Trends in Chronic Kidney Disease Care in the US by Race and Ethnicity, 2012-2019.

Importance: Significant racial and ethnic disparities in chronic kidney disease (CKD) progression and outcomes are well documented, as is low use of guideline-recommended CKD care. Objective: To examine guideline-recommended CKD care delivery by race and ethnicity in a large, diverse population. Design, Setting, and Participants: In this serial cross-sectional study, adult patients with CKD that did not require dialysis, defined as a persistent estimated glomerular filtration rate less than 60 mL/min/1.73 m2 or a urine albumin-creatinine ratio of 30 mg/g or higher for at least 90 days, were identified in 2-year cross-sections from January 1, 2012, to December 31, 2019. Data from the OptumLabs Data Warehouse, a national data set of administrative and electronic health record data for commercially insured and Medicare Advantage patients, were used. Exposures: The independent variables were race and ethnicity, as reported in linked electronic health records. Main Outcomes and Measures: On the basis of guideline-recommended CKD care, the study examined care delivery process measures (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker prescription for albuminuria, statin prescription, albuminuria testing, nephrology care for CKD stage 4 or higher, and avoidance of chronic nonsteroidal anti-inflammatory drug prescription) and care delivery outcome measures (blood pressure and diabetes control). Results: A total of 452 238 patients met the inclusion criteria (mean [SD] age, 74.0 [10.2] years; 262 089 [58.0%] female; a total of 7573 [1.7%] Asian, 49 970 [11.0%] Black, 15 540 [3.4%] Hispanic, and 379 155 [83.8%] White). Performance on process measures was higher among Asian, Black, and Hispanic patients compared with White patients for angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use (79.8% for Asian patients, 76.7% for Black patients, and 79.9% for Hispanic patients compared with 72.3% for White patients in 2018-2019), statin use (72.6% for Asian patients, 69.1% for Black patients, and 74.1% for Hispanic patients compared with 61.5% for White patients), nephrology care (64.8% for Asian patients, 72.9% for Black patients, and 69.4% for Hispanic patients compared with 58.3% for White patients), and albuminuria testing (53.9% for Asian patients, 41.0% for Black patients, and 52.6% for Hispanic patients compared with 30.7% for White patients). Achievement of blood pressure control to less than 140/90 mm Hg was similar or lower among Asian (71.8%), Black (63.3%), and Hispanic (69.8%) patients compared with White patients (72.9%). Achievement of diabetes control with hemoglobin A1c less than 7.0% was 50.1% in Asian patients, 49.3% in Black patients, and 46.0% in Hispanic patients compared with 50.3% for White patients. Conclusions and Relevance: Higher performance on CKD care process measures among Asian, Black, and Hispanic patients suggests that differences in medication prescription and diagnostic testing are unlikely to fully explain known disparities in CKD progression and kidney failure. Improving care delivery processes alone may be inadequate for reducing these disparities.

Cost Structures of US Organ Procurement Organizations.

BACKGROUND: The goal is to provide a national analysis of organ procurement organization (OPO) costs. METHODS: Five years of data, for 51 of the 58 OPOs (2013-2017, a near census) were obtained under a FOIA. OPOs are not-for-profit federal contractors with a geographic monopoly. A generalized 15-factor cost regression model was estimated with adjustments to precision of estimates (P) for repeated observations. Selected measures were validated by comparison to IRS forms. RESULTS: Decease donor organ procurement is a $1B/y operation with over 26 000 transplants/y. Over 60% of the cost of an organ is overhead. Profits are $2.3M/OPO/y. Total assets are $45M/OPO and growing at 9%/y. "Tissue" (skin, bones) generates $2-3M profit/OPO/y. A comparison of the highest with the lower costing OPOs showed our model explained 75% of the cost difference. Comparing costs across OPOs showed that highest-cost OPOs are smaller, import 44% more kidneys, face 6% higher labor costs, report 98% higher compensation for support personnel, spend 46% more on professional education, have 44% fewer assets, compensate their Executive Director 36% less, and have a lower procurement performance (SDRR) score. CONCLUSIONS: Profits and assets suggest that OPOs are fiscally secure and OPO finances are not a source of the organ shortage. Asset accumulation ($45M/OPO) of incumbents suggests establishing a competitive market with new entrants is unlikely. Kidney-cost allocations support tissue procurements. Professional education spending does not reduce procurement costs. OPO importing of organs from other OPOs is a complex issue possibly increasing cost ($6K/kidney).

The organ procurement costs of expanding deceased donor organ acceptance criteria: Evidence from a cost function model.

