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Because informed consent requires discussion of alternative treatments, proper consent for dialysis should incorporate discussion about other renal replacement options including kidney transplantation (KT). Accordingly, dialysis providers are required to indicate KT provision of information (KTPI) on CMS Form-2728; however, provider-reported KTPI does not necessarily imply adequate provision of information. Furthermore, the effect of KTPI on pursuit of KT remains unclear. We compared provider-reported KTPI (Form-2728) with patient-reported KTPI (in-person survey of whether a nephrologist or dialysis staff had discussed KT) in a prospective ancillary study of 388 hemodialysis initiates. KTPI was reported by both patient and provider for 56.2% of participants, by provider only for 27.8%, by patient only for 8.3%, and by neither for 7.7%. Among participants with provider-reported KTPI, older age was associated with lack of patient-reported KTPI. Linkage with the Scientific Registry for Transplant Recipients showed that 20.9% of participants were subsequently listed for KT. Patient-reported KTPI was independently associated with a 2.95-fold (95% confidence interval [95% CI], 1.54 to 5.66; P=0.001) higher likelihood of KT listing, whereas provider-reported KTPI was not associated with listing (hazard ratio, 1.18; 95% CI, 0.60 to 2.32; P=0.62). Our findings suggest that patient perception of KTPI is more important for KT listing than provider-reported KTPI. Patient-reported and provider-reported KTPI should be collected for quality assessment in dialysis centers because factors associated with discordance between these metrics might inform interventions to improve this process.

Low serum magnesium has been associated with kidney function decline in persons with diabetes as well as cardiovascular disease in the general population. As the association of serum magnesium with incident kidney disease in the general population is unknown, we assessed this in 13,226 participants (aged 45-65) in the Atherosclerosis Risk in Communities study with baseline estimated glomerular filtration rate of at least 60 ml/min per 1.73 m(2) in years 1987-89 and followed through 2010. The risks for incident chronic kidney disease (CKD) and end-stage renal disease (ESRD) associated with baseline total serum magnesium levels were evaluated using Cox regression. There were 1965 CKD and 208 ESRD events during a median follow-up of 21 years. In adjusted analysis, low serum magnesium levels (0.7 mmol/l or less) had significant associations with incident CKD and ESRD compared with the highest quartile with adjusted hazard ratio of 1.58 (95% CI: 1.35-1.87) for CKD and 2.39 (95% CI: 1.61-3.56) for ESRD. These associations remained significant after excluding users of diuretics and across subgroups stratified by hypertension, diabetes, and self-reported race. Thus, in a large sample of middle-aged adults, low total serum magnesium was independently associated with incident CKD and ESRD. Further studies are needed to determine whether modification of serum magnesium levels might alter subsequent incident kidney disease rates.

Beta-2 microglobulin (B2M) is a component of the major histocompatibility complex (MHC) class I molecule and has been studied as a biomarker of kidney function, cardiovascular diseases and mortality. Little is known about the genes influencing its levels directly or through glomerular filtration rate (GFR). We conducted a genome-wide association study of plasma B2M levels in 6738 European Americans from the Atherosclerosis Risk in Communities study to identify novel loci for B2M and assessed its association with known estimated GFR (eGFR) loci. We identified 2 genome-wide significant loci. One was in the human leukocyte antigen (HLA) region on chromosome 6 (lowest p value = 1.8 × 10(-23) for rs9264638). At this locus, 6 index SNPs accounted for 3.2 % of log(B2M) variance, and their association with B2M could largely be explained by imputed classical alleles of the MHC class I genes: HLA-A, HLA-B, or HLA-C. The index SNPs at this locus were not associated with eGFR based on serum creatinine (eGFRcr). The other locus of B2M was on chromosome 12 (rs3184504 at SH2B3, beta = 0.02, p value = 3.1 × 10(-8)), which was previously implicated as an eGFR locus. In conclusion, although B2M is known to be a component of MHC class I molecule, the association between HLA class I alleles and plasma B2M levels in a community-based population is novel. The identification of the two novel loci for B2M extends our understanding of its metabolism and informs its use as a kidney filtration biomarker.

