强直性脊柱炎患者MICA基因第2、3和4外显子的多态性及其与HLA-B抗原的连锁不平衡

目的探讨皖籍汉族人群MICA基因（major histocompatibility complex class Ⅰchain-related gene A，MICA）第2、3、4外显子的多态性，及其与HLA-B抗原的连锁不平衡在强直性脊柱炎（ankylosing spondylitis，AS）发病中的作用。方法采用聚合酶链反应-序列特异性寡核苷酸探针杂交（polymerase chain reactionsequence-specific oligonucleotide probing，PCR-SS0）技术对56例AS患者和112名正常对照人群进行MICA基因第2、3、4外显子的多态性和HLA-B抗原的检测。结果AS患者和正常对照人群的MICA等位基因分布均以MICA＊008占优势，频率分别为32．14％和30．36％。两组人群MICA＊007等位基因的分布差异有统计学意义（X^2=10．18，P〈0．05，RR=2．50）。单倍型分析显示，AS患者和正常对照人群的MICA等位基因均显示出与多个HLA-B位点的连锁不平衡现象，两组间差异有统计学意义的单倍型为MICA＊007-B27（X^2=18．46，P〈0．05，RR=7．47）。分层分析结果显示，HLA-B27阳性与AS的相关性有统计学意义（P〈0．05），但MICA＊007基因与AS的相关性无统计学意义（P〉0．05）。结论AS患者中MICA＊007等位基因频率的显著升高可能源于MICA基因与HLA-B位点间的广泛连锁不平衡。     

Premature ovarian failure

Premature ovarian failure (POF) causing hypergonadotrophic hypogonadism occurs in 1% of women. In majority of cases the underlying cause is not identified. The known causes include: (a) Genetic aberrations, which could involve the X chromosome or autosomes. A large number of genes have been screened as candidates for causing POF; however, few clear causal mutations have been identified. (b) Autoimmune ovarian damage, as suggested by the observed association of POF with other autoimmune disorders. Anti-ovarian antibodies are reported in POF by several studies, but their specificity and pathogenic role are questionable. (c) Iatrogenic following surgical, radiotherapeutic or chemotherapeutic interventions as in malignancies. (d) Environmental factors like viral infections and toxins for whom no clear mechanism is known. The diagnosis is based on finding of amenorrhoea before age 40 associated with FSH levels in the menopausal range. Screening for associated autoimmune disorders and karyotyping, particularly in early onset disease, constitute part of the diagnostic work-up. There is no role of ovarian biopsy or ultrasound in making the diagnosis. Management essentially involves hormone replacement and infertility treatment, the only proven means for the latter being assisted conception with donated oocytes. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation hold promise in cases where ovarian failure is foreseeable as in women undergoing cancer treatments.     

Cognitive ability and academic achievement in the Colorado Adoption Project: A multivariate genetic analysis of parent-offspring and sibling data

To test the hypothesis that the etiology of covariation among measures of cognitive ability and academic achievement is due at least in part to shared genetic influences, data from 198 adoptive and 220 nonadoptive families participating in the Colorado Adoption Project were subjected to multivariate behavioral genetic analyses. Data on measures of cognitive ability (verbal comprehension and perceptual organization) and academic achievement (reading recognition and mathematics achievement) from related and unrelated sibling pairs tested at age 7, as well as from adoptive and nonadoptive parents, were analyzed. Phenotypic analyses confirmed previous findings of moderate correlations among measures of cognitive ability and achievement, averaging about .35. Although 54% of the covariation between reading and mathematics achievement was due to influences shared with verbal ability, a significant proportion of this covariation was independent of the cognitive ability measures. Heritabilities for the various measures were moderate, ranging from .21 to .37. Moreover, genetic influences accounted for 33–64% of their phenotypic covariation; for example, 33–60% of the observed correlations between verbal comprehension and the achievement measures, 64% of those between perceptual organization and the achievement measures, and 63% of that between reading recognition and mathematics achievement were due to shared genetic influences. Similar to the results of the phenotypic analysis, nearly half of the genetic covariance between reading and mathematics achievement was independent of cognitive ability. Their remaining covariance was due primarily to nonshared environmental influences.     

Marfan syndrome: exclusion of genetic linkage to the COL1A2 gene

Marfan Syndrome is a genetic disorder of the connective tissue. Individuals from one large family with this disorder were genotyped for COL1A2 gene associated RFLPs. Our results demonstrated that the COL1A2 gene, encoding the proa2(I) collagen chain, segregated independently of the phenotype and it is therefore excluded as the mutant locus in this family.     

Paraffin wax-embedded material as a source of DNA for the detection of somatic genetic changes

Loss of genetic material, corresponding to chromosomal deletions, has been detected in a wide range of tumours and may indicate the position of a tumour suppressor gene. In order to identify the position of such a gene more precisely, many tumour samples must be studied until a minimum consensus deletion is characterized. This process is particularly necessary for lung tumours in which the deletion in chromosome 3, seen with such high frequencies in all histological subtypes, is almost always large. We have recently described the use of the polymerase chain reaction (PCR) for restriction fragment length polymorphism (RFLP) analysis of DNA isolated from small bronchial biopsies of lung tumours. In this study we adapted this technique to allow genotyping of DNA isolated from paraffin wax-embedded material (PWEM) microdissected from glass slides. We have investigated 12 lung tumours at polymorphic loci on chromosome 3 and showed allelic loss in all samples. In adapting PCR–RFLP analysis for DNA isolated from PWEM, we have concentrated on those approaches which might be adaptable to routine clinical practice. Somatic genetic changes are now being identified in many tumour types, and this information is expected to be of diagnostic and prognostic significance.     

