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9. Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

Author

Padmanabhan, S., Melander, O., Johnson, T., Blasio, A.M. di, Lee, W.K., Gentilini, D., Hastie, C.E., Menni, C., Monti, M.C., Delles, C., Laing, S., Corso, B., Navis, G., Kwakernaak, A.J., Harst, P. van der, Bochud, M., Maillard, M., Burnier, M., Hedner, T., Kjeldsen, S., Wahlstrand, B., Sjogren, M., Fava, C., Montagnana, M., Danese, E., Torffvit, O., Hedblad, B., Snieder, H., Connell, J.M.C., Brown, M., Samani, N.J., Farrall, M., Cesana, G., Mancia, G., Signorini, S., Grassi, G., Eyheramendy, S., Wichmann, H.E., Laan, M., Strachan, D.P., Sever, P., Shields, D.C., Stanton, A., Vollenweider, P., Teumer, A., Volzke, H., Rettig, R., Newton-Cheh, C., Arora, P., Zhang, F., Soranzo, N., Spector, T.D., Lucas, G., Kathiresan, S., Siscovick, D.S., Luan, J.A., Loos, R.J.F., Wareham, N.J., Penninx, B.W., Nolte, I.M., McBride, M., Miller, W.H., Nicklin, S.A., Baker, A.H., Graham, D., McDonald, R.A., Pell, J.P., Sattar, N., Welsh, P., Munroe, P., Caulfield, M.J., Zanchetti, A., Dominiczak, A.F., and Global BPgen Consortium

Subjects
tamm-horsfall protein chronic kidney-disease urinary-excretion risk-factors loci nephropathy feasibility mutations mortality burden
Abstract

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Published
2010

10. Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

Author

Padmanabhan, S, Melander, O, Johnson, T, Di Blasio, AM, Lee, WK, Gentilini, D, Hastie, CE, Menni, C, Monti, MC, Delles, C, Laing, S, Corso, B, Navis, G, Kwakernaak, AJ, van der Harst, P, Bochud, M, Maillard, M, Burnier, M, Hedner, T, Kjeldsen, S, Wahlstrand, B, Sjögren, M, Fava, C, Montagnana, M, Danese, E, Torffvit, O, Hedblad, B, Snieder, H, Connell, JM, Brown, M, Samani, NJ, Farrall, M, Cesana, G, Mancia, G, Signorini, S, Grassi, G, Eyheramendy, S, Wichmann, HE, Laan, M, Strachan, DP, Sever, P, Shields, DC, Stanton, A, Vollenweider, P, Teumer, A, Völzke, H, Rettig, R, Newton-Cheh, C, Arora, P, Zhang, F, Soranzo, N, Spector, TD, Lucas, G, Kathiresan, S, Siscovick, DS, Luan, J, Loos, RJ, Wareham, NJ, Penninx, BW, Nolte, IM, McBride, M, Miller, WH, Nicklin, SA, Baker, AH, Graham, D, McDonald, RA, Pell, JP, Sattar, N, Welsh, P, Global BPgen Consortium, Munroe, P, Caulfield, MJ, Zanchetti, A, and Dominiczak, AF

Abstract

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Published
2010

11. Willingness to pay for diabetes drug therapy in type 2 diabetes patients : based on LEAD clinical programme results

Author

Jendle, Johan, Torffvit, O., Ridderstråle, M., Ericsson, Å., Nilsen, B., Bøgelund, M., Jendle, Johan, Torffvit, O., Ridderstråle, M., Ericsson, Å., Nilsen, B., and Bøgelund, M.

Abstract

Objective: The purpose of this study was to investigate the preferences of people with diabetes for liraglutide vs other glucose lowering drugs, based on outcomes of clinical trials. Methods: Willingness to pay (WTP) for diabetes drug treatment was assessed by combining results from a recent WTP study with analysis of results from the Liraglutide Effect and Action in Diabetes (LEAD) programme. The LEAD programme included six randomised clinical trials with 3967 participants analysing efficacy and safety of liraglutide 1.2 mg (LEAD 1-6 trials), rosiglitazone (LEAD 1 trial), glimepiride (LEAD 2-3 trials), insulin glargine (LEAD 5 trial), and exenatide (LEAD 6 trial). The WTP survey used discrete choice experimental (DCE) methodology to evaluate the convenience and clinical effects of glucose lowering treatments. Results: People with type 2 diabetes were prepared to pay an extra €2.64/day for liraglutide compared with rosiglitazone, an extra €1.94/day compared with glimepiride, an extra €3.36/day compared with insulin glargine, and an extra €0.81/day compared with exenatide. Weight loss was the largest component of WTP for liraglutide compared with rosiglitazone, glimepiride, and insulin glargine. Differences in the administration of the two drugs was the largest component of WTP for liraglutide (once daily anytime) compared with exenatide (twice daily with meals). A limitation of the study was that it was based on six clinical trials where liraglutide was the test drug, but each trial had a different comparator, therefore the clinical effects of liraglutide were much better documented than the comparators. Conclusions: WTP analyses of the clinical results from the LEAD programme suggested that participants with type 2 diabetes were willing to pay appreciably more for liraglutide than other glucose lowering treatments. This was driven by the relative advantage of weight loss compared with rosiglitazone, glimepiride, and insulin glargine, and administration frequency co

