In the past decade, kidney disease diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. The population prevalence of chronic kidney ...disease exceeds 10%, and is more than 50% in high-risk subpopulations. Independent of age, sex, ethnic group, and comorbidity, strong, graded, and consistent associations exist between clinical prognosis and two hallmarks of chronic kidney disease: reduced glomerular filtration rate and increased urinary albumin excretion. Furthermore, an acute reduction in glomerular filtration rate is a risk factor for adverse clinical outcomes and the development and progression of chronic kidney disease. An increasing amount of evidence suggests that the kidneys are not only target organs of many diseases but also can strikingly aggravate or start systemic pathophysiological processes through their complex functions and effects on body homoeostasis. Risk of kidney disease has a notable genetic component, and identified genes have provided new insights into relevant abnormalities in renal structure and function and essential homoeostatic processes. Collaboration across general and specialised health-care professionals is needed to fully address the challenge of prevention of acute and chronic kidney disease and improve outcomes.
Kidney diseases constitute a serious public health burden worldwide, with substantial associated morbidity and mortality. The role of a genetic contribution to kidney disease is supported by ...heritability studies of kidney function measures, the presence of monogenic diseases with renal manifestations, and familial aggregation studies of complex kidney diseases, such as chronic kidney disease. Because complex diseases arise from the combination of multiple genetic and environmental risk factors, the identification of underlying genetic susceptibility variants has been challenging. Recently, genome-wide association studies have emerged as a method to conduct searches for such susceptibility variants. They have successfully identified genomic loci that contain variants associated with kidney diseases and measures of kidney function. For example, common variants in the UMOD and PRKAG2 genes are associated with risk of chronic kidney disease; variants in CLDN14 with risk of kidney stone disease; and variants in or near SHROOM3, STC1, LASS2, GCKR, NAT8/ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, FAM122A/PIP5K1B, ATXN2, DACH1, UBE2Q2/FBXO22 , and SLC7A9 , with differences in glomerular filtration rate. The purpose of this review is to provide an overview of the genome-wide association study method as it relates to nephrology research and summarize recent findings in the field. Results from genome-wide association studies of renal phenotypes represent a first step toward improving our knowledge about underlying mechanisms of kidney function and disease and ultimately may aid in the improved treatment and prevention of kidney diseases.
Background Identifying individuals at risk of chronic kidney disease (CKD) is critical for timely treatment initiation to slow progression of the disease. Neutrophil gelatinase-associated lipocalin ...(NGAL) and kidney injury molecule 1 (KIM-1) are known biomarkers of acute kidney injury, but it is unknown whether these markers are associated with incident CKD stage 3 in the general population. Study Design Matched case-control study. Setting & Participants African American and white participants from the Atherosclerosis Risk in Communities (ARIC) Study who at baseline had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and urinary albumin-creatinine ratio ≤30 mg/g. 143 controls were matched for age, sex, and race to 143 cases of incident CKD stage 3 after 8.6 years of follow-up. Predictors Quartile of NGAL and KIM-1. Outcomes & Measurements Incident CKD stage 3 (eGFR <60 mL/min/1.73 m2 at follow-up and a decrease in eGFR from baseline to follow-up ≥25%). Results Both NGAL ( P = 0.05) and KIM-1 levels ( P < 0.001) were correlated positively with baseline urinary albumin-creatinine ratio; neither was associated with baseline eGFR. Participants with NGAL concentrations in the fourth quartile had more than 2-fold higher odds (adjusted OR, 2.11; 95% CI, 0.96-4.64) of incident CKD stage 3 compared with participants in the first quartile after multivariable adjustment ( P -trend = 0.03). Adjustment for urinary creatinine and albumin levels resulted in a nonsignificant association (highest quartile adjusted OR, 1.52; 95% CI, 0.64-3.58; P = 0.2). No significant association between KIM-1 level and incident CKD was observed in crude or adjusted models. Limitations The relatively small sample size of the study limits precision and power to detect weak associations. Conclusions Higher NGAL, but not KIM-1, levels were associated with incident CKD stage 3. Adjustment for urinary creatinine and albumin concentration attenuated this association. Additional studies are needed to confirm these findings and assess the utility of urinary NGAL as a marker of CKD risk.
