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Ciccarone Center Research

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Genetics

Landmark Article

Electrocardiographic QT interval and mortality: A meta-analysis.
By: Zhang Y, Post WS, Blasco-Colmenares E, Dalal D, Tomaselli GF, Guallar E.
Extremely abnormal prolongation of the electrocardiographic QT interval is associated with malignant ventricular arrhythmias and sudden cardiac death. However, the implications of variations in QT-interval length within normal limits for mortality in the general population have been unclear. We found consistent associations between prolonged QT interval and increased risk of total, cardiovascular, coronary, and sudden cardiac death. QT-interval length is a determinant of mortality in the general population.
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Meta-analysis of genome-wide association studies from CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.
By: Bis JC, Kavousi M, Francheschini N, Isaacs A, Abecasis GR, Schminke U, Post WS, Smith AV, et al.

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

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Schnitzler’s syndrome associated with pancreatitis: a disease of IL-1 dysregulation.
By: Larocca CA, McEvoy JW, Ellis CL, Junkins-Hopkins J, Kolb T, Baer AN, Garibaldi BT.
Schnitzler's syndrome (SS) is a rare inflammatory disease of unknown origin characterized by chronic urticaria and monoclonal gammopathy (usually IgM) associated with at least two of the following components: fever, arthralgia or arthritis, bone pain, hepato- and/or splenomegaly, lymphadenopathy, elevated erythrocyte sedimentation rate, leukocytosis, and/or abnormal findings on bone morphological investigations. To date, about 100 cases have been described with only 4 being reported in the USA. The mean time to diagnosis from the onset of disease is 5.4 years, given the varied symptoms with which patients may present. The pathogenesis of SS remains unknown but likely involves dysregulation of the IL-1 pathway. We describe here a 48-year-old woman with a monoclonal IgM gammopathy and a 3-year history of chronic pruritic urticarial dermatosis, unexplained fevers, chronic polyarthritis, lymphadenopathy, leukocytosis, hepatomegaly, and weight loss. She also had a history of chronic pancreatitis as well as a family history of recurrent pancreatitis. The diagnosis of Schnitzler's syndrome was made, and she was successfully treated with the IL-1 receptor antagonist, anakinra.
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Polymorphisms of the beta adrenergic receptor predict left ventricular remodeling following acute myocardial infarction.
By: McLean RC, Hirsch GA, Becker LC, Kasch-Semenza L, Gerstenblith G, Schulman SP.
Prior studies demonstrate an association between specific beta-adrenergic receptor (?-AR) polymorphisms and clinical outcomes in patients with chronic heart failure and following acute coronary syndromes. The underlying mechanism may be due to differences in left ventricular remodeling. This study was undertaken to explore the relationship between LV remodeling after myocardial infarction and polymorphisms in the cardiac ?1-AR and ?2-AR genes. We found that polymorphisms of the ?1-AR and ?2-AR genes are associated with differential LV remodeling in patients treated with a ?1 receptor antagonist following ST-segment elevation myocardial infarction.
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Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.
By: Arking DE, Junttila MJ, Goyette P, Huertas-Vazquez A, Eijgelsheim M, Blom MT, Newton-Cheh C, Reinier K, Teodorescu C, Uy-Evanado A, Carter-Monroe N, Kaikkonen KS, Kortelainen ML, Boucher G, Lagacé C, Moes A, Zhao X, Kolodgie F, Rivadeneira F, Hofman A, Witteman JC, Uitterlinden AG, Marsman RF, Pazoki R, Bardai A, Koster RW, Dehghan A, Hwang SJ, Bhatnagar P, Post W, Hilton G, Prineas RJ, Li M, Köttgen A, Ehret G, Boerwinkle E, Coresh J, Kao WH, Psaty BM, Tomaselli GF, Sotoodehnia N, Siscovick DS, Burke GL, Marbán E, Spooner PM, Cupples LA, Jui J, Gunson K, Kesäniemi YA, Wilde AA, Tardif JC, O’Donnell CJ, Bezzina CR, Virmani R, Stricker BH, Tan HL, Albert CM, Chakravarti A, Rioux JD, Huikuri HV, Chugh SS.
Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping. Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD.
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Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the multi-ethnic study of atherosclerosis (MESA).
By: Wassel CL, Pankow JS, Rasmussen-Torvik LJ, Li N, Taylor KD, Guo X, Goodarzi MO, Palmas WR, Post WS.
Circulating adiponectin is associated with both clinical and subclinical CVD. Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal cIMT, presence of CAC, and CAC scores (in those with CAC) in 2,847 participants in MESA. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African Americans and Hispanics. Replication as well as assessment of other ADIPOQ SNPs is warranted.
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Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project.
By: Lettre G, Palmer CD, Young T, Ejebe KG, Allayee H, Benjamin EJ, Bennett F, Bowden DW, Chakravarti A, Dreisbach A, Farlow DN, Folsom AR, Fornage M, Forrester T, Fox E, Haiman CA, Hartiala J, Harris TB, Hazen SL, Heckbert SR, Henderson BE, Hirschhorn JN, Keating BJ, Kritchevsky SB, Larkin E, Li M, Rudock ME, McKenzie CA, Meigs JB, Meng YA, Mosley TH, Newman AB, Newton-Cheh CH, Paltoo DN, Papanicolaou GJ, Patterson N, Post WS, Psaty BM, Qasim AN, Qu L, Rader DJ, Redline S, Reilly MP, Reiner AP, Rich SS, Rotter JI, Liu Y, Shrader P, Siscovick DS, Tang WH, Taylor HA, Tracy RP, Vasan RS, Waters KM, Wilks R, Wilson JG, Fabsitz RR, Gabriel SB, Kathiresan S, Boerwinkle E.
CHD is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study in 8,090 African Americans from five population-based cohorts. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.
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Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification.
By: Shen H, Bielak LF, Ferguson JF, Streeten EA, Yerges-Armstrong LM, Liu J, Post W, O’Connell JR, Hixson JE, Kardia SL, Sun YV, Jhun MA, Wang X, Mehta NN, Li M, Koller DL, Hakonarson H, Keating BJ, Rader DJ, Shuldiner AR, Peyser PA, Reilly MP, Mitchell BD.
The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with CVD risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in CAC. A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.
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Familial defective ApoB-100 is a major cause of increased LDL-cholesterol and coronary artery calcification in the old order Amish.
By: Shen H, Damcott CM, Rampersaud E, Pollin TI, Bielak LF, Post WS, Chang Y-PC, Rumberger JA, Shuldiner AR, Mitchell BD.

Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels. The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.

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Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish.
By: Shen H, Damcott CM, Rampersaud E, Pollin TI, Horenstein RB, McArdle PF, Peyser PA, Bielak LF, Post WS, Chang YP, Ryan KA, Miller M, Rumberger JA, Sheedy PF 2nd, Shelton J, O’Connell JR, Shuldiner AR, Mitchell BD.
Elevated LDL-C levels are a major CVD risk factor. Genetic factors are an important determinant of LDL-C levels. To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for CAC in 1,018 of these individuals. We concluded that the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, is a major determinant of LDL-C levels and CAC in the Amish.
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