Kristina Kudelko

All Publications

• Two Cases of Pulmonary Tumor Thrombotic Microangiopathy Associated with ROS1-Rearranged Non-Small-Cell Lung Cancer. Clinical lung cancer Shah, A. T., Bernardo, R. J., Berry, G. J., Kudelko, K., Wakelee, H. A. 2020

  View details for DOI 10.1016/j.cllc.2020.09.020

  View details for PubMedID 33153897

• PROGNOSTIC VALUE OF THE RELATIVE PULMONARY PRESSURE RATIO AND ITS TRAJECTORY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION Bagherzadeh, S. P., Amsallem, M., Denault, A., Sweatt, A., Kudelko, K., Sung, Y., Haddad, F., Zamanian, R. ELSEVIER SCIENCE INC. 2020: 2096

  View details for Web of Science ID 000522979102081

• Hemodynamic trajectories and outcomes in patients with pulmonary arterial hypertension. Pulmonary circulation Amsallem, M., Bagherzadeh, S. P., Boulate, D., Sweatt, A. J., Kudelko, K. T., Sung, Y. K., Feinstein, J. A., Fadel, E., Mercier, O., Denault, A., Haddad, F., Zamanian, R. 2020; 10 (4): 2045894020941343

  Abstract

  The relative pulmonary to systemic pressure ratio (mean pulmonary arterial pressure/mean arterial pressure) has been proven to be valuable in cardiac surgery. Little is known on the prognostic value of baseline and trajectory of mean pulmonary arterial pressure/mean arterial pressure in pulmonary arterial hypertension. Patients with confirmed idiopathic, familial, drug and toxins, or connective tissue disease-related pulmonary arterial hypertension and at least one complete right heart catheterization were included and prospectively followed-up for 5.9?±?4.03 years. Correlates of the primary end point (i.e. death or lung transplant need) during follow-up were determined using Cox regression modeling. Results showed that among the 308 patients included, 187 had at least one follow-up catheterization (median time between catheterizations: 2.16 (1.16-3.19) years). In the total cohort (mean age 47.3?±?14.9 years, 82.8% of female and 58.1% in New York Heart Association class 3 or 4), mean pulmonary arterial pressure/mean arterial pressure (1.38 (1.07-1.77)) was associated with outcome (p?=?0.01). Mean pulmonary arterial pressure/mean arterial pressure was incremental to a basic model (including right atrial pressure, systolic blood pressure, New York Heart Association class 3 or 4, and connective tissue disease) for outcome prediction, while mean pulmonary arterial pressure was not. In the 187 patients with a follow-up catheterization, both delta mean pulmonary arterial pressure and delta mean pulmonary arterial pressure/mean arterial pressure were associated with outcome (1.32 (1.11-1.58) and 1.31 (1.1-1.57) respectively, p?

  View details for DOI 10.1177/2045894020941343

  View details for PubMedID 33335708

  View details for PubMedCentralID PMC7724418

• EXPRESS: Myocardial Bridge - An Unrecognized Cause of Chest Pain in Pulmonary Arterial Hypertension. Pulmonary circulation Rajmohan, D., Sung, Y. K., Kudelko, K., Perez, V. i., Haddad, F., Tremmel, J., Schnittger, I., Zamanian, R. T., Spiekerkoetter, E. F. 2019: 2045894019860738

  View details for DOI 10.1177/2045894019860738

  View details for PubMedID 31187693

• EXPRESS: Non-invasive Right Ventricular Load Adaptability Indices in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension. Pulmonary circulation French, S., Amsallem, M., Ouazani, N., Li, S., Kudelko, K., Zamanian, R., Haddad, F., Chung, L. 2018: 2045894018788268

  View details for PubMedID 29938590

• Features and Outcomes of Methamphetamine Associated Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Zamanian, R. T., Hedlin, H., Greuenwald, P., Wilson, D. M., Segal, J. I., Jorden, M., Kudelko, K., Liu, J., Hsi, A., Rupp, A., Sweatt, A. J., Tuder, R., Berry, G. J., Rabinovitch, M., Doyle, R. L., De Jesus Perez, V., Kawut, S. M. 2017

