TUB is a candidate gene for late-onset obesity in women

Aims/hypotheses We recently reported significant associations between BMI and three TUB single nucleotide polymorphisms (SNPs) in two Dutch cohorts enriched for type 2 diabetes. Here, we attempted a replication of these associations in a large population-based cohort of female twins comprehensively phenotyped for measures of general and central obesity. Methods Two TUB SNPs (rs2272382, rs2272383) and a third (rs1528133), 22 kb distal to RIC3, were genotyped in 2694 Europid women from the St Thomas’ UK Adult Twin Registry (Twins UK) (mean age ± SD: 47.6 ± 12.7 years; 42.8% postmenopausal). We explored the hypothesis that TUB is a candidate gene for late-onset obesity in humans through testing the interaction of the SNPs by menopausal status. Results In the whole cohort, none of the three SNPs showed a significant main effect on measures of general or central obesity. However, for central obesity the rs2272382 SNP showed a significant interaction with menopausal status (p = 0.036). Postmenopausal women homozygous for the minor allele of rs2272382 showed significantly more general obesity (p = 0.022) and central obesity (p = 0.009) than carriers of the major allele. Differences (beta [95% CI]) between the two genotype groups were 0.92 kg/m² (0.03–1.81) for BMI (p = 0.036), 2.73 cm (0.62–4.84) for waist circumference (p = 0.013) and 2.43% (0.27–4.60) for per cent central fat (p = 0.027). These associations were confirmed by a sibling transmission disequilibrium test for central obesity, waist circumference and per cent central fat. Conclusions/interpretation We have replicated associations of TUB SNP rs2272382 with measures of general and central obesity in normal postmenopausal women. These findings confirm TUB as a candidate gene for late-onset obesity in humans.     

Prostasin: a possible candidate gene for human hypertension

BackgroundProstasin, a serine protease, is suggested to be a novel mechanism regulating the epithelial sodium channel (ENaC) expressed in the distal nephron. This study aimed to evaluate whether the human prostasin gene is a novel candidate gene underlying blood pressure (BP) elevation.MethodsIn a sample of healthy African-American (AA) and European-American (EA) twin subjects aged 17.6 +/- 3.3 years (n = 920, 45% AAs), race-specific tagging single-nucleotide polymorphisms (tSNPs) were identified to tag all the available SNPs +/- 2 kb up- and downstream of the prostasin gene from HapMap at r(2) of 0.8-1.0. Selection yielded four tSNPs in AAs and one in EAs, with one tSNP (rs12597511: C to T) present in both AAs and EAs.ResultsFor rs12597511, CT and TT genotypes exhibited higher systolic BP (SBP) than CC genotype (115.9 +/- 1.1 mm Hg vs. 113.7 +/- 0.6 mm Hg, P = 0.025 (AAs); and 110.7 +/- 0.5 mm Hg vs. 109.6 +/- 0.6 mm Hg, P = 0.115 (EAs)). CT and TT genotypes compared with CC genotype showed a significant increase in diastolic BP (DBP) in both racial groups (62.5 +/- 0.7 mm Hg vs. 60.4 +/- 0.4 mm Hg, P = 0.003 (AAs); and 58.2 +/- 0.3 mm Hg vs. 56.7 +/- 0.4 mm Hg, P = 0.007 (EAs)). Furthermore, there was an increase in radial pulse wave velocity (PWV) in subjects with CT and TT genotype as compared with those with CC genotype (6.5 +/- 0.1 vs. 6.1 +/- 0.1 m/s, P < 0.0001) (EAs); and 6.7 +/- 0.1 vs. 6.6 +/- 0.1 m/s, P = 0.354 (AAs)). Analyses combining AAs and EAs consistently demonstrated a statistical significance of rs12597511 on all the phenotypes including SBP/DBP and PWV.ConclusionGenetic variation of the prostasin gene may be implicated in the development of hypertension in youths.American Journal of Hypertension (2008). doi 10.1038/ajh.2008.224American Journal of Hypertension (2008); 21, 9, 1028-1033. doi 10.1038/ajh.2008.224.     

