Abstract:Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.
“…The frequencies of copy number classes were not given explicitly by Nuytten et al [52], but are reconstructed here from the data in their Figure seven (a). Jespersgaard et al [47] do not give details of individual copy number counts, but instead give counts above or below a copy number of 6.Figure 3
Segregation of haplotypes in the three-generation CEPH family 1341. In addition to the copy number, segregating haplotypes (boxed) are distinguished by the composition of other variants for which ratios were determined in this study.…”
Section: Resultsmentioning
confidence: 99%
“…The frequencies of copy number classes were not given explicitly by Nuytten et al [52], but are reconstructed here from the data in their Figure seven (a). Jespersgaard et al [47] do not give details of individual copy number counts, but instead give counts above or below a copy number of 6.…”
Section: Resultsmentioning
confidence: 99%
“…We can therefore use these observations to suggest that a strong influence of DEFA1A3 copy number on predisposition to any of these phenotypes in European populations is unlikely, despite the published evidence suggesting the influence of DEFA1A3 copy number in Crohn’s disease [47] and of increased alpha-defensin production on HIV progression [48]. It also provides a simple (SNP-based) method for further investigation of other phenotypes in which DEFA1A3 copy number may be implicated, such as the published association with sepsis [49], in a way that would not be complicated by the difficulties of direct copy number measurement.…”
BackgroundMulti-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing.ResultsIn this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples.ConclusionsWe have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn’s disease, type I diabetes, HIV progression and multiple sclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-14-719) contains supplementary material, which is available to authorized users.
“…The frequencies of copy number classes were not given explicitly by Nuytten et al [52], but are reconstructed here from the data in their Figure seven (a). Jespersgaard et al [47] do not give details of individual copy number counts, but instead give counts above or below a copy number of 6.Figure 3
Segregation of haplotypes in the three-generation CEPH family 1341. In addition to the copy number, segregating haplotypes (boxed) are distinguished by the composition of other variants for which ratios were determined in this study.…”
Section: Resultsmentioning
confidence: 99%
“…The frequencies of copy number classes were not given explicitly by Nuytten et al [52], but are reconstructed here from the data in their Figure seven (a). Jespersgaard et al [47] do not give details of individual copy number counts, but instead give counts above or below a copy number of 6.…”
Section: Resultsmentioning
confidence: 99%
“…We can therefore use these observations to suggest that a strong influence of DEFA1A3 copy number on predisposition to any of these phenotypes in European populations is unlikely, despite the published evidence suggesting the influence of DEFA1A3 copy number in Crohn’s disease [47] and of increased alpha-defensin production on HIV progression [48]. It also provides a simple (SNP-based) method for further investigation of other phenotypes in which DEFA1A3 copy number may be implicated, such as the published association with sepsis [49], in a way that would not be complicated by the difficulties of direct copy number measurement.…”
BackgroundMulti-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing.ResultsIn this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples.ConclusionsWe have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn’s disease, type I diabetes, HIV progression and multiple sclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-14-719) contains supplementary material, which is available to authorized users.
“…14 CNVs and gene polymorphisms of DEFA1 or/and DEFA3 are found associated with multiple immune-related diseases such as Crohn's disease. 17 All the above discoveries highlighted the critical role of α-defensins in autoimmunity, including mucosal innate immunity. SNPs together with CNVs may contribute to the making up of the IgAN susceptibility background.…”
Section: Discussionmentioning
confidence: 99%
“…It has been reported that they have an effect on several diseases. [11][12][13][14][15][16][17][18] Two GWASs discovered variants in the association of DEFA locus with IgAN susceptibility. However, the top SNPs were inconsistent.…”
IgA nephropathy (IgAN) is a complex syndrome with high genetic heterogeneity. More recently, a genome-wide association study (GWAS) from Southern Han population revealed that variants within 8p23.1, where the DEFA genes encoding a-defensins assembled, were associated with susceptibility to IgAN. To replicate the association and fine-map the genetic variants, a case-control genetic study from an independent Northern Han cohort was conducted. A total of 60 single-nucleotide polymorphisms in a region spanning 350 kb encompassing the DEFA genes cluster were analyzed in 2096 individuals. Copy number variations of DEFA1A3 within the loci were also checked for the independent association. Functional significance of the associated variants was further examined by the in silico method as well as by cis-acting expression quantitative trait loci analysis with mRNA. It showed that 17 out of 60 (28.3%) variants were associated with susceptibility to IgAN. Two independent signals with functional potentials were discovered (rs2738058, P=4.64 × 10(-5), odds ratio (OR)=0.76, 95% confidence interval (CI) 0.66-0.87 and rs9644778, P=4.78 × 10(-3), OR=1.21, 95% CI 1.06-1.39). Besides, marginally significant association of rs9644778 risk genotype with lower proportion of gross hematuria (CC+CA vs AA 35.2% vs 30.2%, P=0.073) was observed. In conclusion, DEFA gene polymorphisms have potentially pathogenic roles in IgAN, and the role of mucosal immunity in the pathogenesis of IgAN has to be emphasized.
Our recent genome-wide association study (GWAS) had discovered a new locus at 8p23 (rs2738048) associated with IgA nephropathy (IgAN) in Chinese Han patients, implicating the DEFA gene family within this locus as susceptibility genes. However, it is still unknown whether there are additional variations within these genes associated with the disease susceptibility. The aim of this study is to investigate the polymorphisms of DEFA genes in the susceptibility to IgAN and explore possible disease mechanisms. Sixteen tag single-nucleotide polymorphisms (tag SNPs) were selected for association study in 1,000 IgAN cases and 1,000 controls by using Sequenom MassArray system or TaqMan SNP genotyping assays. We found seven SNPs within DEFA genes that were significantly associated with IgAN, including rs2738048 discovered in our previous GWAS (p = 0.0007, OR = 0.77) and additional 6 SNPs (rs2615787, p = 0.0001, OR = 0.74; rs2738081, p = 0.0003, OR = 0.72; rs2738058, p = 0.0001, OR = 0.73; rs4288398, p = 0.0008, OR = 0.78; rs6984215, p = 0.002, OR = 0.63; rs12716641, p = 0.00002, OR = 0.71). Electrophoretic mobility shift assays and luciferase assays demonstrated that fragments containing rs2738048, rs2738081 and rs6984215 were transcription factor binding sites for CTF, SP1 and CdxA, respectively, and the allele status of rs2738048 and rs6984215 could significantly change the luciferase activity. These results suggest that polymorphisms within DEFA genes are involved in gene transcriptional regulation, and this may have some effect in mediating susceptibility to IgAN in southern Chinese.
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