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.

The adverse impact of obesity on heart rate variability is modified by a NFE2L2 gene variant: The SAPALDIA cohort.

BACKGROUND: Overweight has been associated with an increase in inflammatory markers and with an imbalance in the autonomic nervous system, such as a decrease in heart rate variability (HRV). In this study we aimed to investigate the modifying effect of a genetic variation in a major anti-inflammatory marker gene, NFE2L2, on the relationship between overweight and HRV. METHODS: We analyzed participants of the SAPALDIA cohort aged 50years and older, twice in 2002/2003 (N=1472) and 2010/2011 (N=1235). We included persons with valid genotype data, who underwent ambulatory 24-h electrocardiogram monitoring, and reported on medical history and lifestyle. The association between HRV and BMI, measured as standard deviation of normal-to-normal intervals (SDNN) by BMI and the modifying effect of the cardiovascular health-related NFE2L2 gene variant rs2364723 were tested, applying multivariable mixed linear regression models. RESULTS: We found study participants with overweight (BMI>25) over two follow-up surveys 10years apart to have a negative association between SDNN, calculated as geometric means, with BMI. The examined NFE2L2 variant sustainably modified (pinteraction=0.014) the found inverse association between a BMI increment and SDNN, causing a stronger decrement in SDNN for participants with the CC genotype (-20.7%; 95%-confidence interval: -12.33 to -28.28) compared with participants carrying the GC (-7.43; 95%CI: -3.56 to -11.15) or GG (-11.26%; 95%CI: -7.68 to -14.7) genotype, estimated for the difference from the 90th to the 10th percentile of BMI by the NFE2L2 variant. CONCLUSIONS: Our results are consistent with the hypothesis that overweight decreases heart rate variability through inflammatory processes.

Influence of DNA extraction methods on relative telomere length measurements and its impact on epidemiological studies.

Measurement of telomere length is widely used in epidemiologic studies. Insufficient standardization of the measurements processes has, however, complicated the comparison of results between studies. We aimed to investigate whether DNA extraction methods have an influence on measured values of relative telomere length (RTL) and whether this has consequences for epidemiological studies. We performed four experiments with RTL measurement in quadruplicate by qPCR using DNA extracted with different methods: 1) a standardized validation experiment including three extraction methods (magnetic-particle-method EZ1, salting-out-method INV, phenol-chloroform-isoamyl-alcohol PCI) each in the same 20 samples demonstrated pronounced differences in RTL with lowest values with EZ1 followed by INV and PCI-isolated DNA; 2) a comparison of 307 samples from an epidemiological study showing EZ1-measurements 40% lower than INV-measurements; 3) a matching-approach of two similar non-diseased control groups including 143 pairs of subjects revealed significantly shorter RTL in EZ1 than INV-extracted DNA (0.844 ± 0.157 vs. 1.357 ± 0.242); 4) an association analysis of RTL with prevalent cardiovascular disease detected a stronger association with INV than with EZ1-extracted DNA. In summary, DNA extraction methods have a pronounced influence on the measured RTL-values. This might result in spurious or lost associations in epidemiological studies under certain circumstances.

Modifying effect of a common polymorphism in the interleukin-6 promoter on the relationship between long-term exposure to traffic-related particulate matter and heart rate variability.

BACKGROUND: Exposure to particulate matter (PM) has been associated with an increase in many inflammatory markers, including interleukin 6 (IL6). Air pollution exposure has also been suggested to induce an imbalance in the autonomic nervous system (ANS), such as a decrease in heart rate variability (HRV). In this study we aimed to investigate the modifying effect of polymorphisms in a major proinflammatory marker gene, interleukin 6 (IL6), on the relationship between long-term exposure to traffic-related PM10 (TPM10) and HRV. METHODS: For this cross-sectional study we analysed 1552 participants of the SAPALDIA cohort aged 50 years and older. Included were persons with valid genotype data, who underwent ambulatory 24-hr electrocardiogram monitoring, and reported on medical history and lifestyle. Main effects of annual average TPM10 and IL6 gene variants (rs1800795; rs2069827; rs2069840; rs10242595) on HRV indices and their interaction with average annual exposure to TPM10 were tested, applying a multivariable mixed linear model. RESULTS: No overall association of TPM10 on HRV was found. Carriers of two proinflammatory G-alleles of the functional IL6 -174 G/C (rs1800795) polymorphism exhibited lower HRV. An inverse association between a 1 µg/m3 increment in yearly averaged TPM10 and HRV was restricted to GG genotypes at this locus with a standard deviation of normal-to-normal intervals (SDNN) (GG-carriers: -1.8%; 95% confidence interval -3.5 to 0.01; pinteraction(additive) = 0.028); and low frequency power (LF) (GG-carriers: -5.7%; 95%CI: -10.4 to -0.8; pinteraction(dominant) = 0.049). CONCLUSIONS: Our results are consistent with the hypothesis that traffic-related air pollution decreases heart rate variability through inflammatory mechanisms.

Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: a systematic in-depth review.

High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals. HDLC levels are under considerable genetic control with heritability estimates of up to 80%. The identification and characterization of genetic variants associated with HDLC concentrations can provide new insights into the background of longevity. This review provides an extended overview on the current genetic-epidemiological evidence from association studies on genes involved in HDLC metabolism. It provides a path through the jungle of association studies which are sometimes confusing due to the varying and sometimes erroneous names of genetic variants, positions and directions of associations. Furthermore, it reviews the recent findings from genome-wide association studies which have identified new genes influencing HDLC levels. The yet identified genes together explain only a small amount of less than 10% of the HDLC variance, which leaves an enormous room for further yet to be identified genetic variants. This might be accomplished by large population-based genome-wide meta-analyses and by deep-sequencing approaches on the identified genes. The resulting findings will probably result in a re-drawing and extension of the involved metabolic pathways of HDLC metabolism.

