Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction

Ozaki, Kouichi; Ohnishi, Yozo; Iida, Aritoshi; A, Sekine; Yamada, Ryo; Tsunoda, Tatsuhiko; Sato, Hiroshi; Sato, Hideyuki; Hori, Masatsugu; Nakamura, Yusuke; Tanaka, Toshihiro

doi:10.1038/ng1047

Cited by 863 publications

(678 citation statements)

References 23 publications

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“…136 The recent identification of the IkBL (NFKBIL1) gene as the second MHC susceptibility locus for RA with the identification of a IkBL promoter SNP (À62) as disrupting a putative binding motif for a transcription repressor 43 demonstrates that broad mapping of the MHC is a powerful strategy. Interestingly, this locus was also identified in studies of myocardial infarction 44 and breast cancer susceptibility. 156 Okazi et al 44 opted for LTA as their disease causing locus, and showed that two variants were functional in in vitro assays, which is supported by the recent identification of differential expression from LTA alleles.…”

Section: Discussionmentioning

confidence: 85%

“…Interestingly, this locus was also identified in studies of myocardial infarction 44 and breast cancer susceptibility. 156 Okazi et al 44 opted for LTA as their disease causing locus, and showed that two variants were functional in in vitro assays, which is supported by the recent identification of differential expression from LTA alleles. 198 However, they also showed that the IkBL promoter SNP (described as À63) affects promoter activity in transient transfection assays, illustrating the difficulty of clearly identifying the causative genetic lesion.…”

Section: Discussionmentioning

confidence: 85%

“…24,42 This gene was then identified as IkBL (NFKBIL1), 43 which has also been implicated in susceptibility to myocardial infarction. 44 Further studies are needed to show that the variants of IkBL or LTA are functional and directly contribute to the pathogenesis of RA and further fine mapping of the TNF region must rule out linkage to other disease loci.…”

Section: Autoimmune Disease Associationsmentioning

confidence: 99%

“…43,44,136,156 From the studies discussed above it is clear that certain diseases are not associated in any way with the TNF region, including MS and the response to interferon-alpha therapy of hepatitis, but the inconsistency of the reports with regard to other diseases perhaps suggests that in these cases a genuine linkage may exist to a nearby disease-causing locus. In the light of the factors discussed above, this impression may simply result from a small number of poorly conducted studies, or from ethnic factors determining linkage, but confirmation requires large studies that include a broad region of the MHC.…”

Section: Disease Associations-conclusionmentioning

confidence: 99%

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Is there a future for TNF promoter polymorphisms?

2004

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The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied À308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 85%

Section: Autoimmune Disease Associationsmentioning

confidence: 99%

Section: Disease Associations-conclusionmentioning

confidence: 99%

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Is there a future for TNF promoter polymorphisms?

2004

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“…Recently, GWA studies have been used to investigate common and complex traits such as coronary artery disease [65,66], atrial fibrillation [67], prolonged QT interval, and SCD [68,69]. Following on from the discovery that common polymorphisms in the 5′ regulatory region of NOS1AP, encoding the protein Capon, modulate QTc, investigators are now examining the role of this set of variants in mediating SCD susceptibility in the NHLBI's ARIC (athereoscelerosis risk in communities) and CHS (cardiovascular health study-total enrollment >20,000), longitudinal studies.…”

Section: Current and Future Directionsmentioning

confidence: 99%

Genomics, heart failure and sudden cardiac death

Darbar

2008

Heart Fail Rev

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Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lowerrisk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD. KeywordsSudden cardiac death; Genomics; Heart failure; Single nucleotide polymorphisms Heart failure and SCD Heart failure (HF) afflicts approximately 5 million people in the United States, with 550,000 new cases reported annually, but as the population ages both the incidence and prevalence is expected to rise [1]. HF is associated with high mortality and is reportedly responsible for 300,000 deaths annually in the US [1]. Prior to advent of neuro-hormonal antagonists, the mean duration of survival after onset of HF was 1.7 years for men and 3.2 years for women, with only half of patients still alive after 5 years of onset [2]. The two modes of death in patients with HF are circulatory failure due to progressive left ventricular (LV) dysfunction associated with gradual worsening of symptoms, or sudden cardiac death (SCD) in relatively clinically stable patients [3].Although the proportion of sudden deaths in published trials varies significantly, probably due to varying interpretations of reported modes of death, clinical trials data suggests that SCD accounts for approximately one-third of all HF deaths [4]. Epidemiologic evidence from the Framingham heart study suggests that about one-half of all deaths due to HF occur...

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