  Abstract

  While amphetamines are recognized as "likely" agents to cause drugs and toxins associated pulmonary arterial hypertension (PAH), (meth)amphetamine associated PAH (Meth-APAH) has not been well described.To prospectively characterize the clinical presentation, histopathology, and outcomes of Meth-APAH compared to those of idiopathic PAH (iPAH).We performed a prospective cohort study of Meth-APAH and iPAH patients presenting to the Stanford University Pulmonary Hypertension Program between 2003-2015. Clinical, pulmonary angiography, histopathology, and outcomes data were compared. We used data from the Healthcare Cost and Utilization Project to estimate the epidemiology of PAH in (meth)amphetamine abusers hospitalized in California.The study sample included 90 Meth-APAH and 97 iPAH patients. Meth-APAH patients were less likely to be female, but similar in age, body mass index, and six minute walk distance to iPAH patients. Meth-PAH patients reported more advanced heart failure symptoms, had significantly higher right atrial pressure (12.7±6.8 vs. 9.8±5.1 mmHg, p=0.001), and lower stroke volume index (22.2±7.1 vs 25.5±8.7 mL/m2, p=0.01). Event-free survival in Meth-APAH was 64.2%, 47.2%, and 25% at 2.5, 5, and 10 years respectively, representing more than double the risk of clinical worsening or death compared to iPAH (HR 2.04, 95% CI 1.28-3.25, p=0.003) independent of confounders. California data demonstrated a 2.6 fold increase in risk of PAH diagnosis in hospitalized (meth)amphetamine users.Meth-APAH is a severe and progressive form of PAH with poor outcomes. Future studies should focus on mechanisms of disease and potential therapeutic considerations.

  View details for PubMedID 28934596

• [POSTER] Benchmarking quality initiatives in the care of pulmonary arterial hypertension patients at an academic medical center. Am. J. Respir. Crit. Care Med. Kholdani, C., Hedlin, H., Hsi, A., Kudelko, K., Sung, Y., De Jesus Perez, V., Spiekerkoetter, E., Liu, J., Zamanian, R. T. 2016; A6304
• Special Considerations for the Pulmonary Hypertension Patient Pulmonary Hypertension: Basic Science to Clinical Medicine Kudelko, K. T., Zamanian, R. T., De Jesus Perez, V. A. Springer. 2016: 345?58

  View details for DOI 10.1007/978-3-319-23594-3_22

• Current Clinical Management of Pulmonary Arterial Hypertension CIRCULATION RESEARCH Zamanian, R. T., Kudelko, K. T., Sung, Y. K., Perez, V. D., Liu, J., Spiekerkoetter, E. 2014; 115 (1): 131-147

  Abstract

  During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.

  View details for DOI 10.1161/CIRCRESAHA.115.303827

  View details for Web of Science ID 000337738900016

• Current clinical management of pulmonary arterial hypertension. Circulation research Zamanian, R. T., Kudelko, K. T., Sung, Y. K., de Jesus Perez, V., Liu, J., Spiekerkoetter, E. 2014; 115 (1): 131?47

  Abstract

  During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.

  View details for PubMedID 24951763

• A case of recurrent pericardial constriction presenting with severe pulmonary hypertension PULMONARY CIRCULATION Brunner, N. W., Ramachandran, K., Kudelko, K. T., Sung, Y. K., Spiekerkoetter, E., Yang, P. C., Zamanian, R. T., Perez, V. d. 2013; 3 (2): 436-439

  Abstract

  Chronic constrictive pericarditis (CP) is a relatively rare condition in which the pericardium becomes fibrotic and noncompliant, eventually resulting in heart failure due to impaired ventricular filling. The only curative treatment is pericardiectomy. Classically, CP does not usually cause severe pulmonary hypertension. When attempting to differentiate CP from restrictive cardiomyopathy, the presence of severely elevated pulmonary arterial pressure is used as a diagnostic criterion ruling against CP. We present a case of proven recurrent pericardial constriction following pericardiectomy presenting with severe pulmonary hypertension.

  View details for DOI 10.4103/2045-8932.114780

  View details for Web of Science ID 000209981500020

  View details for PubMedCentralID PMC3757841

• Safety and efficacy of transition from systemic prostanoids to inhaled treprostinil in pulmonary arterial hypertension. American journal of cardiology de Jesus Perez, V. A., Rosenzweig, E., Rubin, L. J., Poch, D., Bajwa, A., Park, M., Jain, M., Bourge, R. C., Kudelko, K., Spiekerkoetter, E., Liu, J., Hsi, A., Zamanian, R. T. 2012; 110 (10): 1546-1550

  Abstract

  Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.