A potential solution to the deceased donor organ shortage is to expand donor acceptability criteria. The procurement cost implications of using nonstandard donors is unknown. Using 5 years of US organ procurement organization (OPO) data, we built a cost function model to make cost projections: the total cost was the dependent variable; production outputs, including the number of donors and organs procured, were the independent variables. In the model, procuring one kidney or procuring both kidneys from double/en bloc transplantation from a single-organ donor resulted in a marginal cost of $55 k (95% confidence interval [CI] $28 k, $99 k) per kidney, and procuring only the liver from a single-organ donor results in a marginal cost of $41 k (95% CI $12 k, $69 k) per liver. Procuring two kidneys for two candidates from a donor lowered the marginal cost to $36 k (95% CI $22 k, $66 k) per kidney, and procuring two kidneys and a liver lowers the marginal cost to $24 k (95% CI $17 k, $45 k) per organ. Economies of scale were observed, where high OPO volume was correlated with lower costs. Despite higher cost per organ than for standard donors, kidney transplantation from nonstandard donors remained cost-effective based on contemporary US data.

Estimated impact of novel coronavirus-19 and transplant center inactivity on end-stage renal disease-related patient mortality in the United States.

To predict whether the COVID-19 pandemic and transplant center responses could have resulted in preventable deaths, we analyzed registry information of the US end-stage renal disease (ESRD) patient population awaiting kidney transplantation. Data were from the Organ Procurement and Transplantation Network (OPTN), the US Centers for Disease Control and Prevention, and the United States Renal Data System. Based on 2019 OPTN reports, annualized reduction in kidney transplantation of 25%-100% could result in excess deaths of wait-listed (deceased donor) transplant candidates from 84 to 337 and living donor candidate excess deaths from 35 to 141 (total 119-478 potentially preventable deaths of transplant candidates). Changes in transplant activity due to COVID-19 varied with some centers shutting down while others simply heeded known or suspected pandemic risks. Understanding potential excess mortality for ESRD transplant candidates when circumstances compel curtailment of transplant activity may inform policy and procedural aspects of organ transplant systems allowing ways to best inform patients and families as to potential risks in shuttering organ transplant activity. Considering that more than 700 000 Americans have ESRD with 100 000 awaiting a kidney transplant, our highest annual estimate of 478 excess total deaths from postponing kidney transplantation seems modest.

Changes in employment status prior to initiation of maintenance hemodialysis in the USA from 2006 to 2015.

BACKGROUND: Hemodialysis (HD) patients have high unemployment rates associated with higher mortality and poor quality of life. Changes in employment status prior to dialysis initiation may predict subsequent patient outcomes. We sought to examine US national trends in employment status prior to and at HD initiation, risk factors for job loss and their association with transplantation and mortality. METHODS: Employment was defined as working full-time or part-time for 496 989 patients initiating maintenance HD from 2006 to 2015. Associations between patient and dialysis facility characteristics and employment change were analyzed using multivariable logistic regression. Cox regression was used to assess job loss with mortality and transplantation. RESULTS: About 26% (n = 129 622) of patients were employed 6 months prior compared with 15% (n = 75 719) at HD initiation. Employment rates 6 months prior to HD initiation decreased from 29% in 2006 to 23% in 2014. Employed patients who maintained employment increased from 57% in 2006 to 64% in 2015. Patients who were older, female, Hispanic, Black, with more comorbidities or living in low-income zip codes were less likely to maintain employment. Facility characteristics associated with employment maintenance included nonprofit status, more stations, dialysis availability after 5 p.m. and home dialysis training. Patients maintaining employment during the 6 months prior to HD had lower mortality and higher transplantation rates than patients who became unemployed. CONCLUSIONS: Employment rates among HD patients are low and employment changes common during the 6 months prior to HD. Maintaining employment status was associated with key patient and facility characteristics, kidney transplantation and survival.

Chronic disease burdens of incident U.S. dialysis patients, 1996 - 2015
.

