Relevance Of Genetic Factors Research Articles

Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.

What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs. N/A. A limited number of cases were included. Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.

Dietary alterations modulate susceptibility to Plasmodium infection.

The relevance of genetic factors in conferring protection to severe malaria has been demonstrated, as in the case of sickle cell trait and G6PD deficiency 1 . However, it remains unknown whether environmental components, such as dietary or metabolic variations, can contribute to the outcome of infection 2 . Here, we show that administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90%. Plasmodium sporozoites can successfully invade and initiate replication but die inside hepatocytes, thereby are unable to cause severe disease. Transcriptional analyses combined with genetic and chemical approaches reveal that this impairment of infection is mediated by oxidative stress. We show that reactive oxygen species, probably spawned from fatty acid β-oxidation, directly impact Plasmodium survival inside hepatocytes, and parasite load can be rescued by exogenous administration of the antioxidant N-acetylcysteine or the β-oxidation inhibitor etomoxir. Together, these data reveal that acute and transient dietary alterations markedly impact the establishment of a Plasmodium infection and disease outcome.

Polymorphisms of genes involved in extracellular matrix remodeling and abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) has a multifactorial etiology and the relevance of genetic factors is getting increasing interest, in particular those related to the destructive remodeling of extracellular matrix. We performed a candidate gene association study of polymorphisms in genes coding matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and elastin (ELN) in AAA. DNA samples from 423 AAA patients and 423 controls were genotyped for 12 polymorphisms in 10 genes: MMP1 (-1607G/GG), MMP2 (-735C/T; -1306C/T; -1575 G/A), MMP3 (5A/6A), MMP9 (-1562C/T), MMP10 (A180G), MMP-12 (-82A/G), MMP-13 (-77A/G), TIMP1 (C434T), TIMP3 (-1296T/C), and ELN (G1355A). Genotype distribution was significantly different between patients and controls for the following polymorphisms: -1306C/T MMP2; 5A/6A MMP3; -77A/G MMP-13; G1355A ELN; and C434T TIMP1. In a multivariable logistic regression analysis adjusted for traditional cardiovascular risk factors and chronic obstructive pulmonary disease, -1306C/T MMP2 (odds ratios [OR] = 0.55 [95% confidence interval, CI .34-.85], P < .007) and G1355A ELN (OR = 0.64 ([95% CI .41-.99], P = .046) polymorphisms resulted in independent protective factors for abdominal aortic aneurysm (AAA), whereas 5A/6A MMP3 (OR = 1.82 [95% CI 1.04-3.12], P = .034) and -77 A/G MMP-13 (OR = 2.14 [95% CI 1.18-3.86], P = .012) polymorphisms resulted in independent risk factors for AAA. In a multivariable logistic regression analysis adjusted for traditional cardiovascular factors and chronic obstructive pulmonary disease, the prevalence of the contemporary presence of three or four genetic risk conditions was a strong and independent determinant of AAA disease (OR = 2.96, 95% CI 1.67-5.24, P < .0001). For those polymorphisms independently associated with AAA in this study (-1306C/T MMP2, 5A/6A MMP3, -77A/G MMP-13, and G1355A ELN polymorphisms), we performed a meta-analysis of the available data (this paper and literature data). We found a significant association with an increased risk of AAA for MMP3 (AAA patients n = 1258, controls n = 1406: OR = 1.48 [95% CI = 1.23-1.78], I(2) = 0%) and MMP-13 (AAA patients n = 800, controls n = 843: OR = 1.37 [95% CI = 1.04-1.82], I(2) = 25%) polymorphisms and a trend that did not reach the statistical significance, toward a decreased risk of AAA for MMP2 (AAA patients n = 1090, controls n = 1077: OR = 0.83 [95% CI = .60-1.15], I(2) =7 1%) and ELN (AAA patients n = 904, controls n = 1069: OR = 0.79 [95% CI = .53-1.18], I(2) = 72%) polymorphisms. These findings suggest that polymorphisms in MMP2, MMP3, MMP-13, and ELN genes may independently contribute to the pathogenesis of AAA.

Genetische Risikofaktoren für schizophrene Erkrankungen

The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. Schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes.

Review article: diabetes, genetics and ethnicity

The prevalence of insulin resistance and diabetes has increased in the past decades at an alarming rate in all Western countries and in those countries which are adopting a 'western life style'. This trend suggests the impact of environmental factors such as diet, obesity and physical activity on the pathogenesis of diabetes. However it is known that the prevalence and variation of prevalence, as consequence of environmental changes, it is different in various ethnic groups. Studies conducted in multiethnic populations suggest that some ethnic groups, such as Hispanics or Asian Indians, might have a particular predisposition, possibly on genetic basis, to develop insulin resistance and diabetes, when exposed to adverse conditions. According to the 'thrifty gene' hypothesis, a clustering of different genetic defects or polymorphisms, developed as genetic advantage in some populations, could predispose some ethnic groups to insulin resistance and diabetes in presence of an increased food supply. Multiple mutations, associated with small changes in insulin sensitivity, when combined, may induce a significant reduction in insulin sensitivity. This review deals with the possible relevance of genetic factors in the expression of insulin resistance and diabetes in relation to ethnicity.