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

Carbon isotopic signatures (“δ13C”) might reflect consumption of corn- and cane-based sweeteners. The authors hypothesized that the δ13C value of human serum is higher for individuals with high versus low intakes of corn- and cane-based sweeteners (measured as sweetened beverage intake). They conducted a cross-sectional study within the Atherosclerosis Risk in Communities Magnetic Resonance Imaging study (Maryland, 2005–2006). Diet was assessed by food frequency questionnaire, and blinded serum samples were assayed by natural abundance stable isotope mass spectroscopy. Studied were 186 participants (53% male; mean age, 71 years; mean body mass index, 30 kg/m2). Serum δ13C values for individuals with high sweetened beverage intakes were significantly higher than for those with low intakes (−19.15‰ vs. −19.47‰, P < 0.001). Serum δ13C value increased 0.20‰ for every serving/day of sweetened beverages (P < 0.01). The association between sweetened beverages and serum δ13C value remained significant after adjustment for confounding by corn-based product intake (P < 0.001). Serum δ13C values were also associated with waist circumference, body mass index, and waist-to-hip ratio. This study provides the first known evidence that the δ13C value of human serum differs between persons consuming low and high amounts of sweets. Within the proper framework, serum δ13C value could be developed into an objective biomarker promoting more reliable assessment of dietary sweets intake.

OBJECTIVE—The purpose of this study was to examine the association between parental history of type 2 diabetes and glycemic control among diabetic urban African Americans. RESEARCH DESIGN AND METHODS—Study participants included 359 African Americans with type 2 diabetes from Baltimore, Maryland, enrolled in Project Sugar 2. Participants underwent an interview-administrated questionnaire that asked about family history, sociodemographics, clinical characteristics, and knowledge and perception of adequate glycemic control. Regression analysis was used to determine the association between parental history of diabetes and glycemic control, as measured by A1C. RESULTS—In the comparisons between participants with and without a parental history of diabetes, those with a positive parental history tended to be younger, have higher glucose levels, and have higher blood glucose levels before calling a doctor (all P < 0.05). After adjustments for age, sex, and BMI, there was a significant association (P = 0.02) between A1C and parental history with the mean A1C difference between those with a positive and a negative parental history being 0.58%. However, after adjustment for duration of diabetes, the association was no longer significant (P = 0.11). However, there was a tendency for individuals with two diabetic parents to have higher A1C (P = 0.011). CONCLUSIONS—From these results, we conclude that among the urban African American participants who were aware of their parental history of diabetes, a positive parental history was associated with worse glycemic control, partly due to longer duration of diabetes. Parental history did not appear to be associated with better knowledge or perception of adequate glycemic control.

Background and objectives Trajectories of eGFR in patients with CKD are highly variable. Only a subset of patients with CKD experiences a steady decline in eGFR. The objective of our study was to investigate whether eGFR trajectory patterns differ by APOL1 risk status. Design, setting, participants, & measurements Our study was a longitudinal observational study of 622 participants in the African American Study of Kidney Disease and Hypertension with APOL1 genotyping and sufficient follow-up for estimating GFR trajectories. The predictor was APOL1 high–risk status (having two copies of the G1 or G2 risk alleles) versus low-risk status (zero or one copy of the risk alleles), and the outcome was four eGFR trajectory patterns on the basis of the joint probabilities of linearity and progression: steady decline, unsteady decline, steady stable, and unsteady stable. Results Over a median follow-up of 9 years, 24.0% of participants experienced steady eGFR decline, 25.9% had an unsteady decline, 25.6% were steady and stable, and 24.6% were unsteady but stable. Those experiencing steady decline had lower eGFR and higher urine protein-to-creatinine ratio at baseline than participants with the other eGFR trajectory patterns. The APOL1 high–risk group was associated with a greater odds for the steady decline pattern than the APOL1 low–risk group (unadjusted odds ratio, 2.45; 95% confidence interval, 1.62 to 3.69). This association remained significant after adjusting for demographic factors, baseline eGFR, urine protein-to-creatinine ratio, treatment assignment, and follow-up time (adjusted odds ratio, 1.59; 95% confidence interval, 1.00 to 2.52). Conclusions Among patients with CKD attributed to hypertension, those with the APOL1 high–risk genotype were more likely to experience a steady decline trajectory in eGFR than those without the APOL1 high–risk genotype. These findings suggest a persistent underlying pathophysiologic process in those patients with the APOL1 high–risk genotype.

