Comparison of Heritability of Cystatin C‐ and Creatinine‐Based Estimates of Kidney Function and Their Relation to Heritability of Cardiovascular Disease

Arpegård, Johannes; Viktorin, Alexander; Chang, Zheng; Fairé, Ulf dé; Magnusson, Patrik K. E.; Svensson, Per

doi:10.1161/jaha.114.001467

Cited by 46 publications

(47 citation statements)

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“…The heritabilities of our phenotypes are generally in alignment with those quoted in the literature, except for pulse pressure, whose heritability in our data (0.13, SE 0.01) is approximately half of the heritability quoted in the literature (0.24, SE 0.08) [22]. Conversely, our estimates of the heritability of serum creatinine (0.44, SE 0.01) are more than twice the heritability quoted in the literature (0.19, SE 0.07) [23]. …”

Section: Resultscontrasting

confidence: 43%

Exploration of haplotype research consortium imputation for genome-wide association studies in 20,032 Generation Scotland participants

et al. 2017

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BackgroundThe Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based population cohort with DNA, biological samples, socio-demographic, psychological and clinical data from approximately 24,000 adult volunteers across Scotland. Although data collection was cross-sectional, GS:SFHS became a prospective cohort due to of the ability to link to routine Electronic Health Record (EHR) data. Over 20,000 participants were selected for genotyping using a large genome-wide array.MethodsGS:SFHS was analysed using genome-wide association studies (GWAS) to test the effects of a large spectrum of variants, imputed using the Haplotype Research Consortium (HRC) dataset, on medically relevant traits measured directly or obtained from EHRs. The HRC dataset is the largest available haplotype reference panel for imputation of variants in populations of European ancestry and allows investigation of variants with low minor allele frequencies within the entire GS:SFHS genotyped cohort.ResultsGenome-wide associations were run on 20,032 individuals using both genotyped and HRC imputed data. We present results for a range of well-studied quantitative traits obtained from clinic visits and for serum urate measures obtained from data linkage to EHRs collected by the Scottish National Health Service. Results replicated known associations and additionally reveal novel findings, mainly with rare variants, validating the use of the HRC imputation panel. For example, we identified two new associations with fasting glucose at variants near to Y_RNA and WDR4 and four new associations with heart rate at SNPs within CSMD1 and ASPH, upstream of HTR1F and between PROKR2 and GPCPD1. All were driven by rare variants (minor allele frequencies in the range of 0.08–1%). Proof of principle for use of EHRs was verification of the highly significant association of urate levels with the well-established urate transporter SLC2A9.ConclusionsGS:SFHS provides genetic data on over 20,000 participants alongside a range of phenotypes as well as linkage to National Health Service laboratory and clinical records. We have shown that the combination of deeper genotype imputation and extended phenotype availability make GS:SFHS an attractive resource to carry out association studies to gain insight into the genetic architecture of complex traits.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0414-4) contains supplementary material, which is available to authorized users.

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Section: Resultscontrasting

confidence: 43%

Exploration of haplotype research consortium imputation for genome-wide association studies in 20,032 Generation Scotland participants

et al. 2017

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“…No twin study that formally determines heritability (h 2 ) of ESRD has been published thus far and so this is the first study estimating the heritability of ESRD. The high heritability for ESRD in the present study is similar to the heritability estimated for different measures of kidney functions [48, 49]. We therefore do not believe that our results overestimate the heritability of ESRD because severe phenotypes are often more heritable than less severe phenotypes such as the measure of kidney function in a cohort of twins.…”

Section: Discussionsupporting

confidence: 83%

“…Our results are in line with the recent rapid progression of genome-wide association studies (GWAS) of various kidney traits and disorders [50]. Genetic studies, used to investigate traits that define CKD, such as estimated glomerular filtration rate or urinary albumin/creatinine ratio, have identified more than 50 associated genomic regions [49]. Most interestingly, genomic regions identified in GWAS of CKD-defining traits partly overlap with the causal genes for monogenic kidney diseases.…”

Section: Discussionsupporting

confidence: 82%

“…Previously, a twin study (the Vietnam Era Twin Registry) by Raggi et al [48] has shown a heritability of 50% for estimated glomerular filtration rate. Another twin study by Arpegård et al [49] estimated the heritability of Cystatin C (60%) and creatinine (59%). No twin study that formally determines heritability (h 2 ) of ESRD has been published thus far and so this is the first study estimating the heritability of ESRD.…”

Section: Discussionmentioning

confidence: 99%

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Heritability of End-Stage Renal Disease: A Swedish Adoption Study