INTRODUCTION: The United States Renal Data System has collected data on incident hemodialysis (HD) and peritoneal dialysis (PD) patients since 1995, allowing prevalence of chronic diseases over the past 20 years to be measured. MATERIALS AND METHODS: All first-time HD/PD patients 1996 - 2015 were analyzed. Diabetes and cardiovascular diseases were grouped into single variables. Prevalence of each condition was evaluated with logistic regression. Odds ratios (OR) for a 5-year difference in year of dialysis initiation were calculated. Models were adjusted for age, sex, and race, with interactions between modality and year. One- and 5-year mortality were calculated. RESULTS: Age increased among 1,847,212 HD and 156,965 PD patients; PD patients were younger. First-year mortality fell from 24.4 to 21.1% in HD patients and from 17.1 to 8.5% in PD. 5-year mortality fell from 65.9 to 58.6% in HD patients and from 56.3 to 40.4% in PD. Hypertension increased (OR = 1.34 for HD, 1.35 for PD), as did diabetes (OR = 1.16 for HD, 1.06 for PD) and cancer (OR = 1.09 for HD, 1.10 for PD). Cardiovascular disease decreased in PD (OR = 0.87) only. Stroke decreased (OR = 0.98 for HD, 0.90 for PD), as did peripheral vascular disease (OR = 0.91 for HD, 0.82 for PD). Lung disease increased in HD (OR = 1.10) but decreased in PD (OR = 0.97). DISCUSSION: Mortality and cardiovascular disease burden have declined for dialysis patients in the United States despite an aging population that is increasingly hypertensive and diabetic. Comorbid disease burdens among HD and PD patients have diverged over time, with PD patients having fewer comorbid conditions.

The cost of procuring deceased donor kidneys: Evidence from OPO cost reports 2013-2017.

Using 5 years of US organ procurement organization (OPO) data, we determined the cost of recovering a viable (ie, transplanted) kidney for each of 51 OPOs. We also examined the effects on OPO costs of the recovery of nonviable (ie, discarded) kidneys and other OPO metrics. Annual cost reports from 51 independent OPOs were used to determine the cost per recovered kidney for each OPO. A quadratic regression model was employed to estimate the relationship between the cost of kidneys and the number of viable kidneys recovered, as well as other OPO performance indicators. The cost of transplanted kidneys at individual OPOs ranged widely from $24 000 to $56 000, and the average was $36 000. The cost of a viable kidney tended to decline with the number of kidneys procured up to 549 kidneys per year and then increase. Of the total 81 401 kidneys recovered, 66 454 were viable and 14 947 (18.4%) were nonviable. The costs of kidneys varied widely over the OPOs studied, and costs were a function of the recovered number of viable and nonviable organs, local cost levels, donation after cardiac death, year, and Standardized Donor Rate Ratio. Cost increases were 3% per year.

Obstetric Deliveries in US Women With ESKD: 2002-2015.

RATIONALE & OBJECTIVE: Women with end-stage kidney disease (ESKD) have decreased fertility and are at increased risk for pregnancy complications. This study examined secular trends and outcomes of obstetric deliveries in a US cohort of women with ESKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Women aged 18 to 44 years with ESKD and registered in the US Renal Data System from 2002 to 2015. EXPOSURE: ESKD modality (hemodialysis [HD], peritoneal dialysis, transplantation). OUTCOMES: Infant delivery, preterm delivery, cesarean delivery. ANALYTICAL APPROACH: Unadjusted delivery rates were expressed as number of delivering women per 1,000 patient-years among women aged 18 to 44 years within each year during the study period, stratified by ESKD modality. Logistic regression models were used to evaluate associations of delivery, preterm delivery, and cesarean delivery with patient characteristics. RESULTS: The delivery rate in women undergoing HD and women with a kidney transplant increased from 2.1 to 3.6 and 3.1 to 4.6 per 1,000 patient-years, respectively (P<0.001 for each). The delivery rate in patients undergoing peritoneal dialysis was lower and did not increase significantly (P=0.9). Women with a transplant were less likely to deliver preterm compared with women undergoing HD (OR, 0.92; 95% CI, 0.84-1.00), though more likely have a cesarean delivery (OR, 1.18; 95% CI, 1.06-1.31). For deliveries occurring in the 2012 to 2015 period, 75% of women treated with HD were prescribed 4 or fewer outpatient HD treatments per week and 25% were prescribed 5-plus treatments per week in the 30 days before delivery. LIMITATIONS: Ascertainment of outcomes and comorbid conditions using administrative claims data. CONCLUSIONS: The delivery rate in women of reproductive age with ESKD increased from 2002 to 2015 among those treated with transplantation or HD. Women with a functioning transplant were less likely to deliver preterm, but more likely to have a cesarean delivery. Prescriptions for outpatient intensified HD for pregnant women with ESKD were infrequent in 2012 to 2015.

Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals.

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

Prevalence and Risk Factors for CKD: A Comparison Between the Adult Populations in China and the United States.