Kynureninase is a novel candidate gene for hypertension in spontaneously hypertensive rats.

The rostral ventrolateral medulla (RVLM) plays a critical role in the tonic and reflexive regulation of arterial blood pressure. Recent studies have demonstrated that injection of kynurenic acid (KYN) into the RVLM of spontaneously hypertensive rats (SHR) decreases arterial blood pressure. We hypothesized that a relative increase in the excitatory amino acid-mediated drive of RVLM vasomotor neurons in SHR may be due to derangement of one of the enzymes that affect the KYN level in the brain. We selected kynureninase, kynureninase hydroxylase, kynurenine aminotransferase type I, and kynurenine aminotransferase type II as candidates that may affect the KYN level in the brainstem. We conducted association studies between polymorphisms of these genes and blood pressure in an F2 population derived from SHR and Wistar-Kyoto rats (WKY). The cosegregation analysis indicated that only the kynureninase gene (KYNU) polymorphism influenced systolic blood pressure (SBP) and residuals of systolic blood pressure after adjusting for heart rate and body weight (RSBP). KYNU was found to be located on rat chromosome 3, and quantitative trait loci analysis at this locus indicated that the logarithms of the odds scores for KYNU in terms of SBP and RSBP were 2.0 and 3.3, respectively. This association with blood pressure decreased in proportion to the distance from KYNU. The expression level of KYNU mRNA in the brainstem was about 3.1 and 2.9 times higher in 10-week-old and 16-week-old SHR than in age-matched WKY, respectively. The increased expression of KYNU in SHR is thought to decrease the KYN level. KYNU seems to be one of the genes that contributes to hypertension in SHR.     

Serine/threonine kinase gene Stpk-V, a key member of powdery mildew resistance gene Pm21, confers powdery mildew resistance in wheat

Powdery mildew resistance gene Pm21, located on the chromosome 6V short arm of Haynaldia villosa and transferred to wheat as a 6VS·6AL translocation (T6VS·6AL), confers durable and broad-spectrum resistance to wheat powdery mildew. Pm21 has become a key gene resource for powdery mildew resistance breeding all over the world. In China, 12 wheat varieties containing Pm21 have been planted on more than 3.4 million hectares since 2002. Pm21 has been intractable to molecular genetic mapping because the 6VS does not pair and recombine with the 6AS. Moreover, all known accessions of H. villosa are immune to powdery mildew fungus. Pm21 is still defined by cytogenetics as a locus. In the present study, a putative serine and threonine protein kinase gene Stpk-V was cloned and characterized with an integrative strategy of molecular and cytogenetic techniques. Stpk-V is located on the Pm21 locus. The results of a single cell transient expression assay showed that Stpk-V could decrease the haustorium index dramatically. After the Stpk-V was transformed into a susceptible wheat variety Yangmai158, the characterized transgenic plants showed high and broad-spectrum powdery mildew resistance similar to T6VS·6AL. Silencing of the Stpk-V by virus-induced gene silencing in both T6VS·6AL and H. villosa resulted in their increased susceptibility. Stpk-V could be induced by Bgt and exogenous H(2)O(2), but it also mediated the increase of endogenous H(2)O(2), leading to cell death and plant resistance when the plant was attacked by Bgt.     

Serine/threonine kinase PKR: a sentinel kinase that discriminates a signaling pathway mediated by TLR4 from those mediated by TLR3 and TLR9

Cells of the innate immune system discriminate between "noninfectious self" and "infectious nonself" via pattern recognition receptors known as Toll-like receptors (TLRs). Though TLRs and the related interleukin 1 receptors share considerable homology in their cytoplasmic domains and adaptor molecules, signaling cascades may substantially differ from one another depending on the adaptor proteins recruited. Here we show that ectopic overexpression of catalytically inactive dominant-negative PKR expression system suppressed NF- kappa B activation mediated by TLR3, TLR9, TNF receptor 1 and 2 (TNF-R 1/2), but not by TLR4. Physiological relevance of the observations described here are discussed.     

Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies

Emerging evidence suggests an inverse relation between vitamin D and blood pressure. We examined the independent association between intake of vitamin D and the risk of incident hypertension among participants of 3 large and independent prospective cohorts: Nurses Health Study I (NHS I; n=77,436), NHS II (n=93,803), and Health Professionals' Follow-up Study (HPFS; n=38,074). Relative risks and 95% confidence intervals for incident hypertension were computed according to quintiles of vitamin D intake using Cox proportional hazards regression and adjusted for relevant covariates. Each cohort was followed for > or =8 years. Vitamin D intake was not associated with the risk of developing hypertension. The multivariable relative risk estimates for the highest compared with lowest quintile of intake were 0.98 (0.93 to 1.04) in NHS I, 1.13 (0.99 to 1.29) in NHS II, and 1.03 (0.93 to 1.15) in HPFS. When we compared participants who consumed > or =1600 to <400 IU per day and those who consumed > or =1000 to <200 IU per day, no association was found. We conclude that higher intake of vitamin D is not associated with a lower risk of incident hypertension.     

Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies

Objective

To examine the association of biomarkers of inflammation with preclinical rheumatoid arthritis (RA).

Methods

A nested case–control study was performed using samples from 2 large, prospectively studied cohorts of women (the Women's Health Study [WHS] and the Nurses' Health Study [NHS]). Blood samples obtained prior to symptom onset in women who later developed RA were selected as incident RA cases, and 3 controls per case were randomly chosen, matched for age, menopausal status, postmenopausal hormone use, and day, time, and fasting status at the time of collection. Plasma was tested for levels of interleukin‐6 (IL‐6), soluble tumor necrosis factor receptor II (sTNFRII) (as a proxy for TNFα), and high‐sensitivity C‐reactive protein. Relationships between biomarkers and RA were assessed using conditional logistic regression models, adjusting for age, body mass index, smoking habits, ethnicity, and reproductive factors.

Results

In 93 incident cases in the NHS and 77 incident cases in the WHS, the mean time between blood collection and the onset of RA symptoms was 5.2 years (range 0.3–12 years). Median IL‐6 and sTNFRII levels were significantly higher in preclinical RA cases compared with matched controls in the NHS (P = 0.03 and P = 0.003, respectively) though not in the WHS. Pooled analysis of the NHS and WHS cohorts demonstrated significant association of sTNFRII with RA (relative risk 2.0 [95% confidence interval 1.1–3.6], P for trend = 0.004), and a modest association of IL‐6 with RA (relative risk 1.4 [95% confidence interval 0.8–2.5], P for trend = 0.06).

Conclusion

Levels of sTNFRII, a biomarker typically associated with active RA, were elevated up to 12 years prior to the development of RA symptoms and were positively associated with incident RA in these nested case–control studies. Studies with repeated assessments of biomarkers prior to RA development may provide further insight into the timing of biomarker elevation in preclinical RA.

     

Mouse Erk-1 gene product is a serine/threonine protein kinase that has the potential to phosphorylate tyrosine.

Bacterial expression of mouse gene Erk-1 yielded an active kinase with the same substrate specificity shown for ERK1 protein purified from rat cells. Although rat gene ERK1 is believed to encode a serine/threonine kinase based on sequence data and known ERK1 substrate phosphorylation sites, bacterially-produced mouse Erk-1 (bt-Erk-1) autophosphorylated on tyrosine in addition to serine and threonine residues. The bt-Erk-1 protein also had the capacity to reactivate the ribosomal protein S6 kinase (S6KII). Furthermore, treatment of bt-Erk-1 with either serine/threonine-specific phosphatase 2A or tyrosine-specific phosphatase 1B significantly decreased its kinase activity. These findings predict that autophosphorylation may play an important role in Erk-1/ERK1 regulation.     