Background Albuminuria has been associated with cardiovascular risk, but the relationship of high-normal albuminuria to subsequent heart failure has not been well established. Study Design ...Prospective observational study, the Atherosclerosis Risk in Communities (ARIC) Study. Setting & Participants 10,975 individuals free from heart failure were followed up from the fourth ARIC Study visit (1996-1998) through January 2006. Predictor Urinary albumin-creatinine ratio (UACR), analyzed continuously and categorically as optimal (<5 mg/g), intermediate-normal (5-9 mg/g), high-normal (10-29 mg/g), microalbuminuria (30-299 mg/g), and macroalbuminuria (≥300 mg/g). Outcomes & Measurements Incident heart failure was defined as a heart failure–related hospitalization or death. Cox proportional hazard models were used to calculate the HR of heart failure after adjustment for age, race, sex, estimated glomerular filtration rate (eGFR), and other cardiovascular risk factors. Results Individuals were followed up for a median of 8.3 years and experienced 344 heart failure events. Compared with normal UACR, albuminuria was associated with a progressively increased risk of heart failure from intermediate-normal (adjusted HR, 1.54; 95% CI, 1.12-2.11) and high-normal UACR (adjusted HR, 1.91; 95% CI, 1.38-2.66) to microalbuminuria (adjusted HR, 2.49; 95% CI, 1.77-3.50) and macroalbuminuria (adjusted HR, 3.47; 95% CI, 2.10-5.72). Results were similar in secondary analyses of participants censored at the time of coronary heart disease event and along a range of eGFRs. Limitations UACR was measured as a single random sample. Conclusions Albuminuria is associated with subsequent heart failure, even in individuals with few cardiovascular risk factors and UACR within the normal range. Our results suggest that the association between albuminuria and heart failure may not be mediated fully by ischemic heart disease or kidney disease, measured using eGFR.
Background Metabolites such as creatinine and urea are established kidney function markers. High-throughput metabolomic studies have not been reported in large general population samples spanning ...normal kidney function and chronic kidney disease (CKD). Study Design Cross-sectional observational studies of the general population. Setting & Participants 2 independent samples: KORA F4 (discovery sample, n = 3,011) and TwinsUK (validation sample, n = 984). Exposure Factors 151 serum metabolites, quantified by targeted mass spectrometry. Outcomes & Measurements Metabolites and their 22,650 ratios were analyzed by multivariable-adjusted linear regression for their association with glomerular filtration rate (eGFR), estimated separately from creatinine and cystatin C levels by CKD-EPI (CKD Epidemiology Collaboration) equations. After correction for multiple testing, significant metabolites ( P < 3.3 × 10−4 for single metabolites; P < 2.2 × 10−6 for ratios) were meta-analyzed with independent data from the TwinsUK Study. Results Replicated associations with eGFR were observed for 22 metabolites and 516 metabolite ratios. Pooled P values ranged from 7.1 × 10−7 to 1.8 × 10−69 for the replicated single metabolites. Acylcarnitines such as glutarylcarnitine were associated inversely with eGFR (−3.73 mL/min/1.73 m2 per standard deviation SD increase, pooled P = 1.8 × 10−69 ). The replicated ratio with the strongest association was the ratio of serine to glutarylcarnitine ( P = 3.6 × 10−81 ). Almost all replicated phenotypes associated with decreased eGFR (<60 mL/min/1.73 m2 ; n = 172 cases) in KORA F4: per 1-SD increment, ORs ranged from 0.29-2.06. Across categories of a metabolic score consisting of 3 uncorrelated metabolites, the prevalence of decreased eGFR increased from 3% to 53%. Limitations Cross-sectional study design, GFR was estimated, limited number of metabolites. Conclusions Distinct metabolic phenotypes were reproducibly associated with eGFR in 2 separate population studies. They may provide novel insights into renal metabolite handling, improve understanding of pathophysiology, or aid in the diagnosis of kidney disease. Longitudinal studies are needed to clarify whether changes in metabolic phenotypes precede or result from kidney function impairment.
Summary Background Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Methods ...Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5·0×10−8 ) or the Rotterdam cohort (p<1·0×10−7 ) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10−168 and 2·9×10−18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10−60 and 9·8×10−4 ), and rs1165205 in SLC17A3 (p=3·3×10−26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95% CI 0·52–0·68, p=7·0×10−14 ), rs2231142 (1·74, 1·51–1·99, p=3·3×10−15 ), and rs1165205 (0·85, 0·77–0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06–2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272–351 μmol/L in the Framingham cohort, 269–386 μmol/L in the Rotterdam cohort, and 303–426 μmol/L in white participants of the ARIC study) and gout (frequency 2–13% in the Framingham cohort, 2–8% in the Rotterdam cohort, and 1–18% in white participants in the ARIC study). Interpretation We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout. Funding Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.
Abstract Background Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. Objectives Through ...a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF). Methods This study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. Results Serum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations. Conclusions Evidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.
