How important are rare variants in common disease?

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How important are rare variants in common disease?

Brief Funct Genomics. 2014 Jul 8;

Authors: Saint Pierre A, Génin E

Abstract
Genome-wide association studies have uncovered hundreds of common genetic variants involved in complex diseases. However, for most complex diseases, these common genetic variants only marginally contribute to disease susceptibility. It is now argued that rare variants located in different genes could in fact play a more important role in disease susceptibility than common variants. These rare genetic variants were not captured by genome-wide association studies using single nucleotide polymorphism-chips but with the advent of next-generation sequencing technologies, they have become detectable. It is now possible to study their contribution to common disease by resequencing samples of cases and controls or by using new genotyping exome arrays that cover rare alleles. In this review, we address the question of the contribution of rare variants in common disease by taking the examples of different diseases for which some resequencing studies have already been performed, and by summarizing the results of simulation studies conducted so far to investigate the genetic architecture of complex traits in human. So far, empirical data have not allowed the exclusion of many models except the most extreme ones involving only a small number of rare variants with large effects contributing to complex disease. To unravel the genetic architecture of complex disease, case-control data will not be sufficient, and alternative study designs need to be proposed together with methodological developments.

PMID: 25005607 [PubMed - as supplied by publisher]

An effective method based on real time fluorescence quenching for single nucleotide polymorphism detection.

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An effective method based on real time fluorescence quenching for single nucleotide polymorphism detection.

J Biotechnol. 2014 Jul 3;

Authors: Xu Y, Han S, Huang X, Zhuo S, Dai H, Li Z, Wang K, Liu J

Abstract
In the Human Genome Project, the most common type of these variations is single nucleotide polymorphisms (SNPs). A large number of different SNP typing technologies have been developed in recent years. Enhancement and innovation for genotyping technologies are currently in progress. We described a rapid and effective method based on real time fluorescence quenching for SNP detection. The new method, Quenching-PCR, offering a single base extension method fully integrated with PCR which used a probe with quencher to eliminate fluorophor of the terminal base according to dideoxy sequencing method. In this platform, dideoxy sequencing reaction and obtaining values of real-time fluorescence occur simultaneously. The assay was validated by 106 DNA templates comparing with Sanger's sequencing and TaqMan assay. Compared with the results of DNA sequencing, the results of Quenching-PCR showed a high concordance rate of 93.40%, while the results of TaqMan platform showed a concordance rate of 92.45%, indicating that Quenching PCR and TaqMan assay were similar in accuracy. Therefore, Quenching PCR will be easily applicable and greatly accelerate the role of SNP detection in physiological processes of human health.

PMID: 24998766 [PubMed - as supplied by publisher]

NT5C3 polymorphisms and outcome of first induction chemotherapy in acute myeloid leukemia.

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NT5C3 polymorphisms and outcome of first induction chemotherapy in acute myeloid leukemia.

Pharmacogenet Genomics. 2014 Jul 3;

Authors: Cheong HS, Koh Y, Ahn KS, Lee C, Shin HD, Yoon SS

Abstract
AIMS: The cytosolic 5'-nucleotidase-III (NT5C3) is involved in the metabolism of the nucleoside analog, cytosine arabinose (AraC), and the expression level of NT5C3 is correlated with sensitivity to AraC in acute myeloid leukemia (AML) patients. The current study examined whether the NT5C3 polymorphisms could affect chemotherapy outcomes in 103 Korean AML patients.
METHODS: Forty-seven single nucleotide polymorphisms in NT5C3 were genotyped using the Illumina GoldenGate genotyping assay. The genetic effects of the polymorphisms on the outcome of chemotherapy were analyzed using χ and logistic regression models.
RESULTS: Although none of the NT5C3 polymorphisms was associated with a complete remission rate, a common single nucleotide polymorphism, rs3750117, showed a significant association with induction rate after the first course of chemotherapy (Pcorr=0.004 and odds ratio=11.28) in AML patients. In addition, NT5C3 expression levels were significantly increased in patients with risk allele homozygote.
CONCLUSIONS: The data suggest that genotyping the NT5C3 polymorphism may have the potential to identify patients more likely to respond to AraC-based chemotherapy.

PMID: 25000516 [PubMed - as supplied by publisher]

The 80 kb DNA duplication on BTA1 is the only remaining candidate mutation for the polled phenotype of Friesian origin.

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The 80 kb DNA duplication on BTA1 is the only remaining candidate mutation for the polled phenotype of Friesian origin.

Genet Sel Evol. 2014 Jul 3;46(1):44

Authors: Rothammer S, Capitan A, Mullaart E, Seichter D, Russ I, Medugorac I

Abstract
BACKGROUND: The absence of horns, called polled phenotype, is the favored trait in modern cattle husbandry. To date, polled cattle are obtained primarily by dehorning calves. Dehorning is a practice that raises animal welfare issues, which can be addressed by selecting for genetically hornless cattle. In the past 20 years, there have been many studies worldwide to identify unique genetic markers in complete association with the polled trait in cattle and recently, two different alleles at the POLLED locus, both resulting in the absence of horns, were reported: (1) the Celtic allele, which is responsible for the polled phenotype in most breeds and for which a single candidate mutation was detected and (2) the Friesian allele, which is responsible for the polled phenotype predominantly in the Holstein breed and in a few other breeds, but for which five candidate mutations were identified in a 260 kb haplotype. Further studies based on genome-wide sequencing and high-density SNP (single nucleotide polymorphism) genotyping confirmed the existence of the Celtic and Friesian variants and narrowed down the causal Friesian haplotype to an interval of 145 kb.
RESULTS: Almost 6000 animals were genetically tested for the polled trait and we detected a recombinant animal which enabled us to reduce the Friesian POLLED haplotype to a single causal mutation, namely a 80-kb duplication. Moreover, our results clearly disagree with the recently reported perfect co-segregation of the POLLED mutation and a SNP at position 1 390 292 bp on bovine chromosome 1 in the Holstein-Friesian population.
CONCLUSION: We conclude that the 80-kb duplication, as the only remaining variant within the shortened "Friesian" haplotype, represents the most likely causal mutation for the polled phenotype of Friesian origin.

PMID: 24993890 [PubMed - as supplied by publisher]

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