Monogenic causes of chronic kidney disease in adults.

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

Progressive improvement in short-, medium- and long-term graft survival in kidney transplantation patients in Ireland - a retrospective study.

It is often quoted that while short-term graft survival in kidney transplantation has improved in recent years, it has not translated into a commensurate improvement in long-term graft survival. We considered whether this was true of the entire experience of the national kidney transplant program in Ireland. A retrospective analysis of the National Kidney Transplant Service (NKTS) database was undertaken to investigate patient and graft survival for all adult first deceased donor kidney transplant recipients in Ireland, 1971-2015. Three thousand two hundred and sixty recipients were included in this study. Kaplan-Meier methods were used to estimate survival at each time period post transplant for the various eras of transplantation. Uncensored graft survival has improved over the course of the program in Ireland at various time points despite risk factors for graft failure progressively increasing over successive eras. For example the graft survival at 15 years post transplant has increased from 10% in 1971-1975 to 45% by 1996-2000. Ireland has experienced a progressive improvement in long-term graft survival following kidney transplantation. Whether these trends are attributable to biological or nonbiological factors is unclear but likely involves a combination of both.

Kidney Disease in Women is Associated with Disadvantaged Childhood Socioeconomic Position.

BACKGROUND: Socioeconomic position (SEP) is an important determinant of health and it is dynamic across the entire lifespan. We sought to investigate the relationship between life-course SEP and chronic kidney disease (CKD) using 3 conceptual models: critical period, pathway and accumulation. METHODS: Cross-sectional analysis of 4,996 participants from The Irish Longitudinal Study on Ageing, a nationally representative cohort of community-dwelling adults aged ≥50 years. We defined childhood and adulthood SEP according to father's and respondent's occupation respectively. SEP was categorised as high (reference), intermediate, low and never worked. CKD was defined as a glomerular filtration rate < 60 mL/min/1.73 m2 estimated from the combination of creatinine and cystatin C. We used logistic regression to estimate the age-adjusted association between SEP and CKD separately in men and women. RESULTS: Low childhood SEP was strongly associated with CKD in women, after adjusting for adulthood SEP (OR 1.90 [95% CI 1.24-2.92]), supporting the critical period hypothesis. This association was not explained by traditional CKD risk factors. Women who experienced low childhood SEP and whose circumstances improved in adulthood also had increased odds of CKD, further supporting a critical period effect in childhood. There was comparatively less evidence in support of the pathway or accumulation models. We did not observe a statistically significant association between SEP and CKD in men. CONCLUSIONS: Our findings suggest that women exposed to disadvantaged SEP in childhood represent an at-risk group in whom there may be opportunities for identification of CKD and facilitation of health-promoting behaviours from an early age.

C4 Glomerulopathy: A Disease Entity Associated With C4d Deposition.

Complement-mediated glomerulonephritis, which includes C3 glomerulopathy, is characterized by dominant staining of C3 with minimal or no immunoglobulin deposits on immunofluorescence studies. We describe a new entity of complement-mediated glomerulonephritis that is characterized by bright C4d staining but with no or minimal C3 or immunoglobulin deposits on immunofluorescence studies. We label this entity as C4 glomerulopathy. C4 glomerulopathy includes C4 dense deposit disease and C4 glomerulonephritis. C4 dense deposit disease is characterized by bright C4d staining and dense deposits along glomerular basement membranes. C4 glomerulonephritis is characterized by bright C4d staining and many mesangial electron-dense deposits, with or without rare intramembranous electron-dense deposits. We describe clinical features and kidney biopsy results in a short series of 3 patients to highlight these findings. All 3 patients presented with proteinuria, and 2 patients also had hematuria. Kidney function was preserved in 2 patients, whereas 1 patient presented with declining kidney function. Evaluation for autoimmune disease, infection, and paraprotein yielded negative results in all patients. Complement levels were normal, although 1 patient had borderline low C4 levels. Kidney biopsy showed mesangial proliferative or membranoproliferative glomerulonephritis with bright C4d staining and absent or minimal C1q, C3, and immunoglobulin. Laser microdissection and mass spectrometry of glomeruli in all 3 patients showed large to moderate numbers of spectra matching C4. Furthermore, analysis of amino acid sequences showed that they were localized to the C4d portion of C4, consistent with immunofluorescence findings. Further studies are required to determine the underlying cause. In summary, we describe a novel complement-mediated glomerulonephritis that is characterized by bright glomerular C4d staining with minimal or absent staining for C1q, C3, and immunoglobulin.

The Irish living kidney donor program - why potential donors do not proceed to live kidney donation?