INSIG2 polymorphism is neither associated with BMI nor with phenotypes of lipoprotein metabolism.

OBJECTIVE: A previous epidemiological study showed an association of the insulin-induced gene 2 (INSIG2) gene with BMI. Additionally, experimental investigations in animals and cell culture provided evidence that this gene might be involved in lipoprotein and free fatty acid (FFA) metabolism. Therefore, the aim of this study was to examine the association between the rs7566605 variant near the INSIG2 gene and BMI and to extend it to other quantitative measures of obesity, as well as parameters of lipoprotein and FFA metabolism. METHODS AND PROCEDURES: We genotyped rs7566605 in a group of severely obese white patients (n = 1,026) with an average BMI of 46.0 kg/m(2) and a control group (n = 818) from Utah, as well as in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study from Austria, which is based on a healthy working population (n = 1,696). RESULTS: We observed no difference in the genotype frequency of rs7566605 of INSIG2 between obese subjects and population-based controls from Utah. Furthermore, we did not find evidence of an association with measures of body composition (BMI, waist, waist-to-hip ratio, percentage body fat, amount of visceral and subcutaneous abdominal adipose fat) or lipoprotein metabolism (total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides, and FFAs) in the Utah study population or in the independent SAPHIR study. DISCUSSION: Our results do not support an association of the INSIG2 gene with the regulation of body weight or parameters related to lipoprotein metabolism.

Genome-wide association analysis of high-density lipoprotein cholesterol in the population-based KORA study sheds new light on intergenic regions.

BACKGROUND: High-density lipoprotein cholesterol (HDLC) is a strong risk factor for atherosclerosis and is assumed to be under considerable genetic control. We aimed to identify gene regions that influence HDLC levels by a genome-wide association analysis in the population-based KORA (Cooperative Health Research in the Region of Augsburg) study. METHODS AND RESULTS: In KORA S3/F3 (n=1643), we analyzed 377 865 quality-checked single-nucleotide polymorphisms (SNPs; 500K, Affymetrix, Santa Clara, Calif), complemented by the publicly available genome-wide association results from the Diabetes Genetics Initiative (n=2631) and by replication data from KORA S4 (n=4037) and the Copenhagen City Heart Study (n=9205). Among the 13 SNPs selected from the KORA S3/F3 500K probability value list, 3 showed consistent associations in subsequent replications: 1 SNP 10 kb upstream of CETP (pooled probability value=8.5x10(-27)), 1 SNP approximately 40 kb downstream of LIPG (probability value=4.67x10(-10)), both independent of previously reported SNPs, and 1 from an already reported region of LPL (probability value=2.82x10(-11)). Bioinformatical analyses indicate a potential functional relevance of the respective SNPs. CONCLUSIONS: The present genome-wide association study identified 2 interesting HDLC-relevant regions upstream of CETP and downstream of LIPG. This draws attention to the importance of long-range effects of intergenic regions, which have been underestimated so far, and may impact future candidate-gene-association studies toward extending the region analyzed. Furthermore, the present study reinforced CETP and LPL as HDLC genes and thereby underscores the power of this type of genome-wide association approach to pinpoint associations of common polymorphisms with effects explaining as little as 0.5% of the HDLC variance in the general population.

Apolipoprotein A-IV predicts progression of chronic kidney disease: the mild to moderate kidney disease study.

It has not been established firmly whether dyslipidemia contributes independently to the progression of kidney disease. Lipid and lipoprotein parameters, including levels of total, HDL, and LDL cholesterol; triglycerides; lipoprotein(a); apolipoprotein A-IV; and the apolipoprotein E and A-IV polymorphisms, were assessed in 177 patients who had mostly mild to moderate renal insufficiency and were followed prospectively for up to 7 yr. Progression of kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure necessitating renal replacement therapy. In univariate analysis, patients who reached a progression end point (n = 65) were significantly older and had higher serum creatinine and proteinuria as well as lower GFR and hemoglobin levels. In addition, baseline apolipoprotein A-IV and triglyceride concentrations were higher and HDL cholesterol levels were lower. Multivariate Cox regression analysis revealed that baseline GFR (hazard ratio 0.714; 95% confidence interval [CI] 0.627 to 0.814 for an increment of 10 ml/min per 1.73 m(2); P < 0.0001) and serum apolipoprotein A-IV concentrations (hazard ratio 1.062; 95% CI 1.018 to 1.108 for an increment of 1 mg/dl; P = 0.006) were significant predictors of disease progression. Patients with apolipoprotein A-IV levels above the median had a significantly faster progression (P < 0.0001), and their mean follow-up time to a progression end point was 53.7 mo (95% CI 47.6 to 59.8) as compared with 70.0 mo (95% CI 64.6 to 75.4) in patients with apolipoprotein A-IV levels below the median. For the apolipoprotein E polymorphism, only the genotype epsilon2/epsilon4 was associated with an increased risk for progression. In summary, this prospective study in patients with nondiabetic primary kidney disease demonstrated that apolipoprotein A-IV concentration is a novel independent predictor of progression.