Identification of genetic loci associated with Helicobacter pylori serologic status.

IMPORTANCE: Helicobacter pylori is a major cause of gastritis and gastroduodenal ulcer disease and can cause cancer. H. pylori prevalence is as high as 90% in some developing countries but 10% of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H. pylori susceptibility. OBJECTIVE: To identify genetic loci associated with H. pylori seroprevalence in 2 independent population-based cohorts and to determine their putative pathophysiological role by whole-blood RNA gene expression profiling. DESIGN, SETTING, AND PARTICIPANTS: Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H. pylori IgG serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n = 3830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS-II (recruitment, 2000-2001 [n = 7108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n = 991]), and fecal H. pylori antigen in SHIP-TREND (n = 961). MAIN OUTCOMES AND MEASURES: H. pylori seroprevalence. RESULTS: Of 10,938 participants, 6160 (56.3%) were seropositive for H. pylori. GWASs identified the toll-like receptor (TLR) locus (4p14; top-ranked single-nucleotide polymorphism (SNP), rs10004195; P = 1.4 × 10(-18); odds ratio, 0.70 [95% CI, 0.65 to 0.76]) and the FCGR2A locus (1q23.3; top-ranked SNP, rs368433; P = 2.1 × 10(-8); odds ratio, 0.73 [95% CI, 0.65 to 0.81]) as associated with H. pylori seroprevalence. Among the 3 TLR genes at 4p14, only TLR1 was differentially expressed per copy number of the minor rs10004195-A allele (ß = -0.23 [95% CI, -0.34 to -0.11]; P = 2.1 × 10(-4)). Individuals with high fecal H. pylori antigen titers (optical density >1) also exhibited the highest 25% of TLR1 expression levels (P = .01 by χ2 test). Furthermore, TLR1 exhibited an Asn248Ser substitution in the extracellular domain strongly linked to the rs10004195 SNP. CONCLUSIONS AND RELEVANCE: GWAS meta-analysis identified an association between TLR1 and H. pylori seroprevalence, a finding that requires replication in nonwhite populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H. pylori infection.

Analysis of arterial pressure regulating systems in renal post-transplantation hypertension.

OBJECTIVE: To investigate if blood volume expansion, increased sodium retention, changes in neurohumoral arterial pressure control, or altered extrarenal resistance vessel function contribute to the development of renal post-transplantation hypertension. METHODS: F1-hybrids (F1H) obtained from crossing spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats received either an SHR or an F1H kidney graft. Groups consisted of 8-12 animals and were investigated between days 1 and 14 after renal transplantation in three sets of experiments including arterial pressure recordings, plasma volume measurements, metabolic studies, and small vessel myography. RESULTS: Two days after completion of bilateral nephrectomy, arterial pressure was elevated by 15-20 mmHg in recipients of an SHR kidney, compared with syngeneically transplanted controls. There was no evidence for increased sodium and fluid retention during the early development of renal post-transplantation hypertension despite a 35% reduced creatinine clearance in recipients of an SHR kidney. The plasma renin-angiotensin-aldosterone system was similarly suppressed in both recipients of an SHR kidney and controls. The arterial pressure response to ganglionic blockade did not differ between groups and there was no evidence for changes in extrarenal resistance vessel function, which could be involved in the genesis of this form of hypertension. CONCLUSIONS: None of the investigated mechanisms was altered in a way that might help to explain the rapid and consistent development of hypertension in recipients of an SHR kidney. We conclude that post-transplantation hypertension in recipients of an SHR kidney is due to mechanisms other than those investigated in the present study.

Intracellular calcium and sodium-lithium countertransport in type 2 diabetic patients with and without albuminuria.

Increased intracellular calcium concentrations ([Ca(2+)](i)) and enhanced sodium-lithium countertransport (Na/Li CT) activities may play a role in the development of diabetic complications such as diabetic nephropathy. The present study was designed to test the hypothesis that albuminuria in patients with type 2 diabetes is associated with increased [Ca(2+)](i) in response to stimulation with platelet-activating factor (PAF) or with enhanced Na/Li CT activities. The study population comprised 203 type 2 diabetic patients. Albuminuria was defined as an albumin excretion rate exceeding 30 mg/d (117 cases). PAF-evoked rises in [Ca(2+)](i) and Na/Li CT activities were determined in Epstein-Barr-virus-immortalized lymphoblasts. Albuminuria was related to high stimulated [Ca(2+)](i) but not to high basal [Ca(2+)](i). The association was independent of age, sex and several non-diabetes related confounders, but depended on diabetes-related factors, such as the duration of diabetes. The risk of albuminuria was highest in subjects with high [Ca(2+)](i) who reported a diabetes duration of < or =10 years. There was no association between Na/Li CT activities and albuminuria. The present results support the hypothesis that albuminuria in type 2 diabetic patients is associated with a primary defect in intracellular calcium homeostasis. The association between stimulated [Ca(2+)](i) and albuminuria is most prominent in early diabetes.

Sodium/lithium countertransport and intracellular calcium concentration in patients with essential hypertension and coronary heart disease.

The present study was designed to test the hypothesis that enhanced intracellular calcium signalling and increased sodium/lithium countertransport (Na(+)/Li(+) CT) activity may be associated with coronary heart disease (CHD) in non-diabetic patients with essential hypertension. Platelet-activating factor (PAF)-evoked rises in the intracellular calcium concentration ([Ca(2+)](i)) were measured in Epstein-Barr-virus-immortalized lymphoblasts from 62 hypertensive patients with CHD and 34 patients without CHD. Na(+)/Li(+) CT activity was assessed in erythrocytes from 80 hypertensive patients with CHD and 46 patients without CHD. Baseline values of unstimulated and PAF-stimulated [Ca(2+)](i) were not significantly different between hypertensive subjects with (baseline, 126+/-5 nmol/l; stimulated, 550+/-43 nmol/l) and without (baseline, 125+/-5 nmol/l; stimulated, 654+/-105 nmol/l) CHD. Similarly, Na(+)/Li(+) CT activity was not significantly different between the two groups (patients with CHD, 219+/-8 micromol x l(-1) x h(-1); patients without CHD, 234+/-10 micromol x l(-1) x h(-1)). We conclude that intracellular signal transduction, as indicated by PAF-induced rises in [Ca(2+)](i) and Na(+)/Li(+) CT activity, is not associated with an increased risk of CHD in non-diabetic patients with essential hypertension.