Strategies for Mapping and Identifying Quantitative Trait Loci Specifying Behavioral Responses to Alcohol

Most responses to alcohol in both humans and animals are heritable, and this genetic sensitivity to ethanol is determined by multiple genes. However, the number of genes, their identities, and just how they determine susceptibility to the actions of alcohol are unknown. Herein, we describe a multistage strategy for mapping quantitative trait loci (QTLs) using recombinant inbred strains and F2 mice. Precise mapping of the chromosome positions of these QTLs should increase our understanding of the genetic causes for individual differences in behavioral sensitivity to alcohol by (1) identifying genomic markers associated with sensitivity to alcohol, (2) allowing the genes specifying behavior to be cloned by position, and (3) elucidating "candidate" genes demonstrating linkage to markers associated with behavioral responses to alcohol. Syntenic conservation between the mouse and human genomes should facilitate the eventual mapping and cloning of human homologs of these QTLs. Ultimately, cloning of these genes may allow the development of gene therapies or other therapeutic interventions for management or prevention of alcoholism and alcohol abuse.     

Factor relationships of metabolic syndrome and echocardiographic phenotypes in the HyperGEN study

BACKGROUND: Metabolic syndrome and its risk factors are predictors of cardiovascular events. Metabolic syndrome is also directly associated with echocardiographic phenotypes. METHODS: The current study is the first to investigate the factors associated with both metabolic syndrome risk factors and echocardiographic phenotypes and assess their heritability. Multivariate factor analysis was performed on 15 traits in 1393 African-Americans and 1133 whites, as well as stratified by type 2 diabetes mellitus status. RESULTS: Factor analysis with varimax rotation established four to five latent factors across ethnicities and diabetes mellitus stratifications. Among metabolic syndrome risk factors, blood pressure was the most highly correlated with cardiac traits. The factor domains, in the order of the proportion of variance explained, were 'left ventricle wall thickness', 'left ventricle geometry', 'blood pressure', 'BMI-insulin', and 'lipid-insulin'. Factor analysis without any rotation identified special (cross domain) metabolic syndrome-echocardiographic factors, 'blood pressure-left ventricle geometry' and 'blood pressure-left ventricle dimension-wall thickness' in whites. Fifty to 57% of the total original risk factor variance was explained by the latent factors. Heritability was highest for BMI-insulin (37-53%), lowest for 'blood pressure' factors (15-27%), and intermediate for metabolic syndrome-echocardiographic factors. CONCLUSION: These latent factors identified can be utilized as summary phenotypes in epidemiological, linkage, and association studies.     

Effect of early revascularisation in cardiogenic shock complicating acute myocardial infarction. A single center experience

BACKGROUND: Five to 10% of patients with acute myocardial infarction develop cardiogenic shock and the majority of these patients are expected to die within the first few weeks. In this study, we review our recent experience in the management of patients with cardiogenic shock complicating MI and examine the effect of early invasive revascularisation on mortality. METHODS: Thirty-six consecutive patients who developed cardiogenic shock less than 48 h after MI were retrospectively evaluated and divided into two treatment groups. One group received early invasive revascularisation (n=24) and the other group had no early invasive revascularisation, but received similar conventional intensive care medical treatment (n=12). RESULTS: Baseline characteristics and hemodynamic variables were similar in both groups. Apart from invasive revascularisation and the use of intra aortic balloon counterpulsation (IABP), treatment strategies did not differ between the two groups. Thirty-day mortality was 21% in the revascularised group of patients and 58% in the non-revascularised group (P<0.05). CONCLUSIONS: Our data support previous observations suggesting that an aggressive treatment strategy including early invasive revascularisation and IABP is associated with improved short and long-term survival in patients with cardiogenic shock. Since early revascularisation appears safe with a considerable treatment benefit, this approach must be considered in patients with short shock duration early after MI.     

Cancer characteristics in Swedish families fulfilling criteria for hereditary nonpolyposis colorectal cancer

BACKGROUND & AIMS: The present study quantified the prevalence of families that fulfill the Amsterdam or Bethesda criteria for hereditary nonpolyposis colorectal cancer (HNPCC) in the whole Swedish population and investigated the extent to which tumors in the classified families are HNPCC-related. METHODS: The families of the Swedish Family-Cancer Database with at least 4 generations (N = 566,877) were classified according to the Amsterdam and the Bethesda criteria. Survival methods were used to assess the risk of cancer in the classified families, the prognosis of cancer patients, and the risk of subsequent malignancies after colorectal adenomas and after colorectal/endometrial adenocarcinomas. RESULTS: The Bethesda criteria identified 0.9% of all Swedish families and 11.2% of patients with colorectal cancer. Families that fulfilled the Bethesda criteria showed increased risks of cancer in the colorectum, endometrium, small bowel, ovary, stomach, bile ducts, renal pelvis, and ureter; members of Bethesda criteria families were at decreased risks of lung and cervical cancers. The prognosis of cancer in the ureter, renal pelvis, stomach, ovary, and colorectum, but not in the endometrium, was better in Bethesda criteria than in nonclassified families. CONCLUSIONS: Most malignancies in the classified families reflect typical features of HNPCC (association with subsequent malignancies, accelerated adenoma-carcinoma sequence, and better survival). The data presented in this study should help to define surveillance strategies for members of families that fulfill the criteria for HNPCC testing.