Lakshman Subrahmanyan

Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus

OBJECTIVE To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients. METHODS Two functional polymorphisms in the MIF gene, a -794 CATT(5-8) microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were assessed for association with SLE in 3,195 patients and healthy controls. We also measured MIF plasma levels in relation to genotypes and clinical phenotypes, and assessed Toll-like receptor 7 (TLR-7)-stimulated MIF production in vitro. RESULTS Both Caucasians and African Americans with the high-expression MIF haplotype -794 CATT(7)/-173*C had a lower incidence of SLE (in Caucasians, odds ratio [OR] 0.63, 95% confidence interval [95% CI] 0.53-0.89, P = 0.001; in African Americans, OR 0.46, 95% CI 0.23-0.95, P = 0.012). In contrast, among patients with established SLE, reduced frequencies of low-expression MIF genotypes (-794 CATT(5)) were observed in those with nephritis, those with serositis, and those with central nervous system (CNS) involvement when compared to patients without end-organ involvement (P = 0.023, P = 0.005, and P = 0.04, respectively). Plasma MIF levels and TLR-7-stimulated MIF production in vitro reflected the underlying MIF genotype of the studied groups. CONCLUSION These findings suggest that MIF, which has both proinflammatory properties and macrophage and B cell survival functions, exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE and may contribute to an enhanced clearance of infectious pathogens. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage.

Rare Nonconservative LRP6 Mutations Are Associated with Metabolic Syndrome

A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.

Sequence variation in the human T-cell receptor loci

Summary: Identifying common sequence variations known as single nucleotide polymorphisms (SNPs) in human populations is one of the current objectives of the human genome project. Nearly 3 million SNPs have been identified. Analysis of the relative allele frequency of these markers in human populations and the genetic associations between these markers, known as linkage disequilibrium, is now underway to generate a high‐density genetic map. Because of the central role T cells play in immune reactivity, the T‐cell receptor (TCR) loci have long been considered important candidates for common disease susceptibility within the immune system (e.g., asthma, atopy and autoimmunity). Over the past two decades, hundreds of SNPs in the TCR loci have been identified. Most studies have focused on defining SNPs in the variable gene segments which are involved in antigenic recognition. On average, the coding sequence of each TCR variable gene segment contains two SNPs, with many more found in the 5′, 3′ and intronic sequences of these segments. Therefore, a potentially large repertoire of functional variants exists in these loci. Association between SNPs (linkage disequilibrium) extends approximately 30 kb in the TCR loci, although a few larger regions of disequilibrium have been identified. Therefore, the SNPs found in one variable gene segment may or may not be associated with SNPs in other surrounding variable gene segments. This suggests that meaningful association studies in the TCR loci will require the analysis and typing of large marker sets to fully evaluate the role of TCR loci in common disease susceptibility in human populations.

Functional Polymorphisms in the Gene Encoding Macrophage Migration Inhibitory Factor Are Associated With Gram-Negative Bacteremia in Older Adults

Macrophage migration inhibitory factor (MIF) is an immune mediator encoded in a functionally polymorphic locus. We found the genotype conferring low expression of MIF to be enriched in a cohort of 180 patients with gram-negative bacteremia, compared with 229 healthy controls (odds ratio [OR], 2.4; P = .04), an association that was more pronounced in older adults (OR, 4.6; P = .01). Among older subjects, those with low expression of MIF demonstrated 20% reduced MIF production from lipopolysaccharide-stimulated peripheral blood monocytes and 30% lower monocyte surface Toll-like receptor 4, compared with those with high expression. Our work suggests that older adults with low expression of MIF may be predisposed to hyporesponsiveness to lipopolysaccharide and gram-negative bacterial infection.

Left ventricular assist device pump thrombosis: is there a role for glycoprotein IIb/IIIa inhibitors?

Left ventricular assist devices (LVADs) fill a critical need by providing circulatory support to patients with end-stage heart failure who are either ineligible for heart transplant or too ill to stably wait for an eventual donor organ. Furthermore, they are critical to the arsenal of the heart failure cardiologist, given the supply/demand mismatch for donor organs. Unfortunately, these devices present their own complications. Despite antiplatelet agents and systemic anticoagulation, a number of patients present with pump thrombosis, a life-threatening event requiring either pump exchange or treatment with systemic thrombolytics. In an effort to avoid these morbid therapies, glycogen IIb/IIIa inhibitors, which have both antiplatelet and thrombolytic properties, have been proposed to treat pump thrombosis. We report here the largest case series using these agents and document a previously unreported high failure rate with this therapy.

Towards patient-specific modeling of mitral valve repair: 3D transesophageal echocardiography-derived parameter estimation

&NA; Transesophageal echocardiography (TEE) is routinely used to provide important qualitative and quantitative information regarding mitral regurgitation. Contemporary planning of surgical mitral valve repair, however, still relies heavily upon subjective predictions based on experience and intuition. While patient‐specific mitral valve modeling holds promise, its effectiveness is limited by assumptions that must be made about constitutive material properties. In this paper, we propose and develop a semi‐automated framework that combines machine learning image analysis with geometrical and biomechanical models to build a patient‐specific mitral valve representation that incorporates image‐derived material properties. We use our computational framework, along with 3D TEE images of the open and closed mitral valve, to estimate values for chordae rest lengths and leaflet material properties. These parameters are initialized using generic values and optimized to match the visualized deformation of mitral valve geometry between the open and closed states. Optimization is achieved by minimizing the summed Euclidean distances between the estimated and image‐derived closed mitral valve geometry. The spatially varying material parameters of the mitral leaflets are estimated using an extended Kalman filter to take advantage of the temporal information available from TEE. This semi‐automated and patient‐specific modeling framework was tested on 15 TEE image acquisitions from 14 patients. Simulated mitral valve closures yielded average errors (measured by point‐to‐point Euclidean distances) of 1.86 ± 1.24 mm. The estimated material parameters suggest that the anterior leaflet is stiffer than the posterior leaflet and that these properties vary between individuals, consistent with experimental observations described in the literature. HighlightsA semi‐automatic framework to build patient‐specific models of mitral valve from medical images under user guidance.Chordae rest length and material parameters are optimized to calibrate patient‐specific models to simulate mitral valve closure consistently with observations from TEE images.First study to our knowledge to estimate material parameters of mitral leaflets on humans from TEE images.Simulated mitral valve closure from 14 sets of images on 15 patients are compared to the ground truth estimated from TEE images with promising accuracy. Graphical abstract Figure. No caption available.

Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.

Background— With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. Methods and Results— We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. Conclusions— Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.

Hepatocellular Carcinoma Metastatic to the Right Ventricle

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4] A 71-year-old man with a history of hepatocellular carcinoma presented with chest pain. An exercise myocardial perfusion scan showed anterior and inferior ischemia, and angiography demonstrated a long tubular stenosis of the mid

Erratum: Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus (American Journal of Human Genetics (2016) 98(6) (1082–1091) (S000292971630057X) (10.1016/j.ajhg.2016.03.022))

‘‘Dorothy unstintingly gave her time and energy to assist others. She volunteered for numerous activities to benefit the clinical genetics community. She was a founding fellow of the American College of Medical Genetics and also a member of the founding board of directors of the American Board of Medical Genetics, for which she served as treasurer and helped to make up queries for the first group of examinees for the board. Along with the other examiners, she had to take the next examination to become board certified and a fellow herself, a requirement she took with good humor.’’