Early‐onset pauciarticular juvenile chronic arthritis is associated with a mutation in the Y‐box of the HLA‐DQA1 promoter

Haas, Johannes-Peter; Kimura, Akinori; Truckenbrodt, H; Suschke, J; Sasazuki, Takehiko; Volgger, A.; Albert, E. D.

doi:10.1111/j.1399-0039.1995.tb02460.x

Cited by 46 publications

(32 citation statements)

References 22 publications

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“…Position ±238 corresponds to a nucleotide site particularly conserved among TNFA Y boxes of different species and among different MHC class II genes [23]. In the mouse the TNFA promoter Y box binds an abundant nuclear factor and is involved in the baseline expression of the TNFA gene [24], while a single base pair substitution in the Y box of the HLA-DQA1 promoter has recently been shown to significantly decrease transcription [25]. Studies aimed at obtaining direct evidence for the effect of the ±238 polymorphism on TNFa expression are currently ongoing in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance

et al. 1998

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Decreased insulin action in skeletal muscle (insulin resistance) is a key feature of non-insulin-dependent diabetes mellitus (NIDDM) and obesity. The mechanisms underlying the development of insulin resistance are not clearly defined but recent interest has focused on tumour necrosis factor-alpha (TNFa). Adipose tissue TNFa expression is increased in human obesity [1], and is closely correlated with circulating insulin levels which serve as an index of insulin resistance [1]. TNFa has also been shown to be expressed in skeletal muscle, and again this is increased in muscle from insulin resistant subjects [2]. More recently it was reported that obese mice homozygous for a targeted null mutation in the TNFa gene were significantly less insulin resistant than normal obese mice [3]. These observations strongly suggest that TNFa impairs insulin action, and the mechanism seems to Diabetologia (1998) Summary Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNFa) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNFa promoter region (positions ±238 and ±-308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The ±238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the ±238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 ± 2.1 [means ± SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 ± 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K ITT (3.8, 3.0 ± 1.0 %/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the ±308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals. [Diabetologia (1998) 41: 430±434]

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Section: Discussionmentioning

confidence: 99%

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance

et al. 1998

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“…The loss of the NF-YA DNA binding protein as it relates to HLA-DR expression appears to be unique to our system. Others have reported that the absence of NF-YA increases HLA-DR expression and increases the susceptibility to rheumatoid arthritis (20,64). Interestingly, the NF-YA protein binds to the long terminal repeat of HIV-1 and human T-cell leukemia virus type 1, can activate transcription of viral gene products, and is related to Rous sarcoma virus enhancer factor I (13,26,63).…”

Section: Hiv-1 Affects Hla-dr Transcriptionmentioning

confidence: 99%

Impaired Regulation of HLA-DR Expression in Human Immunodeficiency Virus-Infected Monocytes

Shao

Sperber

2002

Clin Vaccine Immunol

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“…Furthermore, DQA1 promoter region polymorphisms are associated with quantitative expression differences in cell lines (14), and they affect the strength of transcription factor binding (15). Moreover, specific human DQA1 proximal promoter alleles may be associated with increased susceptibility to a number of autoimmune and infectious diseases (16)(17)(18).…”

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confidence: 99%

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Loisel

Rockman

Wray

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Precise regulation of MHC gene expression is critical to vertebrate immune surveillance and response. Polymorphisms in the 5 proximal promoter region of the human class II gene HLA-DQA1 have been shown to influence its transcriptional regulation and may contribute to the pathogenesis of autoimmune diseases. We investigated the evolutionary history of this cis-regulatory region by sequencing the DQA1 5 proximal promoter region in eight nonhuman primate species. We observed unexpectedly high levels of sequence variation and multiple strong signatures of balancing selection in this region. Specifically, the considerable DQA1 promoter region diversity was characterized by abundant shared (or trans-species) polymorphism and a pronounced lack of fixed differences between species. The majority of transcription factor binding sites in the DQA1 promoter region were polymorphic within species, and these binding site polymorphisms were commonly shared among multiple species despite evidence for negative selection eliminating a significant fraction of binding site mutations. We assessed the functional consequences of intraspecific promoter region diversity using a cell line-based reporter assay and detected significant differences among baboon DQA1 promoter haplotypes in their ability to drive transcription in vitro. The functional differentiation of baboon promoter haplotypes, together with the significant deviations from neutral sequence evolution, suggests a role for balancing selection in the evolution of DQA1 transcriptional regulation in primates.balancing selection ͉ cis-regulatory evolution ͉ major histocompatibility complex ͉ primate molecular evolution

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Early‐onset pauciarticular juvenile chronic arthritis is associated with a mutation in the Y‐box of the HLA‐DQA1 promoter

Cited by 46 publications

References 22 publications

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance

Impaired Regulation of HLA-DR Expression in Human Immunodeficiency Virus-Infected Monocytes

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

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