INTRODUCTION: Chronic kidney disease (CKD) is an important noncommunicable disease globally. Overall prevalence of CKD and distribution of its stages differ between countries. We postulate that these differences may not only be due to variation in prevalence of risk factors but also their differential impact in different populations or settings. METHODS: We used nationally representative data on the adult populations from both the United States (US; National Health and Nutrition Examination Survey [NHANES], 2009 to 2010, N = 5557) and China (China National Survey of CKD, 2009 to 2010, N = 46,949). Age, sex, central obesity, cardiovascular disease, diabetes, hypertension, and hyperuricemia were explored as candidate risk factors for CKD. The prevalence of CKD was calculated using survey weights. RESULTS: The prevalence of decreased estimated glomerular filtration rate (eGFR), defined as eGFR < 60 ml/min per 1.73 m2, was 6.5% in the US versus 2.7% in China, whereas the prevalence of albuminuria (defined as urine albumin to creatinine ratio of ≥30 mg/g) was 8.1% in the US versus 9.5% in China. The distribution of eGFR categories differed between the countries (P < 0.001). Stronger associations of diabetes with both indicators were seen in the US participants, whereas stronger associations of male sex with both indicators and of hypertension with albuminuria were observed in the Chinese participants (P < 0.05). After multivariable adjustment, a 65% change in prevalence difference for decreased eGFR was seen between China and the US. CONCLUSION: People in China and the US share many common risk factors for CKD, but differences in prevalence and the potential impact of these risk factors for CKD were observed.

State-Level Awareness of Chronic Kidney Disease in the U.S.

INTRODUCTION: This study examined state-level variation in chronic kidney disease (CKD) awareness using national estimates of disease awareness among adults in the U.S. with CKD. METHODS: Data on U.S. adults were obtained from two national, population-based surveys: (1) the Behavioral Risk Factor Surveillance System (BRFSS 2011; n=506,467), a state-level phone survey containing information on self-reported kidney disease; and (2) the National Health and Nutrition Examination Survey (NHANES 2005-2012; n=20,831), containing physical health examination, surveys containing data on self-reported kidney disease, risk factors, and laboratory values. CKD was defined as an estimated glomerular filtration rate of 15-59 mL/minute/1.73 m2 or urinary albumin-to-creatinine ratio >30 mg/g. As BRFSS does not include laboratory data, CKD status for each person was imputed (multiple) based on a logistic regression model predicting NHANES CKD status. CKD awareness in each state was estimated as the weighted proportion of BRFSS participants with imputed CKD who reported having kidney disease. RESULTS: Overall, estimated CKD awareness was 9.0% (95% CI=8.0%, 10.0%), ranging from 5.8% (95% CI=4.8%, 6.8%) in Iowa to 11.7% (95% CI=9.7%, 13.7%) in Arizona. Awareness was greater among adults with hypertension (12.0%) and diabetes (15.3%) than among adults without those conditions, and lower in Hispanics (6.0%) than in non-Hispanic whites (8.8%), non-Hispanic blacks (9.9%), and other racial/ethnic groups (12.7%). CONCLUSIONS: Among individuals with CKD, awareness of their condition was very low and varied approximately twofold among states. This is the first study to estimate awareness of kidney disease by state for the U.S. adult population.

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Trends in Prevalence of Chronic Kidney Disease in the United States.

Background: Trends in the prevalence of chronic kidney disease (CKD) are important for health care policy and planning. Objective: To update trends in CKD prevalence. Design: Repeated cross-sectional study. Setting: NHANES (National Health and Nutrition Examination Survey) for 1988 to 1994 and every 2 years from 1999 to 2012. Participants: Adults aged 20 years or older. Measurements: Chronic kidney disease (stages 3 and 4) was defined as an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2, estimated with the Chronic Kidney Disease Epidemiology Collaboration equation from calibrated serum creatinine measurements. An expanded definition of CKD also included persons with an eGFR of at least 60 mL/min/1.73 m2 and a 1-time urine albumin-creatinine ratio of at least 30 mg/g. Results: The unadjusted prevalence of stage 3 and 4 CKD increased from the late 1990s to the early 2000s. Since 2003 to 2004, however, the overall prevalence has largely stabilized (for example, 6.9% prevalence in 2003 to 2004 and in 2011 to 2012). There was little difference in adjusted prevalence of stage 3 and 4 CKD overall in 2003 to 2004 versus 2011 to 2012 after age, sex, race/ethnicity, and diabetes mellitus status were controlled for (P = 0.26). Lack of increase in CKD prevalence since the early 2000s was observed in most subgroups and with an expanded definition of CKD that included persons with higher eGFRs and albuminuria. Limitation: Serum creatinine and albuminuria were measured only once in each person. Conclusion: In a reversal of prior trends, there has been no appreciable increase in the prevalence of stage 3 and 4 CKD in the U.S. population overall during the most recent decade. Primary Funding Source: American Society of Nephrology Foundation for Kidney Research Student Scholar Grant Program, Centers for Disease Control and Prevention, and National Institutes of Health.

Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

Common variants associated with plasma triglycerides and risk for coronary artery disease.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.