Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K(a) renal chloride channel (ClC-K(a)). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combined P = 2.25 × 10(-6)). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy; P = 8.3 × 10(-7)). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-K(a) chloride channel currents revealed ≈ 50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis.     

Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity

A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 y of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease.     

The association of genetically determined serum glycine with cardiovascular risk in East Asians

Background and aimsGlycine is involved in a wide range of metabolic pathways and increased circulating glycine is associated with reduced risk of cardio-metabolic diseases in Europeans but the genetic association between circulating glycine and cardiovascular risk is largely unknown in East Asians.Methods and resultsWe conducted a genome-wide association study (GWAS) in Singaporean Chinese participants and investigated if genetically determined serum glycine were associated with incident coronary artery disease (CAD) (711 cases and 1,246 controls), cardiovascular death (1,886 cases and 21,707 controls) and angiographic CAD severity (as determined by the Modified Gensini score, N = 1,138).ConclusionOur study, a first in East Asians, suggest a protective role of glycine against CAD.     

Genetic Modifiers of Sickle Cell Disease

Sickle cell disease is one of the best characterized human monogenic disorders. Complex genotype/phenotype correlations clearly demonstrate the interaction of multiple genetic and environmental factors. In the last 20 years, scientific research has applied genetic approaches to dissect some of these modifiers. This review highlights the more recent genetic association studies that have been applied to unravel the genetic modifiers of sickle cell disease including Hb F genetics, and the key genetic variants identified. Illumination of such modifying factors may guide future therapeutic interventions and improve prediction of disease severity, with implications for genetic counseling, prenatal diagnosis and implementation of high risk therapy.     

Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects ≈1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 × 10⁻⁶. We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P ≈ 10⁻⁷: 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 × 10⁻⁷) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.     

Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax

A central issue in the control of apoptosis is whether its essential mediators Bax and Bak must be restrained by Bcl-2-like prosurvival relatives to prevent their damaging mitochondria and unleashing apoptosis. The issue is particularly vexed for Bax, which is largely a cytosolic monomer in unstressed cells. To determine whether Bax regulation requires its binding by prosurvival relatives, we replaced a conserved aspartate in its BH3 interaction domain with arginine. Bax D68R functioned and behaved like wild-type Bax in localization and activation but had greatly impaired binding to the prosurvival family members. Nevertheless, Bcl-x_L remained able to block apoptosis induced by Bax D68R. Whereas cells with sufficient Bcl-x_L tolerated expression of Bax D68R, it provoked apoptosis when Bcl-x_L was absent, downregulated, or inactivated. Moreover, Bax D68R rendered membrane bound by a C-terminal anchor mutation overwhelmed endogenous Bcl-x_L and killed cells. These unexpected results suggest that engagement of Bax by its prosurvival relatives is a major barrier to its full activation. We propose that the Bcl-2-like proteins must capture the small proportion of Bax molecules with an exposed BH3 domain, probably on the mitochondrial membrane, to prevent Bax-imposed cell death, but that Bcl-x_L also controls Bax by other 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 1 mg/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.     

红细胞压积与冠状动脉狭窄程度相关性分析

【】目的：探讨红细胞压积(HCT)与冠状动脉狭窄程度相关性。方法：选择2012年2月至2014年10月在我院心内科住院拟诊断冠心病的患者247例,统计患者基本临床资料、入院24h实验室检查及冠状动脉造影检查的结果,并对每位患者冠脉造影结果进行Gensini评分,依据所有患者血清中HCT的水平分为正常组(HCT≤0.396),升高组(HCT＞0.396)并进行危险因素比较,然后分析HCT与冠状动脉病变程度相关性。计量资料采用均数±标准差()表示,采用t检验进行显著性分析。计数资料采用率表示,组间比较用X₂检验,HCT与冠状动脉病变程度相关性采用线性相关分析。结果：与HCT正常组相比,患者年龄、性别、吸烟史、cTnI及UA差异存在统计学意义(p=0.006,p=0.000,p=0.000,p=0.02,p=0.04)；与无病变组相比,单支病变组、两支或左主干病变组及三支病变组HCT水平比较均有统计学差异(p=0.04,p=0.04,p=0.018);HCT与冠状动脉狭窄Gensini评分之间存在线性相关(r=0.73)。结论：HCT与冠状动脉狭窄程度之间存在一定相关性,临床检测HCT对冠心病患者诊疗有参考价值。     

成纤维细胞生长因子21与睡眠呼吸暂停综合征的相关性分析

目的本研究通过对318例男性参与者进行4年的随访,探讨成纤维细胞生长因子(FGF-21)与睡眠呼吸暂停综合征(sleep apnea syndrome,SAS)发生发展的关系。方法记录参与者一般临床资料,采用酶联免疫吸附法(ELISA)测定基线及随访4年后血清FGF-21浓度水平,对比分析SAS组与非SAS组间FGF21浓度水平差异,并采用多因素Logistic回归分析FGF21是否为SAS独立危险因素。结果 SAS组基线FGF21浓度水平明显高于非SAS组,差异有统计学意义(P0.05);SAS组随访4年后FGF21浓度水平明显高于基线FGF21浓度水平,差异有统计学意义(P0.05),非SAS组随访4年后血清FGF21浓度水平与基线FGF21浓度水平差异无统计学意义(P0.05);多因素Logistic回归分析发现BMI、TG、HOMA-IR、FGF21是影响SAS发生的独立危险因素。结论血清FGF-21浓度水平高是SAS发生的独立危险因素,未来有可能成为干预SAS有效的分子靶点。     