  View details for DOI 10.1016/j.amjcard.2012.07.012

  View details for PubMedID 22853986

• Airway Management and Perioperative Decision Making in the Patient With Severe Pulmonary Hypertension Who Requires Emergency Noncardiac Surgery JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Maxwell, B. G., Pearl, R. G., Kudelko, K. T., Zamanian, R. T., Hill, C. C. 2012; 26 (5): 940-944

  View details for DOI 10.1053/j.jvca.2012.06.018

  View details for PubMedID 22943790

• The Intersection of Genes and Environment Development of Pulmonary Arterial Hypertension in a Patient With Hereditary Hemorrhagic Telangiectasia and Stimulant Exposure CHEST Ayala, E., Kudelko, K. T., Haddad, F., Zamanian, R. T., Perez, V. d. 2012; 141 (6): 1598-1600

  Abstract

  Pulmonary arterial hypertension (PAH) is a rare complication of hereditary hemorrhagic telangiectasia (HHT). The triggers that promote the development of PAH in HHT remain poorly understood. We present the case of a 45-year-old woman with decompensated right-sided heart failure secondary to newly diagnosed PAH. The clinical diagnosis of HHT was confirmed on the basis of recurrent spontaneous epistaxis, multiple typical mucocutaneous telangiectasia, and the presence of pulmonary arteriovenous malformation. There was also a suggestive family history. The patient was discovered to have active and extensive stimulant abuse in addition to HHT. We concluded that there may be a temporal relationship between exposure to stimulants and development of PAH in a host with underlying gene mutation. This case highlights the paradigm of PAH development after environmental exposure in a genetically susceptible host.

  View details for DOI 10.1378/chest.11-1402

  View details for Web of Science ID 000305039300054

  View details for PubMedID 22670022

  View details for PubMedCentralID PMC3367481

• Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699

  Abstract

  Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure).By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5-7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m2; OR, 2.7; 95% CI, 1.2-6.3), hyponatremia (serum sodium ?136 mEq/L; OR, 3.6; 95% CI, 1.7-7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation.These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

  View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

  View details for PubMedID 21908586

• Pulmonary Hypertension Associated With Left Heart Disease: Characteristics, Emerging Concepts, and Treatment Strategies PROGRESS IN CARDIOVASCULAR DISEASES Haddad, F., Kudelko, K., Mercier, O., Vrtovec, B., Zamanian, R. T., Perez, V. D. 2011; 54 (2): 154-167

  Abstract

  Left heart disease (LHD) represents the most common causes of pulmonary hypertension (PH). Whether caused by systolic or diastolic dysfunction or valvular heart disease, a hallmark of PH associated with LHD is elevated left atrial pressure. In all cases, the increase in left atrial pressure causes a passive increase in pulmonary pressure. In some patients, a superimposed active component caused by pulmonary arterial vasoconstriction and vascular remodeling may lead to a further increase in pulmonary arterial pressure. When present, PH is associated with a worse prognosis in patients with LHD. In addition to local abnormalities in nitric oxide and endothelin production, gene modifiers such as serotonin polymorphisms may be associated with the pathogenesis of PH in LHD. Optimizing heart failure regimens and corrective valve surgery represent the cornerstone of the treatment of PH in LHD. Recent studies suggest that sildenafil, a phosphodiesterase-5 inhibitor, is a promising agent in the treatment of PH in LHD. Unloading the left ventricle with circulatory support may also reverse severe PH in patients with end-stage heart failure allowing candidacy to heart transplantation.

  View details for DOI 10.1016/j.pcad.2011.06.003

  View details for Web of Science ID 000294880400009

  View details for PubMedID 21875514

• Incidence, Correlates, and Consequences of Acute Kidney Injury in Patients With Pulmonary Arterial Hypertension Hospitalized With Acute Right-Side Heart Failure JOURNAL OF CARDIAC FAILURE Haddad, F., Fuh, E., Peterson, T., Skhiri, M., Kudelko, K. T., Perez, V. D., Winkelmayer, W. C., Doyle, R. L., Chertow, G. M., Zamanian, R. T. 2011; 17 (7): 533-539

  Abstract

  Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH).We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8-8.5), high central venous pressure (OR 1.8, 95% CI 1.1-2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1-8.8). AKI was strongly associated with 30-day mortality after acute right-side heart failure hospitalization (OR 5.3, 95% CI 2.2-13.2).AKI is relatively common in patients with PAH and associated with a short-term risk of death.

