Genome-wide Association Studies and Human Disease

Visscher, Peter M.; Montgomery, Grant W.

doi:10.1001/jama.2009.1643

Cited by 52 publications

(38 citation statements)

References 8 publications

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“…16 This hypothesis-free approach based on linkage disequilibrium (LD) allows the discovery of novel genetic loci, which were previously not regarded to be associated with the trait. 17 Considering that the common genetic variants associated with serum IgG might be identified by the GWAS approach, we performed the present two-stage GWAS in a healthy Chinese male population.…”

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Genome-wide association study identifies common variants at TNFRSF13B associated with IgG level in a healthy Chinese male population

Liao

Zhang

et al. 2012

Genes Immun

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IgG has a crucial role in humoral immune response. Serum IgG level is mainly determined under genetic control. To explore the genetic influence on serum IgG levels, a two-stage genome-wide association study (GWAS) was performed in a healthy Chinese population of 3495 men, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Three single-nucleotide polymorphisms (SNPs) located in TNFRSF13B on 17p11.2 or nearby were significantly associated with IgG level: rs4792800 in the intron (combined P-value ¼ 1.45 Â 10 À 12 ), rs12603708 in the intron (combined P-value ¼ 1.82 Â 10 À 8 ) and rs3751987 at B65 kb downstream of the 5 0 -UTR region of TNFRSF13B (combined P-value ¼ 3.67 Â 10 À 9 ). Additionally, smoking was identified to be associated with IgG level in both stages (Po0.001), but there was no significant interaction between smoking and the identified SNPs (P40.05). The strong association between variants at TNFRSF13B and IgG level may be helpful to further explore the biological mechanism by which the serum IgG is affected by transmembrane activator, calcium modulator and cyclophilin ligand interactor encoded by TNFRSF13B.Genes and Immunity (2012) 13, 509-513; doi:10.1038/gene.2012.26; published online 7 June 2012Keywords: IgG; genome-wide association studies; TNFRSF13B; TACI; smoking INTRODUCTION IgG, constituting some 80% of total serum immunoglobulin, is the most abundant class of antibodies (Ab) in serum and extracellular fluid. It has an important role in the defense against various pathogens, toxins and even cancers. 1 As the only isotype that can pass through the human placenta, IgG is able to protect the fetus in utero. 2 Meanwhile, IgG gets involved in chronic inflammatory processes contributed to the destruction of healthy tissues in autoimmune diseases, such as arthritis and systemic lupus erythematosus. 3 Serum IgG level varies considerably from one person to another, 4 but little when testing the same person repeatedly. 5 This variation in the serum IgG concentration reflects the balance among the rates of synthesis and catabolism. 6 Multitudinous environmental factors including infections, smoking and chemical compounds can contribute to this variation. 7-9 Reports of pedigree studies or twin studies 10,11 have shown that genetic factors are more important than environmental exposures in determining serum immunoglobulin level in human. 12,13 The values of genetic heritability was h 2 ¼ 0.617 þ 0.020 for IgG. 6 Besides, several studies in a population of common variable immunodeficiency patients or IgA deficiency patients implied that there might be an association between some gene loci and serum IgG level. 14,15 However, to the best of our knowledge, no study has ever been conducted to identify the immune loci directly involved in the regulation of the IgG level.Genome-wide association study (GWAS) is a powerful and unbiased tool for the identification of common genetic variants associated with complex traits. 16 This hypothesis-free approach base...

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Genome-wide association study identifies common variants at TNFRSF13B associated with IgG level in a healthy Chinese male population

Liao

Zhang

et al. 2012

Genes Immun

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“…Sequencing of the human genome has led to a plethora of genome-wide association studies demonstrating genetic associations with complex diseases (47)(48)(49). In most cases, the biologic basis for the genetic association remains unknown, attributable, in part, to the fact that polymorphisms typically induce modest alterations in biology, which are challenging to fully characterize (50,51).…”

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Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Lundström

Highfill

Walsh

et al. 2013

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

126

153

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Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Rα competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7Rα also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7Rα and also demonstrate a potentiating effect of sIL7Rα on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7Rα levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.immunology | soluble receptors | tolerance

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“…In an effort to explain an increasing proportion of the heritability of complex metabolic traits, ongoing large-scale gene resequencing studies are focusing on the effects of rare SNPs and structural genetic variants. future science group Review Tarr, Rotger & Telenti HapMap in 2005 [22] and an escalating number of genome-wide association studies (GWAS) of metabolic diseases in the general population [23,24]. We will also outline an approach to studying genetic mechanisms relevant to CAD in HIV-infected individuals.…”

Section: Reviewmentioning

confidence: 99%

Dyslipidemia in HIV-Infected Individuals: from Pharmacogenetics to Pharmacogenomics

2010

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HIV-infected individuals may have accelerated atherogenesis and an increased risk for premature coronary artery disease. Dyslipidemia represents a key pro-atherogenic mechanism. In HIV-infected patients, dyslipidemia is typically attributed to the adverse effects of antiretroviral therapy. Nine recent genome-wide association studies have afforded a comprehensive, unbiased inventory of common SNPs at 36 genetic loci that are reproducibly associated with dyslipidemia in the general population. Genome-wide association study-validated SNPs have now been demonstrated to contribute to dyslipidemia in the setting of HIV infection and antiretroviral therapy. In a Swiss HIV-infected study population, a similar proportion of serum lipid variability was explained by antiretroviral therapy and by genetic background. In the individual patient, both antiretroviral therapy and the cumulative effect of SNPs contribute to the risk of high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol and hypertriglyceridemia. Genetic variants presumably contribute to additional major metabolic complications in HIV-infected individuals, including diabetes mellitus and coronary artery disease. In an effort to explain an increasing proportion of the heritability of complex metabolic traits, ongoing large-scale gene resequencing studies are focusing on the effects of rare SNPs and structural genetic variants.

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Genome-wide Association Studies and Human Disease

Cited by 52 publications

References 8 publications

Genome-wide association study identifies common variants at TNFRSF13B associated with IgG level in a healthy Chinese male population

Genome-wide association study identifies common variants at TNFRSF13B associated with IgG level in a healthy Chinese male population

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Dyslipidemia in HIV-Infected Individuals: from Pharmacogenetics to Pharmacogenomics

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