Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in Chinese

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Helena,the hidden beauty: Resolving the most common West Eurasian mtDNA control region haplotype by massively parallel sequencing an Italian population sample

The analysis of mitochondrial (mt)DNA is a powerful tool in forensic genetics when nuclear markers fail to give results or maternal relatedness is investigated. The mtDNA control region (CR) contains highly condensed variation and is therefore routinely typed. Some samples exhibit an identical haplotype in this restricted range. Thus, they convey only weak evidence in forensic queries and limited phylogenetic information. However, a CR match does not imply that also the mtDNA coding regions are identical or samples belong to the same phylogenetic lineage. This is especially the case for the most frequent West Eurasian CR haplotype 263G 315.1C 16519C, which is observed in various clades within haplogroup H and occurs at a frequency of 3–4% in many European populations.In this study, we investigated the power of massively parallel complete mtGenome sequencing in 29 Italian samples displaying the most common West Eurasian CR haplotype – and found an unexpected high diversity. Twenty-eight different haplotypes falling into 19 described sub-clades of haplogroup H were revealed in the samples with identical CR sequences. This study demonstrates the benefit of complete mtGenome sequencing for forensic applications to enforce maximum discrimination, more comprehensive heteroplasmy detection, as well as highest phylogenetic resolution.     

Association of group‐specific component exon 11 polymorphisms with bronchial asthma in children and adolescents

Several studies have investigated the association of Group‐specific Component (GC) gene, also known as vitamin D‐binding protein (VDBP), and various respiratory disorder susceptibility with conflicting results. In this sense, we aimed to investigate whether rs7041 and rs4588 variants confer susceptibility to bronchial asthma in a sample of an Egyptian population and to elucidate by in silico analysis the structural and functional impact of these variants. Group‐specific Component polymorphisms rs7041 and rs4588 were genotyped in 192 Egyptian children and adolescents (96 with asthma and 96 healthy controls) by TaqMan single nucleotide polymorphism genotyping assay. The rs7041 GG genotype showed a significantly elevated frequency among patients under codominant, dominant, recessive and allelic models where the patient group had greater carriage rate of G allele [OR 2.15, CI 95% (1.32‐3.50; P = 0.002)], while rs4588 CA and AA genotypes were found to be protective genotypes with controls showing a greater carriage rate of A allele [OR 0.52, CI 95% (0.30 ‐ 0.90; P = 0.02)]. Three haplotype allele combinations were identified with frequencies of GC (44.3%), TC (31.3%) and TA (24.5%) in the total study population. GC haplotype was shown to be more frequent in controls, while TC and TA haplotypes were more predominant in the patient group. Only rs7041 variant showed a significant association with family history and pubertal status. In conclusion, both study GC variants could be implicated in childhood bronchial asthma pathogenesis; rs7041 GG genotype and G allele increased asthma risk while rs4588 AA genotype and A allele conferred protection in the study population.     

Functional variants of IL4 and IL6 genes and risk of tobacco-related oral carcinoma in high-risk Asian Indians

Oral Diseases (2011) 17 , 720–726 Background: Tobacco‐related oral squamous cell carcinoma (OSCC) is one of the most common cancers involving Indian males. We assessed the association of IL4 promoter –589 T>C, –33 T>C, and IL6–174 G>C functional genetic polymorphisms with tobacco‐related OSCC in Asian Indians. Patients and Methods: The IL4 and IL6 promoter polymorphisms were assessed in 140 patients with OSCC and 120 normal subjects by PCR–RFLP technique, and significance of the data was determined using chi‐square test. Results: The frequency of TC, CC genotype, and C allele at IL4 promoter sites –589 and –33 were higher in patients when compared with controls. Consequently, TC/CC genotypes and C allele at both sites appeared as susceptible. However, IL6–174 G>C single‐nucleotide polymorphisms (SNP) appeared to be protective in patients with OSCC. Of eight haplotypes, five were associated with two‐ to seven‐fold increased risk of tobacco‐related OSCC. These SNPs further showed heterogeneity among different ethnic population, but their distribution in Asian Indians stand closer to other Asian populations. Conclusions: In this study, IL4–589 CC, –33 CC genotype, and *C allele at both sites appeared to be susceptible, while IL6–174 CC genotype and *C allele appeared to be protective in patients with OSCC; hence, these SNPs may be a potential prognostic markers for tobacco‐related OSCC in Asian Indians.     