Background Higher left ventricular mass (LV) strongly predicts cardiovascular mortality in hemodialysis patients. Although several parameters of preload and afterload have been associated with higher LV mass, whether these parameters independently predict LV mass, remains unclear. Methods This study examined a cohort of 391 adults with incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study. The main exposures were systolic and diastolic blood pressure (BP), pulse pressure, arterial stiffness by pulse wave velocity (PWV), volume status estimated by pulmonary pressures using echocardiogram and intradialytic weight gain. The primary outcome was baseline left ventricular mass index (LVMI). Results Each systolic, diastolic blood, and pulse pressure measurement was significantly associated with LVMI by linear regression regardless of dialysis unit BP or non-dialysis day BP measurements. Adjusting for cardiovascular confounders, every 10 mmHg increase in systolic or diastolic BP was significantly associated with higher LVMI (SBP β = 7.26, 95 % CI: 4.30, 10.23; DBP β = 10.05, 95 % CI: 5.06, 15.04), and increased pulse pressure was also associated with higher LVMI (β = 0.71, 95 % CI: 0.29, 1.13). Intradialytic weight gain was also associated with higher LVMI but attenuated effects after adjustment (β = 3.25, 95 % CI: 0.67, 5.83). PWV and pulmonary pressures were not associated with LVMI after multivariable adjustment (β = 0.19, 95 % CI: −1.14, 1.79; and β = 0.10, 95 % CI: −0.51, 0.70, respectively). Simultaneously adjusting for all main exposures demonstrated that higher BP was independently associated with higher LVMI (SBP β = 5.64, 95 % CI: 2.78, 8.49; DBP β = 7.29, 95 % CI: 2.26, 12.31, for every 10 mmHg increase in BP). Conclusions Among a younger and incident hemodialysis population, higher systolic, diastolic, or pulse pressure, regardless of timing with dialysis, is most associated with higher LV mass. Future studies should consider the use of various BP measures in examining the impact of BP on LVM and cardiovascular disease. Findings from such studies could suggest that high BP should be more aggressively treated to promote LVH regression in incident hemodialysis patients. Electronic supplementary material The online version of this article (doi:10.1186/s12882-015-0131-4) contains supplementary material, which is available to authorized users.

Background and objectives Disparities in kidney transplantation remain; one mechanism for disparities in access to transplantation (ATT) may be patient-perceived concerns about pursuing transplantation. This study sought to characterize prevalence of patient-perceived concerns, explore interrelationships between concerns, determine patient characteristics associated with concerns, and assess the effect of concerns on ATT. Design, setting, participants, & measurements Prevalences of 12 patient-perceived concerns about pursuing transplantation were determined among 348 adults who recently initiated dialysis, recruited from 26 free-standing dialysis centers around Baltimore, Maryland (January 2009–March 2012). Using variable reduction techniques, concerns were clustered into two categories (health-related and psychosocial) and quantified with scale scores. Associations between patient characteristics and concerns were estimated using modified Poisson regression. Associations between concerns and ATT were estimated using Cox models. Results The most frequently cited patient-perceived concerns were that participants felt they were doing fine on dialysis (68.4%) and felt uncomfortable asking someone to donate a kidney (29.9%). Older age was independently associated with having high health-related (adjusted relative risk, 1.35 [95% confidence interval, 1.20 to 1.51], for every 5 years older for those ≥60 years) or psychosocial (1.15 [1.00 to 1.31], for every 5 years older for those aged ≥60 years) concerns, as was being a woman (1.72 [1.21 to 2.43] and 1.55 [1.09 to 2.20]), having less education (1.59 [1.08 to 2.35] and 1.77 [1.17 to 2.68], comparing postsecondary education to grade school or less), and having more comorbidities (1.18 [1.08 to 1.30] and 1.18 [1.07 to 1.29], per one comorbidity increase). Having never seen a nephrologist before dialysis initiation was associated with high psychosocial concerns (1.48 [1.01 to 2.18]). Those with high health-related (0.37 [0.16 to 0.87]) or psychosocial (0.47 [0.23 to 0.95]) concerns were less likely to achieve ATT (median follow-up time 2.2 years; interquartile range, 1.6–3.2). Conclusions Patient-perceived concerns about pursuing kidney transplantation are highly prevalent, particularly among older adults and women. Reducing these concerns may help decrease disparities in ATT.