高血压定位区域犬尿氨酸酶基因多态性与高血压病相关

目的检测中国汉族人群高血压病定位区域2q14-q23内犬尿氨酸酶基因（kynureninase,KYNU）调控区和编码区的单核苷酸多态性（single nucleotide polymorphism,SNP）及与高血压病的相关性。方法采用直接测序法检测KYNU基因启动子区和外显子序列中的SNP。应用变性高效液相色谱分析（DHPLC）技术对位于编码区且改变氨基酸编码的Lys412Glu（A／G）多态在456例高血压病患者和430例正常对照者中进行分型和关联研究。结果共检测得KYNU基因的16个SNP,其中启动子区6个,编码区2个（均改变氨基酸编码）。Lys412Glu多态基因型分布（x^2 = 6．693,P =0．035）和等位基因频率分布（x^2 = 4．188,P = 0．041）在高血压病组和正常对照组间差异均有统计学意义,Lys412Glu等位基因频率分布在男性高血压病组和正常对照组间差异有统计学意义（x^2 = 4．424,P = 0．035）。结论中国汉族高血压病定位区域内KYNU基因Lys412Glu多态可能与高血压病相关。     

Effectiveness of the WHO/UNICEF guidelines on infant feeding for HIV-positive women: results from a prospective cohort study in South Africa

BACKGROUND: The World Health Organization (WHO) and UNICEF recommend that HIV-positive women should avoid all breastfeeding only if replacement feeding is acceptable, feasible, affordable, sustainable and safe. Little is known about the effectiveness of the implementation of these guidelines in developing country settings. OBJECTIVE: To identify criteria to guide appropriate infant-feeding choices and to assess the effect of inappropriate choices on infant HIV-free survival. METHOD: Prospective cohort study of 635 HIV-positive mother-infant pairs across three sites in South Africa to assess mother to child transmission of HIV. Semistructured questionnaires were used during home visits between the antenatal period and 36 weeks after delivery to collect data concerning appropriateness of infant feeding choices based on the WHO/UNICEF recommendations. RESULTS: Three criteria were found to be associated with improved infant HIV-free survival amongst women choosing to formula feed: piped water; electricity, gas or paraffin for fuel; and disclosing HIV status. Using these criteria as a measure of appropriateness of choice: 95 of 311 women who met the criteria (30.5%) chose to breastfeed and 195 of 289 women who did not meet the criteria (67.4%) chose to formula feed. Infants of women who chose to formula feed without fulfilling these three criteria had the highest risk of HIV transmission/death (hazard ratio, 3.63; 95% confidence interval, 1.48-8.89). CONCLUSIONS: Within operational settings, the WHO/UNICEF guidelines were not being implemented effectively, leading to inappropriate infant-feeding choices and consequent lower infant HIV-free survival. Counselling of mothers should include an assessment of individual and environmental criteria to support appropriate infant-feeding choices.     

Weight loss increases and fat loss decreases all-cause mortality rate: results from two independent cohort studies.