Background Serum cystatin C increasingly is used as a marker of glomerular filtration rate and cardiovascular risk. However, information for serum cystatin C levels in the general population, ...specifically across a wide age range and different ethnicities, is lacking. Objectives To determine nationally representative serum cystatin C levels, estimate the prevalence of increased cystatin C levels in the general population, and identify factors associated with increased cystatin C levels. Study Design Cross-sectional survey. Setting and Participants A nationally representative subsample of 7,596 participants aged 12 years or older in the Third National Health and Nutrition Examination Survey conducted in 1988-1994. Predictors Age, sex, race/ethnicity, risk factors for chronic kidney disease. Outcomes Continuous serum cystatin C levels and serum cystatin C level greater than 1.12 mg/L. Measurements Cystatin C was measured in 2006 from stored sera by using an automated particle-enhanced nephelometric assay. Results Overall median serum cystatin C level was 0.85 mg/L. Median cystatin C levels increased steeply with age and were greater in males and non-Hispanic white persons, even in a healthy subgroup of 20- to 39-year-olds. Prevalences of increased serum cystatin C levels (>1.12 mg/L) were 1%, 41%, and greater than 50% in all persons aged younger than 20 years, 60 years or older, and 80 years or older. In persons aged 60 years and older, older age, non-Hispanic white ethnicity, hypertension, current smoking, lower levels of education and high-density lipoprotein cholesterol, and increased body mass index, C-reactive protein, and triglyceride values were associated significantly with increased serum cystatin C levels. Limitations No measured glomerular filtration rate, single measurement of cystatin C, cross-sectional study design. Conclusions Serum cystatin C level is related to sex and ethnicity, even in young healthy individuals. The prevalence of increased cystatin C levels increases dramatically with age, reaching greater than 50% after the age of 80 years in both sexes and all ethnic groups.
Prior to conducting genome-wide association studies (GWAS) of renal traits and diseases, systematic checks to ensure data integrity and analytical work flow should be conducted. Using positive ...controls (ie, known associations between a single-nucleotide polymorphism SNP and a corresponding trait) allows for identifying errors that are not apparent solely from global evaluation of summary statistics. Strong genetic control associations of chronic kidney disease (CKD), as derived from GWAS, are lacking in the non-African ancestry CKD population; thus, in this perspective, we provide examples of and considerations for using positive controls among patients with CKD. Using data from individuals with CKD who participated in the CRIC (Chronic Renal Insufficiency Cohort) Study or PediGFR (Pediatric Investigation for Genetic Factors Linked to Renal Progression) Consortium, we evaluated 2 kinds of positive control traits: traits unrelated to kidney function (bilirubin level and body height) and those related to kidney function (cystatin C and urate levels). For the former, the proportion of variance in the control trait that is explained by the control SNP is the main determinant of the strength of the observable association, irrespective of adjustment for kidney function. For the latter, adjustment for kidney function can be effective in uncovering known associations among patients with CKD. For instance, in 1,092 participants in the PediGFR Consortium, the P value for the association of cystatin C concentrations and rs911119 in the CST3 gene decreased from 2.7 × 10-3 to 2.4 × 10-8 upon adjustment for serum creatinine–based estimated glomerular filtration rate. In this perspective, we give recommendations for the appropriate selection of control traits and SNPs that can be used for data checks prior to conducting GWAS among patients with CKD.
Abstract Background We hypothesized that women with early- and mid-adult life obesity, as well as high mid-adult life waist-to-hip ratios, and high weight gain during adulthood, experience a greater ...incidence of gout. Methods We examined the incidence of gout in the Atherosclerosis Risk in Communities Study, a population-based biracial cohort comprised of individuals aged 45-65 years at baseline (1987-1989). A total of 6263 women without prior history of gout were identified. We examined the association of body mass index (BMI) and obesity at cohort entry and at age 25 years, waist-to-hip ratio, and weight change with gout incidence (1996-1998). Results Over 9 years of follow-up, 106 women developed gout. The cumulative incidence of gout, by age 70 years, according to BMI category at baseline of <25, 25-29.9, 30-34.9, and ≥35 kg/m2 , was 1.9, 3.6, 7.9, and 11.8%, respectively ( P <.001). Obese women (BMI ≥30) at baseline had an adjusted 2.4-fold greater risk of developing gout than nonobese women (95% confidence interval CI, 1.53-3.68). This association was attenuated after further adjustment for urate levels. Further, early adult obesity in women was associated with a 2.8-fold increased risk of gout compared with nonobese women (95% CI, 1.33-6.09), which remained statistically significant after baseline urate adjustment. There was a graded association between each anthropometric measure, including weight gain, with incident gout (each P for trend <.001). The results were similar in black and white women. Conclusions In a large cohort of black and white women, obesity in early- and mid-adulthood, and weight gain during this interval, were each independent risk factors for incident gout in women.
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