Sperm pathology: a step beyond descriptive morphology. Origin, characterization and fertility potential of abnormal sperm phenotypes in infertile men

Sperm pathology is presented as the discipline of characterizing structural and functional deficiencies in abnormal spermatozoa. This concept complements that of sperm morphology mainly concerned with the appearance of spermatozoa. These two notions collaborate in providing correlations of prognostic value with sperm fertilizing capacity, explaining the mechanisms of sperm inefficiency, suggesting strategies to improve fertilization and opening a door to molecular genetic studies. Phenotypes of genetic origin involving sperm heads, flagella and the neck region are presented describing their clinical manifestations, sperm structure, cytochemistry and genetic background. When available, animal models are used to highlight possible genetic mechanisms. Sperm pathologies secondary to andrological conditions or environmental factors are described, stressing the non-specific nature of the sperm response to noxious agents. The available literature on the prognostic value of sperm pathologies in ICSI is also reviewed. Flagellar anomalies bear a good prognosis, but those affecting the acrosome, sperm chromatin and the neck region entail an increasing chance of failure, which highlights the differential roles played by specific sperm components in fertilization, implantation and early embryonic development. A final discussion is devoted to genetic counselling and the risks involved in using immotile or abnormal spermatozoa in assisted reproduction.     

阿昌族与汉族维生素D受体基因Fok多态性

目的　了解维生素 D受体基因多态性在中国不同民族中的分布。方法　应用聚合酶链反应 -限制性片段长度多态性分析、基因测序等技术检测 6 8名阿昌族人和 92名汉族人的维生素 D受体基因Fok 多态性 ,比较两组维生素 D受体基因型和等位基因的分布频率。结果　在 6 8名阿昌族人中 FF基因型占 18%、Ff基因型占 35 %、ff基因型占 4 7% ,而在 92名汉族人中 FF基因型占 2 2 %、Ff基因型占 5 2 %、ff基因型占 2 6 %。两组维生素 D受体基因型的分布频率差异有显著性 (χ2 =7.716 ,P=0 .0 2 1)。结论　阿昌族与汉族维生素 D受体基因 Fok 多态性分布频率差异有显著性。     

What should we do with donated embryos that may be genetically affected?

The ethical and legal issues arising from genetic screening in embryo donation are discussed in relation to two recent cases where embryos with uncertain genetic health were offered for donation.     

Predictive genetic testing in children and adults: a study of emotional impact

AIM—To determine whether, following predictive genetic testing for familial adenomatous polyposis (FAP), children or adults receiving positive results experience clinically significant levels of anxiety or depression, and whether children receiving positive results experience higher levels of anxiety or depression than adults receiving positive results.
DESIGN—Two studies, one cross sectional and one prospective.
SAMPLE—208 unaffected subjects (148 adults and 60 children) at risk for FAP who have undergone genetic testing since 1990.
MAIN MEASURES—Dependent variables: anxiety, depression; independent variables: test results, demographic measures, psychological resources (optimism, self-esteem).
RESULTS—Study 1. In children receiving positive results, mean scores for anxiety and depression were within the normal range. There was a trend for children receiving positive results to be more anxious and depressed than those receiving negative results. In adults, mean scores for anxiety were within the normal range for those receiving negative results, but were in the clinical range for those receiving positive results, with 43% (95% CI 23-65) of the latter having scores in this range. Regardless of test result, adults were more likely to be clinically anxious if they were low in optimism or self-esteem. Children receiving positive or negative results did not experience greater anxiety or depression than adults. Study 2. For children receiving a positive test result, mean scores for anxiety, depression, and self-esteem were unchanged over the year following the result, while mean anxiety scores decreased and self-esteem increased after receipt of a negative test result over the same period of time.
CONCLUSION—Children, as a group, did not show clinically significant distress over the first year following predictive genetic testing. Adults were more likely to be clinically anxious if they received a positive result or were low in optimism or self-esteem, with interacting effects. The association between anxiety, self-esteem, and optimism suggests that counselling should be targeted, not only at those with positive test results, but also at those low in psychological resources.


Keywords: genetic testing; children; familial adenomatous polyposis; emotional impact     

Genetic susceptibility to age related macular degeneration

Age related macular degeneration (AMD) is the leading cause of visual impairment in the elderly and a major cause of blindness in the developed world. The disease can take two forms, geographic atrophy and choroidal neovascularisation. The pathogenesis of AMD is poorly understood. There are undoubtedly environmental and other risk factors involved and the adverse effect of smoking is well established. Several studies have shown that genetic factors are important but leave uncertainty about the magnitude and nature of the genetic component and whether it varies with the type of AMD. Several hereditary retinal dystrophies show similarities to AMD and these genes are potential candidate susceptibility genes. Particular interest has focused on the ABCR gene which is responsible for autosomal recessive Stargardt macular dystrophy. It has been claimed that heterozygotes for ABCR mutations are predisposed to AMD but the data are conflicting. Studies of the genes responsible for autosomal dominant Sorsby fundus dystrophy, Doyne honeycomb retinal dystrophy, and Best disease have given negative results. In one large AMD family, linkage has been reported to markers in 1q25-q31. Recent data suggest that the ApoE epsilon4 allele may be associated with reduced risk of AMD. A better understanding of the genetic factors in AMD would contribute to understanding the pathogenesis. If those at risk could be identified it may be possible to modify lifestyle or develop novel therapies in the presymptomatic stage to prevent disease or decrease its severity.