Role of BMI in the Association of the TCF7L2 rs7903146 Variant with Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI < 25 kg/m2) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk

Validated SNPs for eGFR and their associations with albuminuria

Albuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease and death. We hypothesized that SNPs identified in association with the estimated glomerular filtration rate (eGFR) would also be associated with albuminuria. Within the CKDGen Consortium cohort (n= 31 580, European ancestry), we tested 16 eGFR-associated SNPs for association with the urinary albumin-to-creatinine ratio (UACR) and albuminuria [UACR >25 mg/g (women); 17 mg/g (men)]. In parallel, within the CARe Renal Consortium (n= 5569, African ancestry), we tested seven eGFR-associated SNPs for association with the UACR. We used a Bonferroni-corrected P-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with the UACR in aggregate using a beta-weighted genotype score. In the CKDGen Consortium, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with a lower eGFR, was associated with lower ln(UACR) levels (beta = −0.034, P-value = 0.0002). No additional eGFR-associated SNPs met the Bonferroni-corrected P-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal Consortium, there were no associations between SNPs and UACR with a P< 0.007. Although we found the genotype score to be associated with albuminuria (P= 0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a P-value 0.03, indicating a weak residual aggregate signal. No alleles, previously demonstrated to be associated with a lower eGFR, were associated with the UACR or albuminuria, suggesting that there may be distinct genetic components for these trait

Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression

Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

Building a network of ADPKD reference centres across Europe: the EuroCYST initiative

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic inherited kidney disease, affecting an estimated 600 000 individuals in Europe. The disease is characterized by age-dependent development of a multiple cysts in the kidneys, ultimately leading to end-stage renal failure and the need of renal replacement therapy in the majority of patients, typically by the fifth or sixth decade of life. The variable disease course, even within the same family, remains largely unexplained. Similarly, assessing disease severity and prognosis in an individual with ADPKD remains difficult. Epidemiological studies are limited due to the fragmentation of ADPKD research in Europe. METHODS: The EuroCYST initiative aims: (i) to harmonize and develop common standards for ADPKD research by starting a collaborative effort to build a network of ADPKD reference centres across Europe and (ii) to establish a multicentric observational cohort of ADPKD patients. This cohort will be used to study factors influencing the rate of disease progression, disease modifiers, disease stage-specific morbidity and mortality, health economic issues and to identify predictive disease progression markers. Overall, 1100 patients will be enrolled in 14 study sites across Europe. Patients will be prospectively followed for at least 3 years. Eligible patients will not have participated in a pharmaceutical clinical trial 1 year before enrollment, have clinically proven ADPKD, an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m(2) and above, and be able to provide written informed consent. The baseline visit will include a physical examination and collection of blood, urine and DNA for biomarker and genetic studies. In addition, all participants will be asked to complete questionnaires detailing self-reported health status, quality of life, socioeconomic status, health-care use and reproductive planning. All subjects will undergo annual follow-up. A magnetic resonance imaging (MRI) scan will be carried out at baseline, and patients are encouraged to undergo a second MRI at 3-year follow-up for qualitative and quantitative kidney and liver assessments. CONCLUSIONS: The ADPKD reference centre network across Europe and the observational cohort study will enable European ADPKD researchers to gain insights into the natural history, heterogeneity and associated complications of the disease as well as how it affects the lives of patients across Europ

Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy

The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide

Genome-wide association study of 1,5-anhydroglucitol identifies novel genetic loci linked to glucose metabolism

1,5-anhydroglucitol (1,5-AG) is a biomarker of hyperglycemic excursions associated with diabetic complications. Because of its structural similarity to glucose, genetic studies of 1,5-AG can deliver complementary insights into glucose metabolism. We conducted genome-wide association studies of serum 1,5-AG concentrations in 7,550 European ancestry (EA) and 2,030 African American participants (AA) free of diagnosed diabetes from the ARIC Study. Seven loci in/near EFNA1/SLC50A1, MCM6/LCT, SI, MGAM, MGAM2, SLC5A10, and SLC5A1 showed genome-wide significant associations (P < 5 × 10-8) among EA participants, five of which were novel. Six of the seven loci were successfully replicated in 8,790 independent EA individuals, and MCM6/LCT and SLC5A10 were also associated among AA. Most of 1,5-AG-associated index SNPs were not associated with the clinical glycemic markers fasting glucose or theHbA1c, and vice versa. Only the index variant in SLC5A1 showed a significant association with fasting glucose in the expected opposing direction. Products of genes in all 1,5-AG-associated loci have known roles in carbohydrate digestion and enteral or renal glucose transport, suggesting that genetic variants associated with 1,5-AG influence its concentration via effects on glucose metabolism and handling

A multi-source data integration approach reveals novel associations between metabolites and renal outcomes in the German Chronic Kidney Disease study

Omics data facilitate the gain of novel insights into the pathophysiology of diseases and, consequently, their diagnosis, treatment, and prevention. To this end, omics data are integrated with other data types, e.g., clinical, phenotypic, and demographic parameters of categorical or continuous nature. We exemplify this data integration issue for a chronic kidney disease (CKD) study, comprising complex clinical, demographic, and one-dimensional H-1 nuclear magnetic resonance metabolic variables. Routine analysis screens for associations of single metabolic features with clinical parameters while accounting for confounders typically chosen by expert knowledge. This knowledge can be incomplete or unavailable. We introduce a framework for data integration that intrinsically adjusts for confounding variables. We give its mathematical and algorithmic foundation, provide a state-of-the-art implementation, and evaluate its performance by sanity checks and predictive performance assessment on independent test data. Particularly, we show that discovered associations remain significant after variable adjustment based on expert knowledge. In contrast, we illustrate that associations discovered in routine univariate screening approaches can be biased by incorrect or incomplete expert knowledge. Our data integration approach reveals important associations between CKD comorbidities and metabolites, including novel associations of the plasma metabolite trimethylamine-N-oxide with cardiac arrhythmia and infarction in CKD stage 3 patients

Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10 &lt;sup&gt;-56&lt;/sup&gt; ) and SLC2A9 (p = 4.5 × 10 &lt;sup&gt;-7&lt;/sup&gt; ). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10 &lt;sup&gt;-3&lt;/sup&gt; ). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout