Karen Maresso

CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn’s disease

BACKGROUND & AIMS The risk for Crohns disease (CD) is determined in part by genetic factors. Three recently described mutations in the CARD15(NOD2) gene have been associated with adult-onset CD. We investigated the effect of CARD15 mutations on disease manifestation, disease progression, and the risk for early surgery in childhood-onset CD. METHODS Genotyping for 3 CARD15 mutations: R702W, G908R, and 3020insC, was performed in 186 children with CD from a prospective cohort. A transmission-disequilibrium test was used to test for association with CD. Genotype with disease location and behavior was tested with logistic regression analysis. The effect of mutations on surgical outcome was evaluated using a Cox proportional hazard analysis. RESULTS The mean age at CD diagnosis was 12.4 years. The frequency of allelic mutations observed was 6.6% for R702W, 6% for G908R, and 13.1% for 3020insC. Of Caucasian CD children, 42% had at least one CARD15 mutation. None of the non-Caucasian children with CD had any CARD15 mutation. A significant association was detected for 3020insC (P = .0045). Ileal location (odds ratio, 4.3; P = .003) and stricturing disease (odds ratio, 6.6; P = .0001) was more frequent and the risk for surgery was higher (hazard ratio, 5.8; P < .0001) and surgery occurred earlier (hazard ratio, 2.24) in those children with 3020insC mutation compared with those without 3020insC. CONCLUSIONS In children with pediatric-onset CD, early development of stricturing behavior leading to surgical resection is influenced by ileal location and 3020insC variant of the CARD15 mutation. Genetic testing may identify children with CD who are at risk for early surgery.

Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man.

Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population–based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.

Genotyping platforms for mass-throughput genotyping with SNPs, including human genome-wide scans.

The completion of the Human Genome Project (HGP) in 2003 brought the scientific community one step closer to identifying the genes underlying common, polygenic diseases. Prior to this achievement, the goal of identifying the genetic factors responsible for diseases presenting substantial public health burdens was elusive. Although the theoretical foundation for disease association studies had been discussed before the completion of the HGP, obstacles remained at that time before such studies could be considered feasible. One of these obstacles was the identification and mapping of numerous polymorphisms that could be easily and inexpensively typed. However, this challenge was overcome with the sequencing of the human genome and the subsequent cataloging of single-nucleotide polymorphisms (SNPs). The challenge then became how to rapidly and cost-effectively assay a dense set of these SNPs in the large number of samples required for disease association studies of complex traits. This challenge has been recently met as well, with the commercial offering of mass-throughput oligonucleotide array-based genotyping platforms at affordable prices. These platforms have made genome-wide association scans a reality and bring us closer than ever to elucidating the genetic mechanisms of complex disease. Here, we discuss the need for mass-throughput genotyping and then review and evaluate various platforms now available to investigators wishing to undertake high-throughput genotyping projects with SNPs, particularly genome-wide association scans.

Linkage Analysis for Complex Diseases Using Variance Component Analysis

Variance component linkage analysis has become one of the most popular tools for the analysis of poly genic phenotypes. In particular for cardiovascular disease, such as coronary artery disease and myocardial infarction, variance component analysis holds some unique advantages. This analysis approach is versatile, affording the user the ability to incorporate the interplay between risk factors, genetic susceptibility, the effect of environmental factors, or the joint analysis of multiple phenotypes in the analysis. In this chapter, we present as an introduction the statistical background of variance component analysis as implemented in the genetic analysis package SOLAR.

The Role of Genomics in the Neonatal ICU

Results of both the Human Genome and International HapMap Projects have provided the technology and resources necessary to enable fundamental advances through the study of DNA sequence variation in almost all fields of medicine, including neonatology. Genome-wide association studies are now practical, and the first of these studies are appearing in the literature. This article provides the reader with an overview of the issues in technology and study design relating to genome-wide association studies and summarizes the current state of association studies in neonatal ICU populations with a brief review of the relevant literature. Future recommendations for genomic association studies in neonatal ICU populations are also provided.

Genetics, genomics and the power of stem cells to identify novel treatment options in complex diseases

The advances in human genetics enabled through the implementation of the latest sequencing technologies have the potential to dramatically change the landscape of medicine. As we decipher the polymorphic structure of the genome, the next challenge will focus on understanding the complex functional implications in the context of health and disease. Multiple approaches will be necessary to evaluate genome variation. While computational analyses serve as a starting point and can predict functional effects in silico, further direct functional studies will be required. The development of technologies to generate induced pluripotent stem cells represents one of these approaches. With growing evidence that these cells and derived tissues resemble phenotypes observed in patients, this approach holds tremendous potential for both diagnosis and treatment. While further studies are required to better understand the underlying mechanisms and to improve the methodology for generating induced pluripotent stem cells, this technology appears to be a powerful tool for the functional evaluation of genome variation, drug screening, risk prediction and advanced diagnostics.