Akrawi¹,

PirouziFard

Fjellstedt

et al. 2017

Nephron

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Background/Aims: The heritability of end-stage renal disease (ESRD) among adoptees has not been examined so far. By studying adoptees and their biological and adoptive parents, it is possible to differentiate between the genetic causes and environmental causes of familial aggregation. This nationwide study aimed to disentangle the genetic and shared environmental contribution to the familial transmission of ESRD. Methods: We performed a family study for Swedish-born adoptees (born between 1945 until 1995) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the National Patient Registry for the period 1964–2012. ESRD was defined as patients in active uremic care, that is, chronic dialysis or kidney transplantation. OR for ESRD was determined for adoptees with an affected biological parent with ESRD compared with adoptees without a biological parent with ESRD. The OR for ESRD was also calculated in adoptees with an adoptive parent with ESRD compared with adoptees with an adoptive parent without ESRD. Moreover, heritability for ESRD was estimated with Falconer’s regression. Results: A total of 111 adoptees, 463 adoptive parents, and 397 biological parents were affected by ESRD. The OR for ESRD was 6.41 in adoptees (95% CI 2.96–13.89) of biological parents diagnosed with ESRD. The OR for ESRD was 2.40 in adoptees (95% CI 0.76–7.60) of adoptive parents diagnosed with ESRD. The heritability of ESRD was 59.5 ± 18.2%. Conclusion: The family history of ESRD in a biological parent is an important risk factor for ESRD. The high heritability indicates that genetic factors play an important role in understanding the etiology of ESRD.

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“…We have previously shown a moderate heritability for variations in both cystatin C and kidney function according to GFR calculated by modification of diet in renal disease and CKD‐epi formulas. We have also shown a genetic correlation between cystatin C and prevalent ASCVD, indicating that cystatin C and ASCVD share genetic influences . However, it has not been studied previously whether variation of renal function as measured by levels of cystatin C or creatinine predicts incident ASCVD when controlling for genetic factors.…”

Section: Introductionmentioning

confidence: 55%

Cystatin C Predicts Incident Cardiovascular Disease in Twins

Arpegård

Magnusson

Chen

et al. 2016

JAHA

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BackgroundCystatin C is associated with both renal function and atherosclerotic cardiovascular disease (ASCVD). We have previously shown a genetic correlation between cystatin C and prevalent ASCVD. The objective of this article is to study whether variation in cystatin C or creatinine predicts incident ASCVD when controlled for genetic factors.Methods and ResultsThe predictive value of cystatin C and creatinine for incident ASCVD was studied in 11 402 Swedish twins, free of CVD at baseline, in an adjusted Cox‐regression model during a median follow‐up of 71 months. Twin pairs discordant for incident stroke, myocardial infarction and ASCVD during follow‐up were identified and within‐pair comparisons regarding cystatin C and creatinine levels were performed. We also investigated whether contact frequency and degree of shared environment influences were associated with similarity in cystatin C levels. In univariate analysis, cystatin C predicted incident ASCVD hazard ratio 1.57, 95% CI 1.47–1.67. When adjusted for traditional Framingham risk factors as covariates, cystatin C remained a predictor of incident stroke hazard ratio 1.45, 95% CI (1.25–1.70), ASCVD hazard ratio 1.26, 95% CI (1.13–1.41), and myocardial infarction hazard ratio 1.16, 95% CI (1.01–1.33). In twins discordant for incident stroke, cystatin C at baseline was higher in the twin who experienced a stroke compared to the healthy co‐twin (1.11±0.3 mg/L versus 1.06±0.3 mg/L), whereas creatinine was lower in the twin who developed CVD compared to their healthy co‐twins (76.1±16.9 μmol/L versus 79.4±20.3 μmol/L).ConclusionsVariation in cystatin C relates to incident ASCVD and to stroke when adjusted for genetic confounding. In identical twins, cystatin C may be a sensitive marker of early hypertensive end‐organ damage and small‐vessel disease, whereas creatinine level may reflect nutritional status. The findings in disease‐discordant monozygotic twins indicate that unique, possibly preventable, environmental factors are important.

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Comparison of Heritability of Cystatin C‐ and Creatinine‐Based Estimates of Kidney Function and Their Relation to Heritability of Cardiovascular Disease

Cited by 46 publications

References 45 publications

Exploration of haplotype research consortium imputation for genome-wide association studies in 20,032 Generation Scotland participants

Exploration of haplotype research consortium imputation for genome-wide association studies in 20,032 Generation Scotland participants

Heritability of End-Stage Renal Disease: A Swedish Adoption Study

Cystatin C Predicts Incident Cardiovascular Disease in Twins

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