BACKGROUND: Living donation is not only a method to increase access to kidney transplantation but can also offer superior outcomes. We report the experience of the living donor (LD) program in the Republic of Ireland and explore reasons why potential donors do not proceed to live donation. METHODS: Retrospective cohort study of all potential donors from January 2000 to March 2014 who presented wishing to undergo donor work-up and their subsequent outcomes. RESULTS: A total of 956 donors for 496 recipients contacted the live kidney donation program of which 883 potential donors proceeded to the initial stage of assessment. The donor dropout rate at this stage was 64.2% (614/956 potential donors did not proceed to further evaluation). Thereafter, 269 (28.1%) donors underwent further assessment by the multidisciplinary team. In total, 93 (9.7%) donors were declined following this assessment with 176 (18.4%) donors ultimately proceeding to live kidney donation. The major reason for declining a donor was a medical contraindication (n = 63, 67.7%). In term of recipients, 54.2% (n = 269/496) had a potential donor proceed for further assessment of which 65.4% (n = 176/269) ultimately proceeding to live donation. CONCLUSION: Further evaluation of the declined donor group is warranted to allow for expansion of the LD program.

Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

Influence of socioeconomic status on allograft and patient survival following kidney transplantation.

AIM: Whether socioeconomic status confers worse outcomes after kidney transplantation is unknown. Its influence on allograft and patient survival following kidney transplantation in Ireland was examined. METHODS: A retrospective, observational cohort study of adult deceased-donor first kidney transplant recipients from 1990 to 2009 was performed. Those with a valid Irish postal address were assigned a socioeconomic status score based on the Pobal Hasse-Pratschke deprivation index and compared in quartiles. Cox proportional hazards models and Kaplan-Meier survival analysis were used to investigate any significant association of socioeconomic status with patient and allograft outcomes. RESULTS: A total of 1944 eligible kidney transplant recipients were identified. The median follow-up time was 8.2 years (interquartile range 4.4-13.3 years). Socioeconomic status was not associated with uncensored or death-censored allograft survival (hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.99-1.00, P = 0.33 and HR 1.0, 95% CI 0.99-1.00, P = 0.37, respectively). Patient survival was not associated with socioeconomic status quartile (HR 1.0, 95% CI 0.93-1.08, P = 0.88). There was no significant difference among quartiles for uncensored or death-censored allograft survival at 5 and 10 years. CONCLUSION: There was no socioeconomic disparity in allograft or patient outcomes following kidney transplantation, which may be partly attributable to the Irish healthcare model. This may give further impetus to calls in other jurisdictions for universal healthcare and medication coverage for kidney transplant recipients.

Genome-wide association and functional follow-up reveals new loci for kidney function.

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

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 traits.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality.

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality. STUDY DESIGN: Observational. SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies. PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305. OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis. RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD. LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation. CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

The association of a single-nucleotide polymorphism in CUBN and the risk of albuminuria and cardiovascular disease.

BACKGROUND: Albuminuria is an important risk factor for cardiovascular disease (CVD). We have previously identified a missense single-nucleotide polymorphism (rs1801239) in the CUBN gene that is associated with albuminuria. Whether albuminuria is associated with CVD in the presence of the CUBN mutation is unknown. METHODS: We analyzed participants from the Framingham Heart Study (n=6399, mean age 47 years, 53.4% women) who underwent genotyping of rs1801239. Cox proportional hazards models were used to test the association between microalbuminuria [UACR≥17 mg/g (men) and ≥25 mg/g (women)] and incident CVD stratified by the presence or absence of the CUBN risk allele. We tested whether the association between microalbuminuria and CVD was altered by the presence of the risk allele with interaction testing. RESULTS: Overall, 21.1% of participants carried the risk allele. As expected, carriers of the risk (C) allele had a higher prevalence of microalbuminuria (10.7 versus 8.9%, P=0.04). During a mean follow-up of 10.4 years, 5.6% (n=346) of participants experienced a CVD event. Microalbuminuria was associated with an increased risk of CVD [hazards ratio (HR) 1.46, 95% confidence interval (CI) 1.14-1.88]. When stratified by risk allele carrier status, the HR for CVD was 1.95 (95% CI 1.15-3.29) among those with compared to 1.33 (95% CI 1.00-1.76) among those without the risk allele. There was no interaction between microalbuminuria and rs1801239 on CVD (Pinteraction=0.49). CONCLUSIONS: MA is associated with CVD irrespective of the presence of the CUBN risk allele. These results challenge the concept that albuminuria in the setting of this mutation is benign.

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/1.73m(2) 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.

Elevated galectin-3 precedes the development of CKD.

Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal models and inversely correlates with GFR in humans, but whether galectin-3 predicts incident kidney disease is unknown. Here, we assessed renal outcomes for 2450 Framingham Offspring participants who attended examination 6 (1995-1998) and had follow-up data at examination 8 (2005-2008). Renal outcomes of interest included rapid decline in renal function (≥3 ml/min per 1.73 m(2) per year decline in estimated GFR [eGFR]), CKD (eGFR < 60 ml/min per 1.73 m(2)), and albuminuria (albumin-to-creatinine ratio ≥17 mg/g in men or ≥25 mg/g in women). We used multivariable logistic regression models to evaluate associations between galectin-3 with incident renal outcomes at examination 8. During a mean follow-up of 10.1 years, GFR declined rapidly in 241 (9.2%) participants, incident CKD developed in 277 (11.3%), and albuminuria developed in 194 (10.1%). Higher plasma levels of galectin-3 were associated with rapid decline in eGFR (per 1-SD log-galectin-3; adjusted odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28 to 1.73]) and a higher risk of incident CKD (OR, 1.47; 95% CI, 1.27 to 1.71), but not with the risk of incident albuminuria. The addition of galectin-3 to clinical predictors improved the C-statistic (0.837-0.845; P=0.02) but did not reach predefined thresholds for clinically significant improvements to risk prediction based on reclassification indices. In conclusion, elevated levels of plasma galectin-3 are associated with increased risks of rapid GFR decline and of incident CKD in the community, which calls for further study in higher-risk groups.