Published
2012
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12. Willingness to pay for health improvements associated with anti-diabetes treatments for people with type 2 diabetes

Author

Jendle, Johan, Torffvit, O., Ridderstråle, M., Lammert, M., Ericsson, Å., Bøgelund, M., Jendle, Johan, Torffvit, O., Ridderstråle, M., Lammert, M., Ericsson, Å., and Bøgelund, M.

Abstract

OBJECTIVES: This study aimed to investigate the most important consequences of diabetes medication, as measured by the patients' willingness to pay (WTP). RESEARCH DESIGN AND METHODS: People in Sweden were recruited using existing nationwide e-mail panels if they were adults (>or=18 years) with type 2 diabetes and were receiving pharmacological anti-diabetes treatment(s). Data were collected electronically and results were analysed using a standard statistical model designed for choice games (conditional logit). Six characteristics relating to treatment of diabetes were examined: weight (gain or loss), mean glycated haemoglobin level (HbA(1c)), hypoglycaemic events, nausea, need for injections (with or independently of meals), and blood glucose testing. RESULTS: A total of 461 people with type 2 diabetes (291 males; 170 females) completed an internet questionnaire and were eligible for inclusion. Participants placed high value on weight loss and nausea avoidance; they would pay 176 Swedish Krona (SEK)/euro15.61 per month to lose 1 kg, and would pay SEK 560 (euro49.67) per month to avoid nausea completely. Patients wanting to reduce the number of hypoglycaemic events from three per month to none were willing to pay SEK 419 (euro37.17) per month. Patients valued a 1 percentage point reduction in HbA(1c) at SEK 414 (euro36.72) per month. Participants preferred taking tablets to injections and required a compensation of SEK 376 (euro33.35) to accept one injection/day. Injections independent of meals were preferred to injections with meals (WTP: SEK 140/euro12.42 per month). Potential limitations of this study are that the preferences expressed may not match preferences in real-life situations, and bias through the use of electronic questionnaire, which restricted participation to those with access to, and experience with, the internet. CONCLUSION: People with type 2 diabetes were willing to pay a considerable amount of money each month to lose weight, reduce or avoid, Research funder:Novo Nordisk A/S, Bagsværd, Denmark

Published
2010
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20. Urinary excretion of Tamm-Horsfall protein and epidermal growth factor in chronic nephropathy.

Author

Torffvit, O, Jørgensen, P E, Kamper, A L, Holstein-Rathlou, N H, Strandgaard, S, Leyssac, Paul Peter, Poulsen, Steen Seier, Torffvit, O, Jørgensen, P E, Kamper, A L, Holstein-Rathlou, N H, Strandgaard, S, Leyssac, Paul Peter, and Poulsen, Steen Seier

Abstract

Udgivelsesdato: 1998-null, Tamm-Horsfall protein (THP) and epidermal growth factor (EGF) are both synthesized by tubular cells in the distal part of the nephron and excreted with the urine. The present study examines the urinary excretion rates of the two peptides in relation to functional tubular markers in patients with chronic nephropathy. Four groups of patients with moderate to severely reduced renal function were studied: glomerulonephritis (n = 10), diabetic nephropathy (n = 11), tubulointerstitial nephropathy (n = 13), and polycystic kidney disease (n = 8). The renal function was evaluated by glomerular filtration rate (GFR) as an indicator for the general renal function, lithium clearance (C(Li)) as an indicator for proximal tubular function, and absolute distal reabsorption of sodium (ADR(Na)) as an indicator for distal tubular function. The excretion rate of EGF was rather closely correlated with GFR, C(Li) and ADR(Na) (Spearman coefficients of variation 0.88, 0.69, and 0.74, respectively). The correlations between the excretion rate of THP and GFR, C(Li) and ADR(Na) were weaker (Spearman coefficients of variation 0.68, 0.42, and 0.44). When the effect of GFR had been accounted for by multiple variance analyses, the excretion rates of the two peptides were still associated with ADR(Na) but not with C(Li). In conclusion, the urinary excretion rates of especially EGF but also those of THP were correlated with renal function and distal tubular reabsorption of sodium in patients with chronic nephropathy.