  View details for DOI 10.1016/j.cardfail.2011.03.003

  View details for PubMedID 21703524

• Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead. International journal of clinical practice. Supplement de Jesus Perez, V., Kudelko, K., Snook, S., Zamanian, R. T. 2011: 8-10

  Abstract

  Since the identification of the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs and toxins nearly fifty years ago, the expanding landscape of available pharmaceuticals and illicit drugs is further fueling this association. While some causative agents in drugs and toxins associated PAH (D&T-APAH) have been identified, little is known about the exact biology and clinical implications of the disease. In this review, we discuss the historical evidence that links PAH with exposure to anorexinogens, cocaine, and methamphetamines and concentrate on what is known about potential pathogenesis, clinical manifestations, and current management. We conclude that future research should focus on studies looking at clinical outcome and susceptibility factors.

  View details for DOI 10.1111/j.1742-1241.2010.02606.x

  View details for PubMedID 21176010

• [ABSTRACT] Reassessing vasoreactivity in patients with pulmonary arterial hypertension (PAH) over time shows both loss as well as gain in vasoreactivity. Am. J. Respir. Crit. Care Med. Spiekerkoetter E, Hsi A, De Jesus Perez V, Liu J, Saito S, Kudelko K, Zamanian RT 2011; 183: A5747
• [ABSTRACT] Product of heart rate recovery and six minute walk distance as a predictor of outcomes in pulmonary arterial hypertension Am. J. Respir. Crit. Care Med. Zamanian RT, Spiekerkoetter E, Hsi A, de Jesus Perez V, Saito S, Haddad F, Kudelko K 2011; 183: A5935
• [ABSTRACT] Change in hemoglobin-adjusted diffusion capacity for carbon monoxide as a marker of mortality in pulmonary hypertension Am J Respir Crit Care Med Saito S, Kudelko K, Skhiri M, Hsi A, Deal J, De Jesus Perez V, Spiekerkoetter E, Haddad F, Zamanian RT. 2011; 183: A5948
• Epoprostenol-associated pneumonitis: Diagnostic use of a T-cell proliferation assay JOURNAL OF HEART AND LUNG TRANSPLANTATION Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., Perez, V. D. 2010; 29 (9): 1071-1075

  Abstract

  We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

  View details for DOI 10.1016/j.healun.2010.04.023

  View details for Web of Science ID 000281494800016

  View details for PubMedCentralID PMC2926193

• [ABSTRACT] Characteristics of patients with drugs and toxins-associated pulmonary arterial hypertension: a clinical and outcomes perspective Am. J. Respir. Crit. Care Med. Snook S, Kudelko K, Spiekerkoetter E, De Jesus Perez V, Haddad F, Doyle R, Zamanian RT 2009; 179: A4923
• The Finland-United States Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes AMERICAN JOURNAL OF HUMAN GENETICS Ghosh, S., Watanabe, R. M., Valle, T. T., Hauser, E. R., Magnuson, V. L., Langefeld, C. D., Ally, D. S., Mohlke, K. L., Silander, K., Kohtamaki, K., Chines, P., Balow, J., Birznieks, G., Chang, J., Eldridge, W., Erdos, M. R., Karanjawala, Z. E., Knapp, J. I., Kudelko, K., Martin, C., Morales-Mena, A., Musick, A., Musick, T., Pfahl, C., Porter, R., Rayman, J. B., Rha, D., Segal, L., Shapiro, S., Sharaf, R., Shurtleff, B., So, A., Tannenbaum, J., Te, C., Tovar, J., Unni, A., Welch, C., Whiten, R., Witt, A., Blaschak-Harvan, J., Douglas, J. A., Duren, W. L., Epstein, M. P., Fingerlin, T. E., Kaleta, H. S., Lange, E. M., Li, C., McEachin, R. C., Stringham, H. M., Trager, E., White, P. P., Eriksson, J., Toivanen, L., Vidgren, G., NYLUND, S. J., Tuomilehto-Wolf, E., Ross, E. H., Demirchyan, E., Hagopian, W. A., Buchanan, T. A., Tuomilehto, J., Bergman, R. N., Collins, F. S., Boehnke, M. 2000; 67 (5): 1174-1185

