Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia

The genes for the succinate dehydrogenase (SDH) subunits SDHA, SDHB, SDHC and SDHD are encoded in the autosome. The proteins are assembled in the mitochondria to form the mitochondrial complex 2, a key respiratory enzyme which links the Krebs cycle and the electron transport chain. Thirty percent of phaeochromocytoma and paraganglioma (PHEO/PGL) are hereditary and perhaps as many as half of these familial cases are caused by germline mutations of the SDH subunits. Negative immunohistochemical staining for the SDHB subunit identifies PHEO/PGL associated with germline mutation of any of the mitochondrial complex 2 components and can be used to triage formal genetic testing of all PHEO/PGL for SDH mutations. PHEO/PGL associated with SDHA mutation also show negative staining for SDHA as well as SDHB.A unique subgroup of gastrointestinal stromal tumours (GISTs) are driven by mitochondrial complex 2 dysfunction. These SDH deficient GISTs can also be definitively identified by negative staining for SDHB and show distinct clinical and morphological features including frequent onset in childhood and young adulthood, gastric location, a tendency to multifocality, absence of KIT and PDGFRA mutations, a prognosis not predicted by size and mitotic rate and a tendency to indolent behaviour of metastases. Some of these SDH deficient GISTs are driven by classical SDH mutations, but the precise mechanisms of tumourigenesis in many (including those associated with the Carney triad) remain unknown. Germline SDHB mutation is associated with a newly recognised type of renal carcinoma which commonly but not always demonstrates distinctive morphology and can also be recognised by negative staining for SDHB.Immunohistochemistry for SDHB therefore has emerged as a useful tool to recognise these distinct neoplasias driven by mitochondrial complex 2 dysfunction and to triage formal genetic testing for the associated syndromes.     

Succinate dehydrogenase (SDH)‐deficient neoplasia

The succinate dehydrogenase (SDH) complex is a key respiratory enzyme composed of four subunits: SDHA, SDHB, SDHC and SDHD. Remarkably, immunohistochemistry for SDHB becomes negative whenever there is bi‐alleic inactivation of any component of SDH, which is very rare in the absence of syndromic disease. Therefore, loss of SDHB immunohistochemistry serves as a marker of syndromic disease, usually germline mutation of one of the SDH subunits. Tumours which show loss of SDHB expression are termed succinate dehydrogenase‐deficient. In addition to loss of SDHB, tumours associated with SDHA mutation also show loss of SDHA expression. Fifteen per cent of pheochromocytoma and paraganglioma (PHEO/PGL) are associated with germline SDH mutation, and therefore SDH‐deficient. We recommend screening SDHB immunohistochemistry for all PHEO/PGL. SDH‐deficient gastrointestinal stromal tumours (GISTs) show distinctive features, including absent KIT proto‐oncogene receptor tyrosine kinase/platelet‐derived growth factor receptor A (KIT/PDGFRA) mutations [but positive staining for cKIT and DOG1], virtually exclusive gastric location, lobulated growth, multi‐focality, a prognosis not predicted by size and mitotic rate, frequent metastasis to lymph nodes and primary resistance to imatinib therapy. Thirty per cent are associated with SDHA germline mutation and 50% are associated with SDHC epimutation (post‐zygotic promoter hypermethylation) – the hallmark of the syndromic but non‐hereditary Carney triad (SDH‐ deficient GIST, SDH‐deficient paraganglioma and pulmonary chondroma). SDH‐deficient renal carcinoma is newly recognized under the World Health Organization (WHO) 2016 classification and shows vacuolated eosinophilic cytoplasmic and cytoplasmic inclusions. It is particularly associated with SDHB mutation, although SDHC and SDHA mutation occur. SDH‐deficient pituitary adenomas are recognized, but appear to be the least common SDH‐deficient neoplasm.     

Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma

Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FcɛRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 × 10⁻⁵) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6′-sulfo-sLe^x, a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.     

BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins >90%. Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means. For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.     

糖尿病视网膜病变基因多态性荟萃分析新进展

糖尿病视网膜病变是成年人主要致盲的眼病之一.近年来,随着糖尿病患者的不断增加,糖尿病视网膜病变的患病率也逐年递增,国内外对于此疾病的研究也越来越多,在病因学研究中,基因多态性已成为研究的热点.将多个研究进行大样本荟萃分析可以获得更有意义的结论.本文对近几年来糖尿病视网膜病变患者的基因多态性经过荟萃分析得到的有效结果进行总结.     

Polymorphisms in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1) and lifetime cognitive change

A rare polymorphism in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1: rs846911-C/A) has been associated with an increased risk of Alzheimer's disease. We tested the hypothesis that this and 2 other HSD11B1 polymorphisms (rs12086634-G/T and rs846910-A/G) were associated with lifetime cognitive change in humans. Subjects were 194 participants of the Scottish Mental Survey of 1932 who took the same well-validated mental test at age 11 and age 79. The subjects represented the highest and lowest quintiles with respect to cognitive decline between ages 11 and 79. Despite having non-significantly different IQs at age 11, by age 79 the groups had mean (S.D.) IQs of 80.3 (14.1) and 109.6 (9.1), respectively (p<.001). The polymorphism rs846911-C/A was absent from both groups. There were no significant differences in the frequency of polymorphisms of rs12086634-G/T (p=.91) and rs846910-A/G (p=.90) between the groups. We conclude that these variants in HSD11B1 are not significant contributors to the range of cognitive ageing examined here.     