Published
1998

23. Urinary excretion of epidermal growth factor and Tamm-Horsfall protein in three rat models with increased renal excretion of urine

Author

Thulesen, J, Jørgensen, P E, Torffvit, O, Nexø, Ebba, Poulsen, Steen Seier, Thulesen, J, Jørgensen, P E, Torffvit, O, Nexø, Ebba, and Poulsen, Steen Seier

Abstract

Epidermal growth factor (EGF) and Tamm-Horsfall protein (THP) are synthesized in the kidneys by the distal tubular cells and excreted into urine. The urinary excretion of these peptides has been suggested as a potential index for distal tubular function. The urinary excretion rates of EGF and THP were examined in three groups of rats with increased renal excretion of urine: uninephrectomy, non-osmotic polyuria and diabetic osmotic polyuria. Twenty-four hour urine samples were obtained after 7, 14 and 21 days. The urinary volume per kidney was doubled in uninephrectomy when compared to controls. There was a seven-fold increase in urinary volume in rats with non-osmotic polyuria and diabetic osmotic polyuria, as compared to controls. Uninephrectomy, non-osmotic polyuria and diabetes all affected the urinary excretion of EGF and THP differently. The EGF excretion in uninephrectomized rats was 60-80% of that of the controls, whereas THP excretion was unchanged, indicating that EGF excretion varied with renal tissue mass. Non-osmotic polyuria caused a five-fold increase in THP excretion but no change in EGF excretion. THP excretion in the diabetic rats was increased three-fold after 21 days when compared to controls, whereas EGF excretion was decreased when expressed per kidney weight. Immunohistochemistry demonstrated that EGF and THP were colocalized in the thick ascending limbs of Henle's loops and distal tubules in all five groups of rats. In conclusion, the EGF excretion appears to follow renal tissue mass and seems independent of urinary volume, whereas THP excretion is dependent mainly on urinary volume. This has implications for the use of EGF and/or THP excretion rates as an indicator for distal tubular function.

Published
1997

39. Urine IgM-excretion as a prognostic marker for progression of type 2 diabetic nephropathy.

Author

Tofik R, Torffvit O, Rippe B, and Bakoush O

Abstract

Although the clinical manifestations of type 2 diabetic nephropathy and decline in kidney function are similar to those in type 1, the clinical course and the renal structural changes are more heterogeneous in type 2 diabetic patients. Previous studies have shown that an increased urine IgM excretion in patients with type 1 diabetic nephropathy was associated with poor outcome. In the present follow-up study we examine the prognostic value of baseline urine IgM excretion in patients with type 2 diabetes mellitus. METHODS: A cohort of 106 (74 male and 32 female) patients with type 2 diabetes regularly attending our diabetes out-patient clinic at Skane University Hospital in Lund. They were recruited prospectively under the period between 1992 and 2004. Patients were followed-up until January 2009. The end point was cardiovascular (CV) death or end-stage renal disease (ESRD). The median follow-up time was 5 years (0.5-13 years). Participants were divided according to degree of albuminuria and IgM-uria. RESULTS: During follow-up time, 28 (19 male and 9 female) patients died of CV events and 41 (26 male and 15 female) developed ESRD. The risk of CV mortality was 2.4 fold, and the risk of renal failure 4.9 fold higher in patients with increased urine IgM excretion compared to patients with low urine IgM excretion. Stratified analysis showed that an increased urine IgM excretion was an independent predictor of renal and cardiovascular death irrespective of the degree of albuminuria (HR=3.6, 95% CI: 2.1-6.0, P<0.001). In conclusion, type 2 diabetic nephropathy patients with high urine IgM excretion rates carry an increased risk of renal and cardiovascular death. [ABSTRACT FROM AUTHOR]

Published
2012

42. Signs of nephropathy may occur early in young adults with diabetes despite modern diabetes management: results from the nationwide population-based Diabetes Incidence Study in Sweden (DISS).

Author

Svensson M, Sundkvist G, Arnqvist HJ, Björk E, Blohmé G, Bolinder J, Henricsson M, Nyström L, Torffvit O, Waernbaum I, Östman J, Eriksson JW, Svensson, Maria, Sundkvist, Göran, Arnqvist, Hans J, Björk, Elisabeth, Blohmé, Göran, Bolinder, Jan, Henricsson, Marianne, and Nyström, Lennarth