Background Low serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression. Results The GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta = −0.013, p = 6.1x10−9). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta = −0.028, p = 7.3x10−5) than in those without any hormone use (beta = −0.011, p = 7.0x10−8, p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (

Objectives: To explore whether disparities in age and sex in access to kidney transplantation (KT) originate at the time of prereferral discussions about KT. Design: Cross-sectional survey. Setting: Outpatient dialysis centers in Maryland (n = 26). Participants: Individuals who had recently initiated hemodialysis treatment (N = 416). Measurements: Participants reported whether medical professionals (nephrologist, primary medical doctor, dialysis staff) and social group members (significant other, family member, friend) discussed KT with them and, when applicable, rated the tone of discussions. Relative risks were estimated using modified Poisson regression. Results: Participants aged 65 and older were much less likely than those who were younger to have had discussions with medical professionals (44.5% vs 74.8%, P < .001) or social group members (47.3% vs 63.1%, P = .005). Irrespective of sex and independent of race, health-related factors, and dialysis-related characteristics, older adults were more likely not to have had discussions with medical professionals (relative risk (RR) = 1.13, 95% confidence interval (CI) = 1.03�1.24, for each 5-year increase in age through 65; RR = 1.28, 95% CI = 1.14�1.42, for each 5-year increase in age beyond 65). Irrespective of age, women were more likely (RR = 1.45, 95% CI = 1.12�1.89) not to have had discussions with medical professionals. For each 5-year increase in age, men (RR = 1.04, 95% CI = 0.99�1.10) and women (RR = 1.17, 95% CI = 1.10�1.24) were more likely not to have discussions with social group members. Of those who had discussions with medical professionals or social group members, older participants described these discussions as less encouraging (all P < .01). Conclusion: Older adults and women undergoing hemodialysis are less likely than younger adults and men to have discussions about KT as a treatment option, supporting a need for better clinical guidelines and education for these individuals, their social network, and their providers.

Arsenic species patterns in urine are associated with risk for cancer and cardiovascular diseases. The organic anion transporter coded by the gene SLCO1B1 may transport arsenic species, but its association with arsenic metabolites in human urine has not yet been studied. The objective of this study is to evaluate associations of urine arsenic metabolites with variants in the candidate gene SLCO1B1 in adults from the Strong Heart Family Study. We estimated associations between % arsenic species biomarker traits and 5 single-nucleotide polymorphisms (SNPs) in the SLCO1B1 gene in 157 participants, assuming additive genetics. Linear regression models for each SNP accounted for kinships and were adjusted for sex, body mass index, and study center. The minor allele of rs1564370 was associated with lower %MMA (p = .0003) and higher %DMA (p = .0002), accounting for 8% of the variance for %MMA and 9% for %DMA. The rs1564370 minor allele homozygote frequency was 17% and the heterozygote frequency was 43%. The minor allele of rs2291075 was associated with lower %MMA (p = .0006) and higher %DMA (p = .0014), accounting for 7% of the variance for %MMA and 5% for %DMA. The frequency of rs2291075 minor allele homozygotes was 1% and of heterozygotes was 15%. Common variants in SLCO1B1 were associated with differences in arsenic metabolites in a preliminary candidate gene study. Replication of this finding in other populations and analyses with respect to disease outcomes are needed to determine whether this novel candidate gene is important for arsenic-associated disease risks.