支气管哮喘患者合并变应性鼻炎的临床调查

目的调查支气管哮喘患者中变应性鼻炎的发生率,并对其临床诊治现状作初步分析。方法连续调查98例确诊的哮喘患者,详细了解其临床表现及诊治现状,并对所得数据进行统计学分析。结果 98例哮喘患者中63例（64.3%）并发变应性鼻炎,其中54例（85.7%）被误认为系反复感冒者。哮喘合并变应性鼻炎组（63例）和单纯哮喘组（35例）在年龄、病程等方面差异无显著性（P〉0.05）。仅在9例变应性鼻炎患者中有6例间断使用过鼻喷皮质类固醇激素治疗。结论较多的哮喘患者合并变应性鼻炎,及反复误诊提示应关注哮喘合并变应性鼻炎的诊治。当前对哮喘合并变应性鼻炎的诊治关注不足。     

The mystery of missing heritability: Genetic interactions create phantom heritability

Human genetics has been haunted by the mystery of "missing heritability" of common traits. Although studies have discovered >1,200 variants associated with common diseases and traits, these variants typically appear to explain only a minority of the heritability. The proportion of heritability explained by a set of variants is the ratio of (i) the heritability due to these variants (numerator), estimated directly from their observed effects, to (ii) the total heritability (denominator), inferred indirectly from population data. The prevailing view has been that the explanation for missing heritability lies in the numerator--that is, in as-yet undiscovered variants. While many variants surely remain to be found, we show here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating "phantom heritability." Specifically, (i) estimates of total heritability implicitly assume the trait involves no genetic interactions (epistasis) among loci; (ii) this assumption is not justified, because models with interactions are also consistent with observable data; and (iii) under such models, the total heritability may be much smaller and thus the proportion of heritability explained much larger. For example, 80% of the currently missing heritability for Crohn's disease could be due to genetic interactions, if the disease involves interaction among three pathways. In short, missing heritability need not directly correspond to missing variants, because current estimates of total heritability may be significantly inflated by genetic interactions. Finally, we describe a method for estimating heritability from isolated populations that is not inflated by genetic interactions.     

An introduction to medical statistics for health care professionals: basic statistical tests

This article, the third and final article in the series, aims to give health care professionals (HCPs) a sound and helpful introduction to medical statistics (Thomas, 2004, 2005). A brief summary of the content of the previous articles is given in Table 1. The current article will cover the area of basic statistical tests with the aim of guiding HCPs to the correct test for a particular research question and dataset. The article will not go into great depth of the formal methods of calculation required for all the tests covered but I would suggest that the reader refer to standard textbooks (Jordan et al., 1998; Swinscow, 1998; Altman, 1994; Bland, 2000), the help sections of statistical packages (SPSS or Stata), or consult a statistician. For ease of reference within the article the tests have been grouped by the data type, i.e. numerical or categorical. Further separation within each data type has been carried out depending on the number of groups being compared, whether the groups are independent, the size of the sample, and, in the case of numerical data, the distribution of the variable. For quick reference, two other tables are also presented which summarize which analysis methods should be used in each situation.     

Chronic pancreatitis, HLA and autoimmunity

Summary HLA-A and B antigens were studied in 88 Caucasoids with chronic pancreatitis resident in the Manchester area. In the subgroup of 52 patients with alcohol-related chronic pancreatitis HLA-B21 was significantly increased in frequency compared with 344 local controls (P _c =0.0128). In the non-alcoholic sub-group of 36 patients, the incidence of HLA-A1 was significantly higher than in controls (P _c=0.0021); whilst HLA-B8 was present in 38.8% of patients and 27.9% of controls. When these data are amalgamated with data from Lyon (France), the antigen HLA-A1 is significantly associated with non-alcoholic chronic pancreatitis. Abstracts of this work were presented at a meeting of the British Society of Gastroenterology (Leeds, U.K., 1982) and a Meeting of the European Pancreatic Club (Essen, D.D.R., 1982).     

中华医学会系列杂志2004～2013年布鲁杆菌病文献分析

目的了解中华医学会系列杂志近年来布鲁杆菌病（布病）文献分布情况和研究状况,为布病研究提供文献计量学资料。方法对中华医学会系列杂志2004～2013年的85种期刊进行检索,对布病文献分布情况进行统计,并对文献的内容分类、分析。结果中华医学会系列杂志10年间以布病研究为主的文献共计45篇,分布于16种杂志;其中论著29篇（64．4％）,病例报告13篇（28．9％）,综述3篇（6．7％）;10年间布病研究文献的论著中以流行病学调查和实验室检查研究最多（分别为12篇,36．4％）,其他为临床分析（10篇,30.3％）,其中1篇论著同时进行了临床分析与实验室检查研究;基金资助项目报道8篇（17．8％）;刊文量不少于5篇的为《中华传染病杂志》、《中华流行病学杂志》和《中华实验和临床感染病杂志》。中华医学会系列杂志2009～2013年布病文献刊文数（33篇,73．3％）多于2004—2008年布病文献篇数（12篇,26．7％）,差异有统计学意义（P〈0．05）。结论中华医学会系列杂志是广大医务工作者获取布病知识的重要来源,近5年布病相关研究文献数量显著提高,但布病的刊载量仍显不足,学科建设仍有待加强。