Polymorphisms in the vitamin D receptor gene, ultraviolet radiation, and susceptibility to prostate cancer

Ultraviolet radiation (UVR) exposure may protect against prostate cancer development via a mechanism involving vitamin D. The vitamin D receptor (VDR) gene is therefore a candidate susceptibility factor for prostate cancer. This possibility has been previously investigated with conflicting results. We examined the association of VDR genotypes (variants at the CDX-2, Fok1, and Taq1 sites), haplotypes, and genotype combinations with risk by studying 368 prostate cancer and 243 benign prostatic hypertrophy (BPH) patients. CDX-2, Fok1, and Taq1 genotype and haplotype frequencies were not significantly different in cancer and BPH patients. As the impact of VDR polymorphisms may depend on UVR exposure, we studied associations of variants with risk in men stratified into low (below median) and high (above median) cumulative exposure/year groups. In men with UVR exposure above the median (1,100 hr/year), CDX-2 GA and AA (odds ratios [OR] = 2.11 and 2.02, respectively) and Fok1 ff (OR = 2.91) were associated with increased prostate cancer risk. No associations were observed for Taq1 genotypes. Of the genotype combinations, relative to all other CDX-2 and Taq1 and combinations, GGTT (P = 0.022, OR = 0.30), and relative to all other Fok1 and Taq1 combinations, FFTT (P = 0.026, OR = 0.35) were associated with reduced prostate cancer risk in the presence of the main effects. None of the other two- or three-genotype combinations was associated with risk. These data indicate that VDR variants influence prostate cancer risk and that this association is dependent on the extent of UVR exposure.     

Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis

We examined 906 residents of an area of Papua New Guinea where bancroftian filariasis is endemic for genetic polymorphisms in three innate immunity genes suspected of contributing to susceptibility to infection and lymphatic pathology. Active infection was confirmed by the presence of blood-borne microfilariae and circulating filarial antigen in plasma. Disease was ascertained by physical examination for the presence of overt lymphedema (severe swelling of an arm or leg) or hydrocele. There was no association of infection status, lymphedema of an extremity, or hydrocele with chitotriosidase genotype (CHIT1). Polymorphisms of toll-like receptor-2 and toll-like receptor-4 genes (TLR4 A896G; TLR2 T2178A, G2258A) were not detected (N=200-625 individuals genotyped) except for two individuals heterozygous for a TLR2 mutation (C2029 T). These results indicate that a CHIT1 genotype associated previously with susceptibility to filariasis in residents of southern India and TLR2 and TLR4 polymorphisms do not correlate with infection status or disease phenotype in this Melanesian population.     

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population

Background  

Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results.     

Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease

The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.     

Polymorphisms in inflammasome' genes and susceptibility to HIV-1 infection

The involvement of inflammasome genes in the susceptibility to HIV-1 infection was investigated. Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects and 158 healthy controls. The 2 polymorphisms rs10754558 in NLRP3 and rs1143634 in IL1B were significantly associated to the HIV-1 infection. These findings supported the previously hypothesized involvement of NALP3-inflammasome in HIV-1 pathogenesis, underlining once more the key role of inflammation and innate immunity in the susceptibility to HIV-1 infection.     

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease

Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case-control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3-CCR2-CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-Delta32 was observed with an allele frequency of 10.7% in the control population compared to 6.5% in the KD patients (P = 0.04). Two haplotypes of the CCR3-CCR2-CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5 was observed.     

Polymorphisms for microsomal epoxide hydrolase and genetic susceptibility to COPD

Although smoking is the major causal factor in the development of chronic obstructive pulmonary disease (COPD), only 10-20% of chronic heavy cigarette smokers develop symptomatic COPD, which suggests the presence of genetic susceptibility. The human microsomal epoxide hydrolase (EH) is a metabolizing enzyme which involves the process of numerous reactive epoxide intermediates and contains polymorphic alleles which are associated with altered EH activity and may be linked to increased risk for COPD. To determine whether the EH polymorphisms contributed to increased risk for COPD, prevalence of the EH codons 113 and 139 polymorphisms were compared between COPD patients and controls by a PCR-RFLP analysis using genomic DNA isolated from 131 COPD patients and 262 individually matched controls by age (+/-5 years) among Caucasians with 2:1 ratio. Significantly increased risk for COPD was observed for subjects with the EH(113His/His) genotypes (OR=2.4, 95% CI=1.1-5.1). These results were consistent with the fact that a significant trend towards increased risk was observed with predicted less protective EH codon 113 genotypes (p=0.03, trend test). A similar association was not observed for EH codon 139 polymorphism. As expected, a significant correlation between smoking dose and severity of COPD was observed (p<0.001). These results suggest that EH codon 113 polymorphism may modify risk for COPD.