Abstract

Objective: To estimate the occurrence of early-onset renal involvement in a nationwide population-based cohort of young adults with diabetes in Sweden and relate the findings to glycemic control, type of diabetes, sex, smoking, and blood pressure.Research Design and Methods: The Diabetes Incidence Study in Sweden aims to register all incident cases of diabetes in the age-group 15-34 years. In 1987-1988, 806 patients were reported and invited to participate in a follow-up study focusing on microvascular complications. Of them, 469 subjects participated. The assessment was based on questionnaires (n = 469), blood samples (n = 424), urine samples (n = 251) and, when appropriate, medical records (n = 186).Results: During the follow-up time, median 9 years (range 6-12), 31 of 469 patients (6.6%) with incipient or overt diabetic nephropathy (i.e., micro- or macroalbuminuria) were found, 24 of 426 (5.6%) in type 1 and 7 of 43 (16%) in type 2 diabetic subjects (P = 0.016). Additionally, 24 of 31 patients (77%) had microalbuminuria and 7 (23%) had macroalbuminuria, which mainly occurred in patients with type 2 diabetes. In a Cox regression analysis, high mean HbA(1c) during the follow-up period and high blood pressure at follow-up increased the risk of developing signs of nephropathy (P = 0.020 and P = 0.003, respectively). Compared with patients with type 1 diabetes, those with type 2 diabetes tended to have an increased risk of renal involvement (P = 0.054) when adjusting for sex, tobacco use, glycemic control, and blood pressure.Conclusions: Despite modern treatment and self-monitoring of blood glucose, young adult patients with diabetes may still develop renal involvement during the first 10 years of diabetes duration. Inadequate HbA(1c), high blood pressure, and type 2 diabetes appear to be risk markers for early occurrence of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Published
2003
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43. Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-blind, placebo-controlled study.

Author

Kalani M, Apelqvist J, Blombäck M, Brismar K, Eliasson B, Eriksson JW, Fagrell B, Hamsten A, Torffvit O, Jörneskog G, Kalani, Majid, Apelqvist, Jan, Blombäck, Margareta, Brismar, Kerstin, Eliasson, Björn, Eriksson, Jan W, Fagrell, Bengt, Hamsten, Anders, Torffvit, Ole, and Jörneskog, Gun

Abstract

Objective: Chronic foot ulcers are a common, severe, and expensive complication threatening life and limb in patients with diabetes. The aim of the present study was to investigate the effect of dalteparin on ulcer outcome in patients with diabetes, peripheral arterial occlusive disease, and chronic foot ulcers.Research Design and Methods: A total of 87 patients were investigated in a prospective, randomized, double-blind, placebo-controlled trial. Participants were randomized to treatment with subcutaneous injection of 5000 units dalteparin (Fragmin, Pharmacia Corporation; n = 44) or an equivalent volume of physiological saline (n = 43) once daily until ulcer healing or for a maximum of 6 months. Ulcer outcome was investigated by evaluating the number of patients 1). who healed with intact skin; 2). in whom the study ulcer was improved, unchanged, or impaired; or 3). who were amputated above or below the ankle level, as compared with control subjects.Results: Two patients, one on dalteparin and one on placebo, dropped out of the study. Ulcer outcome was significantly better (P = 0.042, two-sided chi(2) test for trend) in the dalteparin group (n = 43) compared with the placebo group (n = 42). A total of 29 patients healed with intact skin (n = 14) or decreased the ulcer area >or=50% (n = 15) in the dalteparin group compared with 20 (n = 9 and 11, respectively) in the placebo group. Five patients in each group showed impaired ulcer healing, i.e., the ulcer area increased >or=50%. Two patients in the dalteparin group were amputated compared with eight in the placebo group. Time to healing with intact skin was 17 +/- 8 weeks in the dalteparin group compared with 16 +/- 7 weeks in placebo group (NS).Conclusions: The results of the present study indicate that dalteparin improves the outcome of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease. [ABSTRACT FROM AUTHOR]

Published
2003
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44. Urine IgG2/IgG4-ratio indicates the significance of the charge selective properties of the glomerular capillary wall for the macromolecular transport in glomerular diseases.

Author

Tencer, J, Torffvit, O, Thysell, H, Rippe, B, and Grubb, A

Abstract

Background: Alterations of the charge-selective properties of the glomerular capillary wall are important constituents of the pathogenesis of many glomerular diseases. Thus, differences in the degree of such changes could be of help in understanding the mechanism governing the transport of macromolecules across the glomerular capillary wall. [ABSTRACT FROM PUBLISHER]

Published
1999
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49. High proteinuria selectivity index based upon IgM is a strong predictor of poor renal survival in glomerular diseases.

Author

Bakoush, O, Torffvit, O, Rippe, B, and Tencer, J

Abstract

The transport of large proteins across the glomerular capillary wall (GCW) may increase several fold in glomerular diseases. The occurrence of IgM in urine is a consequence of the presence of large defects or shunts in the GCW, whereas albuminuria is probably a result of an altered charge- and size-selectivity of the GCW. In order to examine whether patho-morphological differences influence the renal outcome in proteinuric glomerulopathies, we examined urinary excretion of IgM and albumin as prognostic markers of glomerular disease.

Published
2001
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