Implications of gene copy-number variation in health and diseases

Almal, Suhani; Padh, Harish

doi:10.1038/jhg.2011.108

Cited by 142 publications

(108 citation statements)

References 72 publications

(71 reference statements)

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“…It is interesting to note that the evidence for the association between salivary amylase activity and obesity is currently inconclusive. While there is data to suggest that low copy number of AMY1 was correlated with obesity [22][23][24], there is also evidence to the contrary [25]. As obesity is well-known to be associated with impaired glucose tolerance, the former finding is consistent with the data which we have reported in the present paper.…”

Section: Discussionsupporting

confidence: 83%

Anomalous association of salivary amylase secretion with the postprandial glycaemic response to starch

et al. 2016

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Background: This study is an investigation as to whether salivary amylase secretory rates are correlated with the magnitude of postprandial glycaemic responses to starch ingestion in healthy young Malaysian adults. Methods: Fasting unstimulated and stimulated salivary amylase secretory rates were measured and ranked for 54 participants. Subjects (n = 5) with amylase activities below the median and subjects (n = 5) with amylase activities above the median were selected for subsequent carbohydrate challenge tests. Following an overnight fast, the postprandial glycaemic responses of these subjects were assessed to 50 g carbohydrate bolus challenges; glucose (n = 2), maltose (n = 1) and starch (n = 1), tested in random order. Blood glucose concentrations were estimated before each carbohydrate challenge and at half-hour intervals thereafter for 2 h. The magnitude of each glycaemic response was estimated from the area under the curve (AUC). Results: High amylase secretors responded to the consumption of a starch bolus with significantly lower AUCs than low amylase secretors (267 +/− 64 vs. 159 +/− 72 mmol/L*120 min, p = 0.037; mean +/− SD). However, the glycaemic responses to maltose and glucose did not differ significantly between the two groups. These findings confirm that subjects with higher salivary amylase secretory rates have better glycaemic tolerance to a starch challenge than subjects with lower salivary amylase secretory rates. Conclusion: Low amylase secretion should be considered as a potential prognosticator for impaired glucose tolerance to dietary starch in young Malaysian adults.

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Section: Discussionsupporting

confidence: 83%

Anomalous association of salivary amylase secretion with the postprandial glycaemic response to starch

et al. 2016

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“…Changes in DNA copy number, whether confined to specific genes or affecting whole chromosomes, can have an impact on biological homeostasis and influence interindividual differences in the susceptibility to human disorders, especially to autoimmune diseases (12)(13)(14). Even though a number of risk loci have been identified as genetic factors of RA through GWASs (11,35), it is still unclear how CNV is related to the immune dysfunction, increasing the susceptibility of autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

“…However, the majority of SNPs have modest effects and do not represent the full spectrum of genetic variations. Recently, it has been suggested that CNVs are an important source of human genetic variation-in some analyses potentially as important as SNPs (12). CNV of individual genes can result in cellular and organismal abnormalities, and cumulative effects of CNVs underlie many human diseases, including autoimmune diseases (12).…”

mentioning

confidence: 99%

Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis

Hwang

Jung

Lee

et al. 2015

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

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Copy number variations (CNVs) have been implicated in human diseases. However, it remains unclear how they affect immune dysfunction and autoimmune diseases, including rheumatoid arthritis (RA). Here, we identified a novel leukocyte-specific protein 1 (LSP1) deletion variant for RA susceptibility located in 11p15.5. We replicated that the copy number of LSP1 gene is significantly lower in patients with RA, which correlates positively with LSP1 protein expression levels. Differentially expressed genes in Lsp1-deficient primary T cells represent cell motility and immune and cytokine responses. Functional assays demonstrated that LSP1, induced by T-cell receptor activation, negatively regulates T-cell migration by reducing ERK activation in vitro. In mice with T-cell–dependent chronic inflammation, loss of Lsp1 promotes migration of T cells into the target tissues as well as draining lymph nodes, exacerbating disease severity. Moreover, patients with RA show diminished expression of LSP1 in peripheral T cells with increased migratory capacity, suggesting that the defect in LSP1 signaling lowers the threshold for T-cell activation. To our knowledge, our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype. Particularly, our data highlight the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA and provide previously unidentified insights into the mechanisms underlying T-cell migration toward the inflamed synovium in RA.

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“…Secondly, it is plausible and increasingly demonstrated that rarer single nucleotide changes, or structural variants such as copy number variations (25,26) , which are far more common than originally thought, could make a significant contribution to hidden variability ( Fig. 2) (26)(27)(28) .…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

“…2) (26)(27)(28) . Next generation sequencing is becoming increasingly feasible and affordable and is in more widespread use as a research tool (2,29,30) .…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

The genetic contribution to disease risk and variability in response to diet: where is the hidden heritability?

Minihane

2012

Proc. Nutr. Soc.

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Ten years ago, it was assumed that disease risk prediction and personalised nutrition based on genetic information would now be in widespread use. However, this has not (yet) transpired. The interaction of genetic make-up, diet and health is far more complex and subtle than originally thought. With a few notable exceptions, the impact of identified common genetic variants on phenotype is relatively small and variable in their penetrance. Furthermore, the known variants account for only a fraction of what we believe to be the total genetic contribution to disease risk and heterogeneity in response to environmental change. Here, the question 'how far have we progressed and are we likely to get there ' (Rimbach and Minihane, 2009) is revisited with regard to the translation of genetic knowledge into public health benefit. It is concluded that progress to date has been modest. It is hoped that recent technological developments allowing the detection of rarer variants and future use of more hypothesis-driven targeted data analysis will reveal most of the currently 'hidden' significant genetic variability.

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Implications of gene copy-number variation in health and diseases

Cited by 142 publications

References 72 publications

Anomalous association of salivary amylase secretion with the postprandial glycaemic response to starch

Anomalous association of salivary amylase secretion with the postprandial glycaemic response to starch

Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis

The genetic contribution to disease risk and variability in response to diet: where is the hidden heritability?

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