OBJECTIVE: In epidemiological studies, weight loss is usually associated with increased mortality rate. Contrarily, among obese people, weight loss reduces other risk factors for disease and death. We hypothesised that this paradox could exist because weight is used as an implicit adiposity index. No study has considered the independent effects of weight loss and fat loss on mortality rate. We studied mortality rate as a function of weight loss and fat loss. DESIGN: Analysis of 'time to death' in two prospective population-based cohort studies, the Tecumseh Community Health Study (1890 subjects; 321 deaths within 16y of follow-up) and the Framingham Heart Study (2731 subjects; 507 deaths within 8y of follow-up), in which weight and fat (via skinfolds) loss were assessable. RESULTS: In both studies, regardless of the statistical approach, weight loss was associated with an increased, and fat loss with a decreased, mortality rate (P < 0.05). Each standard deviation (s.d.) of weight loss (4.6 kg in Tecumseh, 6.7 kg in Framingham) was estimated to increase the hazard rate by 29% (95% confidence interval CI), (14%, 47%, respectively) and 39% (95% CI, 25%, 54% respectively), in the two samples. Contrarily, each s.d. of fat loss (10.0 mm in Tecumseh, 4.8 mm in Framingham) was estimated to reduce the hazard rate 15% (95% CI, 4%, 25%) and 17% (95% CI, 8%, 25%) in Tecumseh and Framingham, respectively. Generalisability of these results to severely (that is, body mass index BMI) > or = 34) obese individuals is unclear. CONCLUSIONS: Among individuals that are not severely obese, weight loss is associated with increased mortality rate and fat loss with decreased mortality rate.     

Serine/threonine protein kinase 25 (STK25): a novel negative regulator of lipid and glucose metabolism in rodent and human skeletal muscle

Aims/hypothesis  

This study investigates the role of serine/threonine protein kinase 25 (STK25), a member of the sterile 20 (STE20) superfamily of kinases, in the regulation of skeletal muscle metabolism.     

Screening for primary aldosteronism in a cohort of Brazilian patients with resistant hypertension

The objective was to estimate the prevalence of plasma aldosterone concentration:plasma renin activity ratio >30 ng/dL:ng/mL/h in patients with resistant hypertension and to describe the computed tomography findings of adrenal glands in those with elevated ratios. In a cross-sectional design, 492 patients were enrolled. All patients with plasma aldosterone concentration:plasma renin activity ratio >or=30 ng/dL:ng/mL/h (n=77) underwent abdominal computed tomography. Patients with an adrenal image of possible aldosterone-producing adenoma underwent a saline-loading test. The prevalence of elevated plasma aldosterone concentration:plasma renin activity ratio was 15.7% (95% confidence interval, 12.6-19.2). Twelve patients showed adrenal abnormalities on computed tomography. The level of renin was low in 50% of the sample. Results indicate a low prevalence of aldosterone-producing adenoma. Our evidence points out the importance of confirming the hypothesis that essential hypertension, low-renin hypertension, and idiopathic hyperaldosteronism could be the same disease, but at different neurohormonal stages, and aldosterone-producing adenoma may be yet another disease.     

Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation.

We have isolated murine cDNAs encoding two isoforms of a putative protein-serine/threonine kinase, designated Sak-a and Sak-b, which differ in their noncatalytic C-terminal ends. The kinase domain of Sak is related to the catalytic domains of the Drosophila polo, Saccharomyces cerevisiae CDC5, and murine Snk and Plk kinases, a family of proteins for which a role in controlling cell proliferation has been established (polo, CDC5) or implicated (Snk, Plk). Northern and in situ RNA analyses of Sak gene expression in mouse embryos and adult tissues revealed that expression was associated with mitotic and meiotic cell division. In addition, during embryogenesis, Sak expression was prominent in the respiratory and olfactory mucosa. The pattern of Sak expression and its sequence homology with the polo gene family suggest that the Sak kinase may play a role in cell proliferation. In support of this, cell growth was suppressed by expression of a Sak-a-antisense fragment in CHO cells.     