Physical inactivity accentuates the association of variants in the FTO locus with obesity-related traits but evidence is largely lacking in non-European populations. Here we tested the hypothesis that physical activity (PA) modifies the association of the FTO single-nucleotide polymorphism (SNP) rs9939609 with adiposity traits in 2,656 African Americans (AA) (1,626 women and 1,030 men) and 9,867 European Americans (EA) (5,286 women and 4,581 men) aged 45-66 years in the Atherosclerosis Risk in Communities (ARIC) study. Individuals in the lowest quintile of the sport activity index of the Baecke questionnaire were categorized as low PA. Baseline BMI, waist circumference (WC), and skinfold measures were dependent variables in regression models testing the additive effect of the SNP, low PA, and their interaction, adjusting for age, alcohol use, cigarette use, educational attainment, and percent European ancestry in AA adults, stratified by sex and race/ethnicity. rs9939609 was associated with adiposity in all groups other than AA women. The SNP × PA interaction was significant in AA men (P ≤ 0.002 for all traits) and EA men (P ≤ 0.04 for all traits). For each additional copy of the A (risk) allele, WC in AA men was higher in those with low PA (β(lowPA): 5.1 cm, 95% confidence interval (CI): 2.6-7.5) than high PA (β(highPA): 0.7 cm, 95% CI: -0.4 to 1.9); P (interaction) = 0.002). The interaction effect was not observed in EA or AA women. FTO SNP × PA interactions on adiposity were observed for AA as well as EA men. Differences by sex require further examination.

Objective The minor T-allele of rs780094 in the glucokinase regulator gene (GCKR) associates with a number of metabolic traits including higher triglyceride levels and improved glycemic regulation in study populations of mostly European ancestry. Using data from the Atherosclerosis Risk in Communities (ARIC) Study, we sought to replicate these findings, examine them in a large population-based sample of African American study participants, and to investigate independent associations with other metabolic traits in order to determine if variation in GKCR contributes to their observed clustering. In addition, we examined the association of rs780094 with incident diabetes, coronary heart disease (CHD), and stroke over up mean follow-up times of 8, 15, and 15 years, respectively. Research Design and Methods Race-stratified analyses were conducted among 10,929 white and 3,960 black participants aged 45–64 at baseline assuming an additive genetic model and using linear and logistic regression and Cox proportional hazards models. Results Previous findings replicated among white participants in multivariable adjusted models: the T-allele of rs780094 was associated with lower fasting glucose (p = 10−7) and insulin levels (p = 10−6), lower insulin resistance (HOMA-IR, p = 10−9), less prevalent diabetes (p = 10−6), and higher CRP (p = 10−8), 2-h postprandial glucose (OGTT, p = 10−6), and triglyceride levels (p = 10−31). Moreover, the T-allele was independently associated with higher HDL cholesterol levels (p = 0.022), metabolic syndrome prevalence (p = 0.043), and lower beta-cell function measured as HOMA-B (p = 0.011). Among black participants, the T-allele was associated only with higher triglyceride levels (p = 0.004) and lower insulin levels (p = 0.002) and HOMA-IR (p = 0.013). Prospectively, the T-allele was associated with reduced incidence of diabetes (p = 10−4) among white participants, but not with incidence of CHD or stroke. Conclusions Our findings indicate rs780094 has independent associations with multiple metabolic traits as well as incident diabetes, but not incident CHD or stroke. The magnitude of association between the SNP and most traits was of lower magnitude among African American compared to white participants.