Analysis of a urinary biomarker panel for incident kidney disease and clinical outcomes.

Whether novel biomarkers improve the assessment of incident kidney disease and related adverse outcomes remains to be tested in longitudinal observational studies. We tested 14 urinary biomarkers for association with incident kidney, cardiovascular, and mortality outcomes in 2948 Framingham Heart Study participants. Baseline examinations were performed between 1995 and 1998; mean follow-up was 10.1 years for renal outcomes and 11.2 years for survival analyses. Primary outcomes were incident CKD, incident albuminuria, incident cardiovascular disease, and all-cause mortality. Secondary analyses assessed incident congestive heart failure (CHF) and mortality with coexistent kidney disease. Biomarkers were tested for association with renal end points using logistic regression and incident cardiovascular and mortality outcomes in proportional hazards models; α1-microglobulin, Kim-1, and TFF-3 predicted all-cause mortality (hazard ratio per SD increase in log-transformed biomarker [HR] range, 1.15 to 1.21; 95% confidence interval [CI] range, 1.04 to 1.34; P values=0.007 to <0.001), whereas α1-microglobulin, ß2-microglobulin, KIM-1, and TFF-3 associated with death with coexistent kidney disease (HR range, 1.72-2.25; 95% CI, 1.17 to 3.24; P values<0.01). KIM-1 also associated with the risk of incident CHF (HR, 1.32; 95% CI, 1.07 to 1.63; P=0.008). CTGF associated nominally with CKD (HR, 0.83; 95% CI, 0.71 to 0.98; P=0.03), but no other biomarkers associated with incident CKD or albuminuria. Addition of α1-microglobulin and TFF-3 resulted in a nonsignificant net reclassification index (NRI) of 3% for all-cause mortality beyond clinical risk factors. In conclusion, components of a panel of 14 subclinical biomarkers of kidney injury were associated with important clinical outcomes and merit additional investigation.

Common variants in Mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

The MYH9/APOL1 region and chronic kidney disease in European-Americans.

Polymorphisms in the MYH9 and adjacent APOL1 gene region demonstrate a strong association with non-diabetic kidney disease in African-Americans. However, it is not known to what extent these polymorphisms are present in other ethnic groups. To examine the association of genetic polymorphisms in this region with chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min/1.73 m(2)) in individuals of European ancestry, we examined rs4821480, an MYH9 single-nucleotide polymorphism (SNP) recently identified as associated with kidney disease in African-Americans, in 13 133 participants from the Framingham Heart Study (FHS) and Atherosclerosis Risk in Communities (ARIC) Study. In addition, we further interrogated the MYH9/APOL1 gene region using 282 SNPs for association with CKD using age-, sex- and center-adjusted models and performed a meta-analysis of the results from both studies. Because of prior data linking rs4821480 and kidney disease, we used a P-value of <0.05 to test the association with CKD. In the meta-analysis, rs4821480 (minor allele frequency 4.45 and 3.96% in FHS and ARIC, respectively) was associated with higher CKD prevalence in participants free of diabetes (odds ratio 1.44; 95% confidence interval 1.15-1.80; P = 0.001). No other SNPs achieved significance after adjusting for multiple testing. Results utilizing directly genotyped data confirmed the results of the primary analysis. Recently identified APOL1 risk variants were also directly genotyped, but did not account for the observed MYH9 signal. These data suggest that the MYH9 polymorphism rs4821480 is associated with an increased risk of non-diabetic CKD in individuals of European ancestry.

Overlap between common genetic polymorphisms underpinning kidney traits and cardiovascular disease phenotypes: the CKDGen consortium.

BACKGROUND: Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits. STUDY DESIGN: We conducted 2 targeted analyses. First, we examined whether known single-nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5×10(-4) (0.05/325 tests). SETTING & PARTICIPANTS: Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395), and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium. PREDICTOR: We used 19 kidney SNPs and 64 vascular SNPs. OUTCOMES & MEASUREMENTS: Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber, and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria. RESULTS: In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were nonsignificant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (P = 9.3 ×10(-10)) and diastolic (P = 1.6 ×10(-14)) blood pressure and coronary artery disease (P = 2.2 ×10(-6)), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were nonsignificant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (P = 1.06 ×10(-07) and P = 7.05 ×10(-08)). LIMITATIONS: The combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations. CONCLUSIONS: Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.