Gastro esophageal reflux disease is associated with absence from work： Results from a prospective cohort study

AIM: To study the association of gastro-esophageal reflux disease (GERD) with the absence from work and to estimate the extent of loss in gross domestic product due to inability to work. METHODS: Analysis was based on the prospectively gathered data of a large European cohort study involving 6 215 symptomatic GERD patients (ProGERD). Among these patients, 2 871 were initially employed. The calculation of the loss of gross domestic product was based on the assumption that the prevalence of GERD was about 15% in Germany. According to the German Federal Statistical Office, the mean gross wage of employees was 150 (?)/d in 2002. RESULTS: The data of 2 078 employed patients who were prospectively followed up for over 2 years were analyzed. At study entry, the patients reported a mean of 1.8 d per year of inability to work. During the prospective follow-up under routine clinical care, the proportion of patients reporting days with inability to work decreased from 14% to 6% and the mean number of days per year with inability to work decreased to 0.9 d. Assuming a prevalence of troublesome GERD of 15% in the employed German population, the loss of gross domestic product amounted to 668 million (?)/year in Germany. CONCLUSION: GERD causes a relevant impairment on the national economics by absence from work. The presented data demonstrate the importance of GERD, not only for patients and health insurance companies, but also for the community at large.     

Seven lessons from two candidate genes in human essential hypertension: angiotensinogen and epithelial sodium channel.

The candidate gene approach to understanding the genetics of human essential hypertension is discussed by analyzing the contribution of 2 genes, angiotensinogen (AGT) and epithelial amiloride-sensitive sodium channel (ENaC). From a large series of studies conducted in humans and animals, it appears that the AGT gene plays a significant but modest role in human blood pressure variance. Mutations of the beta- and gamma-ENaC subunits are responsible for Liddle's syndrome, but the implication of the 3 ENaC subunits in essential hypertension is still questionable. Several lessons can be learned from these studies and applied to other candidate genes in essential hypertension: (1) Many linkage or association studies have a limited statistical power; (2) The genetic findings may vary greatly according to the populations studied; (3) There is a need for better phenotyping of the hypertensive population; (4) The causal relationship between molecular variants and hypertension is and will be difficult to establish firmly; (5) The contribution of genetic studied in rodents to the molecular genetics of human hypertension must be re-examined; (6) Most molecular variants lead to a low attributable risk in the population or a low individual effect at the individual level; and (7) It is too early to propose dietary recommendations and specific drug treatment according to patients' genotypes.     

Bone loss in patients with rheumatoid arthritis: results from a population-based cohort of 366 patients followed up for two years

OBJECTIVE: To evaluate the extent of and risk factors for bone loss in a population-based cohort of patients with rheumatoid arthritis (RA) receiving conventional health care. METHODS: In a longitudinal study, clinical data were collected and bone mineral density (BMD) measurements were performed at baseline and after 2 years. Dual-energy x-ray absorptiometry was used for hip and spine BMD measurements. At baseline, patients received advice about lifestyle adjustments and calcium and vitamin D supplementation; during the followup period they were treated with antirheumatic and bone-sparing drugs, according to clinical judgment. RESULTS: After a mean +/- SD of 2.2 +/- 0.2 years, 366 (298 women, 68 men) of the 488 patients who were examined at baseline were reexamined. At that time, 47.9% were current users of corticosteroids and 37.0% were using antiresorptive drugs (hormone replacement therapy, bisphosphonates, or calcitonin). The mean BMD reduction was -0.64% in the femoral neck, -0.77% in the total hip, and -0.29% in the spine at L2-4. BMD was increased at all measurement sites in current users of antiresorptive drugs (0.16-1.64%) but was decreased in patients using calcium and vitamin D alone (-1.99% to -1.39%) and in patients not using any osteoporosis treatment (-1.20% to -0.43%). Current use of corticosteroids was independently associated with increased risk for BMD loss in the total hip (odds ratio [OR] 2.63, 95% confidence interval [95% CI] 1.38-5.00) and spine at L2-4 (OR 2.70, 95% CI 1.30-5.63), whereas current use of antiresorptive drugs was associated with decreased risk for bone loss in the total hip (OR 0.43, 95% CI 0.20-0.89). CONCLUSION: Results of this population-based, 2-year followup study indicate that adequate management of patients with RA, addressing both the rheumatic disease and osteoporosis, protects against bone loss.