus, with eGFRcrea at UMOD , SHROOM3 and GATM-SPATA5L1 , and with eGFRcys at CST and STC1 . UMOD encodes the most common protein in human urine, Tamm-Horsfall protein 2 , and rare mutations in UMOD cause mendelian forms of kidney disease 3 . Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10⁻⁹) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10⁻⁸) were associated with LTL at a genome-wide significance level (P < 5 x 10⁻⁸). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10⁻⁵). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

Use of long-term constitutive expression of VEGF for therapeutic angiogenesis may be limited by the growth of abnormal blood vessels and hemangiomas. We investigated the relationship between VEGF dosage and the morphology and function of newly formed blood vessels by implanting retrovirally transduced myoblasts that constitutively express VEGF164 into muscles of adult mice. Reducing VEGF dosage by decreasing the total number of VEGF myoblasts implanted did not prevent vascular abnormalities. However, when clonal populations of myoblasts homogeneously expressing different levels of VEGF were implanted, a threshold between normal and aberrant angiogenesis was found. Clonal myoblasts that expressed low to medium levels of VEGF induced growth of stable, pericyte-coated capillaries of uniform size that were not leaky and became VEGF independent, as shown by treatment with the potent VEGF blocker VEGF-TrapR1R2. In contrast, clones that expressed high levels of VEGF induced hemangiomas. Remarkably, when different clonal populations were mixed, even a small proportion of cells with high production of VEGF was sufficient to cause hemangioma growth. These results show for the first time to our knowledge that the key determinant of whether VEGF-induced angiogenesis is normal or aberrant is the microenvironmental amount of growth factor secreted, rather than the overall dose. Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors.

Background: Obesity is an established risk factor for gestational diabetes. It is not known whether this risk might be reduced through weight loss between pregnancies. We sought to determine whether weight loss between pregnancies reduced the risk of gestational diabetes among obese women. Methods: We conducted a population-based cohort study of 4102 women with 2 or more singleton live births in Washington State between 1992 and 1998. All subjects were nondiabetic and obese (at least 200 lbs) at their first birth during these years. Weight change was calculated as the difference between prepregnancy weight for the 2 pregnancies. We estimated relative risks of gestational diabetes at the subsequent delivery through stratified analyses and Mantel-Haenszel estimates. Results: Thirty-two percent of women lost weight between pregnancies, with a mean weight loss of 23 lbs. Women who lost at least 10 lbs between pregnancies had a decreased risk of gestational diabetes relative to women whose weight changed by less than 10 lbs (relative risk = 0.63; 95% confidence interval = 0.38-1.02, adjusted for age and weight gain during each pregnancy). Of the 61% of women who gained weight between pregnancies, the mean weight gain was 22 lbs. Women who gained at least 10 lbs had an increased risk of gestational diabetes (1.47; 1.05-2.04). Conclusions: Even moderate changes in prepregnancy weight can apparently affect the risk of gestational diabetes among obese women. This may offer further motivation for interventions aimed at reducing obesity among women of reproductive age.