An adenosine A2A receptor gene haplotype is associated with migraine with aura

The adenosine A2A receptor A2AR facilitates effects of calcitonin gene-related peptide and vasoactive intestinal peptide, two important neuropeptides in migraine pathophysiology, and is the molecular target of caffeine, which is used in migraine treatment. We therefore determined whether A2AR gene variation might influence migraine susceptibility. Migraine patients (n = 265) with or without aura and migraine-free controls (n = 154) were assessed and genotyped for six genetic variants spanning the A2AR gene. A six-marker haplotype was more frequent in migraine patients with aura (P < 0.01) but not in patients without aura, compared with the control group. This indicates that A2AR gene variation may contribute to the pathogenesis of migraine with aura.     

The influence of glucocorticoid receptor single nucleotide polymorphisms on outcome after haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation (HSCT) remains the only cure for most haematological malignancies, however, the mortality rate remains high. Complications after HSCT include relapse, graft versus host disease (GvHD), graft rejection and infection. Over the last few years several groups, have demonstrated that non‐HLA gene polymorphisms can be predictive of outcome after HSCT. Since the glucocorticoid cortisol is pivotal in the regulation of the immune system, we decided to examine single nucleotide polymorphisms (SNPs; rs6198, rs33388 and rs33389) within the glucocorticoid receptor (GR) and correlate with HSCT outcome. The training set consisted of patients (n = 458) who underwent HSCT for acute leukaemia between 1983 and 2005. In the recipients, the absence of the ACT haplotype and absence of the T allele of rs33388 were associated with decreased OS and the absence of the ACT haplotype, the absence of the T allele of rs33388 and the presence of the ATA haplotype were associated with increased risk of relapse. In addition, the presence of the ACT haplotype in the recipient showed a trend to be associated with increased risk of chronic graft versus host disease (cGvHD). The patients in this cohort received mainly myeloablative conditioning (n = 327). The SNPs in the glucocorticoid receptor were then investigated in a validation set (n = 251) of HSCT patients transplanted for acute leukaemia from 2006. This cohort contained significantly more patients that had received reduced intensity conditioning (RIC). Some of the results could be validated in these patients. However, contrary to the training set, the absence of the haplotype ACT in the donor in this cohort was associated with increased risk of cGvHD. Differences in the conditioning were shown to influence the results. These results are the first to associate GR SNPs with HSCT outcome and demonstrate the inherent problems of replicating SNP association studies in HSCT, due to different pre‐transplant regimens.     

Mutation spectra and founder effect of TMC1 in patients with non‐syndromic deafness in Xiamen area,China

To analyze the spectrum and founder effect of TMC1 mutations in patients with non‐syndromic deafness in the Xiamen area. Sporadic pedigrees were detected by targeted next‐generation sequencing, and 110 unrelated patients from Xiamen Special Education School were analyzed through Sanger sequencing for the TMC1 gene. In total, 53 SNPs were designed to analyze the haplotypes of the TMC1 c.2050G>C mutation. The probands of three families were found to be homozygous for TMC1 c.2050G>C, and their parents were all heterozygous for the TMC1 c.2050G>C mutation. In 110 unrelated patients from Xiamen Special Education School, four were found to carry compound heterozygotes of TMC1 c.2050G>C, which were compound heterozygotes of c.804G>A, c.1127T>C, c.1165C>T, and c.1396_1398delAAC, respectively. Three types of TMC1 polymorphisms (c.45C>T, c.1713C>T, c.2208+49C>T) and two heterozygotes of novel variants (c.1764‐4C>A, c.2073G>A[p.K691K]) were found in the remaining 100 patients. In total, four novel variants were detected in this study. These mutations and variants were not detected in 100 normal samples. The haplotypes of the probands of families with TMC1 c.2050G>C were identical. There were unique hotspots and spectra of TMC1 mutations in the Xiamen deaf population. Haplotype analysis is useful to understand the founder effect of the hot spot mutation.