  Abstract

  We performed a genome scan at an average resolution of 8 cM in 719 Finnish sib pairs with type 2 diabetes. Our strongest results are for chromosome 20, where we observe a weighted maximum LOD score (MLS) of 2.15 at map position 69.5 cM from pter and secondary weighted LOD-score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. Our next largest MLS is for chromosome 11 (MLS = 1.75 at 84.0 cM), followed by chromosomes 2 (MLS = 0.87 at 5.5 cM), 10 (MLS = 0.77 at 75.0 cM), and 6 (MLS = 0.61 at 112.5 cM), all under an additive model. When we condition on chromosome 2 at 8.5 cM, the MLS for chromosome 20 increases to 5.50 at 69.0 cM (P=.0014). An ordered-subsets analysis based on families with high or low diabetes-related quantitative traits yielded results that support the possible existence of disease-predisposing genes on chromosomes 6 and 10. Genomewide linkage-disequilibrium analysis using microsatellite marker data revealed strong evidence of association for D22S423 (P=.00007). Further analyses are being carried out to confirm and to refine the location of these putative diabetes-predisposing genes.

  View details for Web of Science ID 000165091600015

  View details for PubMedID 11032783

• The Finland-United States Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION) study. II. An autosomal genome scan for diabetes-related quantitative-trait loci AMERICAN JOURNAL OF HUMAN GENETICS Watanabe, R. M., Ghosh, S., Langefeld, C. D., Valle, T. T., Hauser, E. R., Magnuson, V. L., Mohlke, K. L., Silander, K., Ally, D. S., Chines, P., Blaschak-Harvan, J., Douglas, J. A., Duren, W. L., Epstein, M. P., Fingerlin, T. E., Kaleta, H. S., Lange, E. M., Li, C., McEachin, R. C., Stringham, H. M., Trager, E., White, P. P., Balow, J., Birznieks, G., Chang, J., Eldridge, W., Erdos, M. R., Karanjawala, Z. E., Knapp, J. I., Kudelko, K., Martin, C., Morales-Mena, A., Musick, A., Musick, T., Pfahl, C., Porter, R., Rayman, J. B., Rha, D., Segal, L., Shapiro, S., Sharaf, R., Shurtleff, B., So, A., Tannenbaum, J., Te, C., Tovar, J., Unni, A., Welch, C., Whiten, R., Witt, A., Kohtamaki, K., Ehnholm, C., Eriksson, J., Toivanen, L., Vidgren, G., NYLUND, S. J., Tuomilehto-Wolf, E., Ross, E. H., Demirchyan, E., Hagopian, W. A., Buchanan, T. A., Tuomilehto, J., Bergman, R. N., Collins, F. S., Boehnke, M. 2000; 67 (5): 1186-1200

  Abstract

  Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.

  View details for Web of Science ID 000165091600016

  View details for PubMedID 11032784

• Type 2 diabetes: Evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ghosh, S., Watanabe, R. M., Hauser, E. R., Valle, T., Magnuson, V. L., Erdos, M. R., Langefeld, C. D., Balow, J., Ally, D. S., Kohtamaki, K., Chines, P., Birznieks, G., Kaleta, H. S., Musick, A., Te, C., Tannenbaum, J., Eldridge, W., Shapiro, S., Martin, C., Witt, A., So, A., Chang, J., Shurtleff, B., Porter, R., Kudelko, K., Unni, A., Segal, L., Sharaf, R., Blaschak-Harvan, J., Eriksson, J., Tenkula, T., Vidgren, G., Ehnholm, C., Tuomilehto-Wolf, E., Hagopian, W., Buchanan, T. A., Tuomilehto, J., Bergman, R. N., Collins, F. S., Boehnke, M. 1999; 96 (5): 2198-2203

  Abstract

  We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, chi = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (chi = 57 cM, recurrence risk,lambda(s) = 1. 25, P = 0.009). Weighted logarithm of odds scores of 2.00 (chi = 69.5 cM, P = 0.010) and 1.92 (chi = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2. 12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4alpha) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.

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  View details for PubMedID 10051618