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.

Study queStion

Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.

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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 Swedenaims to register all incident cases of diabetes in the age-group 15-34 years. In 1987In -1988 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 ϭ 469), blood samples (n ϭ 424), urine samples (n ϭ 251) and, when appropriate, medical records (n ϭ 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 ϭ 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 ϭ 0.020 and P ϭ 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 ϭ 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. Diabetes Care 26:2903-2909, 2003O vert diabetic nephropathy, i.e., macroalbuminuria, is a serious complication of diabetes and is linked to a high risk of developing renal failure and cardiovascular disease (1). Persistent microalbuminuria, i.e., incipient nephropathy, can also predict overt diabetic nephropathy and cardiovascular complications (2,3). Improved long-term glycemic control has reduced the risk of developing diabetic nephropathy (4,5). The cumulative incidence of overt diabetic nephropathy after 25-30 years has been reported to be nearly 30% in type 1 diabetes (6). In type 2 diabetes, the incidence and prevalence of nephropathy is more uncertain, but in a cross-sectional study 30% of patients had microalbuminuria and 17% had macroalbuminuria after ϳ10 years of diabetes duration (7).Hyperglycemia is necessary, but other factors, e.g., hypertension, smoking, and genetic susceptibility, contribute to the development of diabetic nephropathy (8 -10). Besides intensified glycemic control, effective blood pressure control is of great importance to delay the development and progression of diabetic nephropathy (11). Accumulating evidence indicates that treatment with AC...