Cerebral dysfunction, neurologic symptoms and recurrent delinquency--I. Review of the literature

Men with polytropic and persistent delinquency constitute a core group of criminal offenders. Criminological research could establish a set of social characteristics for this group, but psychiatric, neurological and neuropsychological variables with importance to the formation of delinquent recidivism are rarely investigated. In this study we give a survey of the results concerning the relevance of genetic factors for delinquent behaviour. Then we review the development of the "minimal brain disorder" conception and its changes to "hyperkinetic syndrome", "attention deficit disorder" and to specific developmental disorders, which are all associated with a higher degree of conduct disorders and delinquent behaviour. We finally discuss the stability and relevance of nonfocal neurological ("soft") signs and depict a tentative model of the relations between the influential factors. Part II of this study (66) gives an account of the results of the "Heidelberg Delinquency Study" in this area.

The genetics of childhood cancer

INTRODUCTION OVERWHELMING EVIDENCE implicates a complex interaction of abnormal intraand extracellular genetic events in the development of cancer. Neoplasia is a dynamic multistep process that ultimately drives a normal cell to proceed towards malignant transformation. The number of steps, their chronological order and the nature of particular genetic events specific to each tumour type are objectives of ongoing studies. Childhood cancers are unique in that their early age of onset suggests that underlying inherited constitutional genetic defects might provide a strong predisposing influence. For example, childhood cancers are common in single-gene disorders, such as neurofibromatosis type I and Beckwith-Wiedemarm syndrome, as well as in DNA breakage sydromes, including Fanconi’s anaemia and Bloom’s syndrome, in which the ability to repair damaged DNA is impaired as a result of deficiencies or defects of specific inherited repair enzymes. The pedigree of a child with cancer often demonstrates other affected family members, suggesting that vertical transmission of a defective or altered gene from generation to generation plays a causative role in cancer development. Various poorly-defined environmental factors may interact with the underlying genetic background of the host to determine the precise phenotype of such childhood and familial cancers. Nevertheless, in only a small percentage of cases of human cancer does evidence for hereditary or familial influences exist 111. This review outlines the roles of the “dominant” oncogenes and “recessive” tumour suppressor genes known to be involved in the formation of paediatric malignancies. Table 1 indicates well characterised genes associated with paediatric tumours. In addition, the genetics of familial cancer syndromes and genomic imprinting will be discussed as they apply to childhood cancer. The clinical relevance of genetic factors in the aetiology of paediatric cancer is discussed, as well as issues surrounding the role of predictive genetic testing for this population of cancer patients. Initiation, promotion, progression and metastasis represent the stepwise stages of human carcinogenesis. At each of these stages, one or several genetic events occur in what are thought to be critical normal cellular growth regulatory pathways. Knudson’s original “two-bit” hypothesis of carcinogenesis [2] suggests that both alleles of one gene need to be altered for turnour formation to occur in tissues with relatively few genetic checkpoints and controls, and the paradigm for this hypothesis is retinoblastoma. The model has now been expanded to

The effects of demographic transition on the opportunity for selection: changes during the last century in Italy

The index of opportunity for selection proposed by Crow has been calculated for the Italian population during the last century. The evolution of its two components, the pre-reproductive mortality and the variance in fertility, has been also analysed and compared with similar data for the United States. The results clearly show the relevance of socio-economic changes to the evolution of selective patterns in our species; in particular the relative incidence of mortality and fertility to selection intensity: the total index has in fact been reduced by 75% during the last century, the relative amount due to fertility increasing from 57 to 89%. The probable different relevance of genetic factors in the two components has also been discussed.

Notes on a Bit of Psychological Nonsense: “Race Differences in Intelligence”

The case for race differences in intelligence, particularly with respect to that reported between the white and black populations of our country, is reviewed along four major lines: (a) the framing of the question, (b) the choice of Ss to be tested, (c) the instrument used to measure intelligence, and (d) the concept of “intelligence” itself. The relevance of genetic factors to the alleged difference is weighed. The conclusion reached is that on all psychological counts the issue of “race differences in intelligence” is a nonsensical one.

Notes on a Bit of Psychological Nonsense: “Race Differences in Intelligence”

The case for race differences in intelligence, particularly with respect to that reported between the white and black populations of our country, is reviewed along four major lines: (a) the framing of the question, (b) the choice of Ss to be tested, (c) the instrument used to measure intelligence, and (d) the concept of “intelligence” itself. The relevance of genetic factors to the alleged difference is weighed. The conclusion reached is that on all psychological counts the issue of “race differences in intelligence” is a nonsensical one.

The Mental Deficiencies

T HE modern concept of mental deficiency derives its connotations from various disciplines. Sociology contributed from the earliest times the observation that there exists a group of individuals who, since childhood, are socially incompetent and incapable of adequate self-support. With the development of mental testing which permitted of an estimation of various grades of intelligence, the concept gained recognition that social incompetence is often associated with defective intellectual development. Following scientific advances in the field of medicine, it became increasingly clear that some diseases occurring during fetal life or in infancy may eventually result in lesions of the brain with consequent mental defect. Finally, with the advent of the science of human genetics the relevance of genetic factors in determining deviations of intelligence was made understandable.