Plasma soluble Receptor for Advanced Glycation End-products (sRAGE) is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P

OBJECTIVE: Although hyperglycemia is hypothesized to increase the short-term risk of infection, this hypothesis has not been well tested in a clinical setting. This study was designed to assess the relationship of perioperative glycemic control to the subsequent risk of infectious complications. RESEARCH DESIGN AND METHODS: A total of 411 adults with diabetes who underwent coronary artery surgery from 1990 to 1995 in the cardiac surgery service of an urban university hospital were included in a nonconcurrent prospective cohort study based on chart review. Perioperative glycemic control was characterized by the mean of six capillary glucose measurements taken during the 36-h interval following surgery. The major outcomes studied were infections of leg and chest wounds, pneumonia, and urinary tract infections. RESULTS: Mean postoperative glucose levels ranged from 121 to 352 mg/dl and were divided into quartiles: quartile 1 (121-206 mg/dl), quartile 2 (207-229 mg/dl), quartile 3 (230-252 mg/dl), and quartile 4 (253352 mg/dl). After simultaneous adjustment for age, sex, race, underlying comorbidity, acute severity of illness, and the length of the stay in the surgical intensive care unit, patients with higher mean capillary glucose readings were at increased risk of developing infections. Compared with people in the lowest quartile of postoperative glucose, those in quartiles 2 (relative odds of infection [95% CI] = 1.17 [0.57-2.40]), 3 (1.86 [0.94-3.68]), and 4 (1.78 [0.86-3.47]) were at progressively higher risk for infection (P = 0.05 for trend). CONCLUSIONS: In patients with diabetes who undergo coronary artery surgery, postoperative hyperglycemia is an independent predictor of short-term infectious complications. Physicians should consider a glucose concentration target of < or =200 mg/dl to reduce the risk of infection.

Background & Aims A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. Methods We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [ PNPLA3 ]), rs2228603 (neurocan [ NCAN ]), rs12137855 ( lysophospholipase-like 1 ), rs780094 (glucokinase regulatory protein [ GCKR ]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [ PPP1R3B ]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. Results The G allele of rs738409 ( PNPLA3 ) and the T allele of rs780094 ( GCKR ) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 ( PPP1R3B ) and the T allele of rs2228603 ( NCAN ) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3 , NCAN , GCKR , and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. Conclusions We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations.

Background This is the first study that has examined non-cardiac incidental findings in research cardiac computed tomography (CT) of hemodialysis patients and their relationship with patient characteristics. Methods We performed a cross-sectional analysis in the Predictors of Arrhythmic and Cardiovascular Events in End-Stage Renal Disease (PACE) study, a prospective cohort study on incident hemodialysis patients. Non-cardiac structures in the cardiac CT scan were reviewed and evaluated. The type and frequencies of non-cardiac incidental CT findings were summarized. Univariate and multivariate logistic regression were performed to analyze the associations between gender, older age, obesity, history of cardiovascular disease (CVD), smoking status, history of chronic pulmonary disease and history of cancer with presence of any incidental CT findings and, separately, pulmonary nodules. Results Among the 260 participants, a total of 229 non-cardiac incidental findings were observed in 145 participants (55.8% of all participants). Of these findings, pulmonary nodules were the most common incidental finding (24.2% of all findings), and 41.3% of them requiring further follow-up imaging per radiology recommendation. Vascular and gastrointestinal findings occurred in 11.8% and 15.3% of participants, respectively. Participants 65 years or older had a higher odds of any incidental findings (Odds Ratio (OR) =2.55; 95% Confidence Intervals (CI) 1.30, 4.99) and pulmonary nodules (OR = 4.80; 95% CI 2.51, 9.18). Prior history of CVD was independently and significantly associated with any incidental findings (OR = 2.00; 95% CI 1.19, 3.40); but not with the presence of pulmonary nodules. Conclusions We demonstrate that the prevalence of incidental findings by cardiac CT scanning is extremely high among patients on hemodialysis. Further investigations to follow-up on the high occurrence of incidental findings during our research study and potentially clinical studies raises important practical, ethical and medico-legal issues that need to be carefully considered in research projects using imaging studies.

Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown. We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter SLC2A9 on chromosome 4p16.1 are associated with uric acid ( , p=3.19×10-23). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women (3.974.935.87 [ 2.55097.5 denoting percentiles], p=4.57×10-23) and independent of previously reported SNPs in SLC2A9 as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes ( ). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude (1.414.707.88, p=5.46×10-03). This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for SLC2A9-mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial.