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PubMed2004

Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures.

UNLABELLED: Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR-based genotyping of lactase gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis. INTRODUCTION: Lactase deficiency is a common autosomal recessive condition resulting in decreased intestinal lactose degradation. A -13910 T/C dimorphism (LCT) near the lactase phlorizin hydrolase gene, reported to be strongly associated with adult lactase nonpersistence, may have an impact on calcium supply, bone density, and osteoporotic fractures in the elderly. MATERIALS AND METHODS: We determined LCT genotypes TT, TC, and CC in 258 postmenopausal women using a polymerase chain reaction-based assay. Genotypes were related to milk intolerance, nutritional calcium intake, intestinal calcium absorption, bone mineral density (BMD), and nonvertebral fractures. RESULTS: Twenty-four percent of all women were found to have CC genotypes and genetic lactase deficiency. Age-adjusted BMD at the hip in CC genotypes and at the spine in CC and TC genotypes was reduced by -7% to -11% depending on the site measured (p = 0.04). LCT(T/C-13910) polymorphisms alone accounted for 2-4% of BMD in a multiple regression model. Bone fracture incidence was significantly associated with CC genotypes (p = 0.001). Milk calcium intake was significantly lower (-55%, p = 0.004) and aversion to milk consumption was significantly higher (+166%, p = 0.01) in women with the CC genotype, but there were no differences in overall dietary calcium intake or in intestinal calcium absorption test values. CONCLUSION: The LCT(T/C-13910) polymorphism is associated with subjective milk intolerance, reduced milk calcium intake, and reduced BMD at the hip and the lumbar spine and may predispose to bone fractures. Genetic testing for lactase deficiency may complement indirect methods in the detection of individuals at risk for both lactose malabsorption and osteoporosis.

Age Factors↗
PubMed2004

Interacting effects of genetic predisposition and depression on adolescent smoking progression.

OBJECTIVE: The goal of the present study was to identify specific genetic associations with smoking progression in adolescents and to determine whether these genetic effects on smoking practices are potentiated by depression symptoms. METHOD: Effects of dopamine transporter (SLC6A3) and dopamine receptor (DRD2) genetic variants on smoking progression were evaluated in a cohort of 615 adolescents, including those who had never smoked, and in a subgroup including only adolescents who had been exposed to nicotine (i.e., smoked at least a puff of a cigarette) (N=292). These adolescents were followed from 9th to 11th grade. Depression symptoms were also assessed. RESULTS: In the model of adolescents with a previous smoking experience, the likelihood of progressing to a higher level of smoking by the 11th grade increased almost twofold with each additional DRD2 A1 allele. The likelihood of smoking progression with each additional A1 allele was more pronounced among adolescents with substantial depression symptoms. The model including never-smokers revealed no significant genetic effects. Neither model revealed effects of SLC6A3. CONCLUSIONS: These results provide the first evidence, to the authors' knowledge, for an association of the DRD2 A1 allele with smoking progression among adolescents. This effect is potentiated by depression symptoms. These effects appear to be specific to adolescents who have had at least some nicotine exposure (i.e., at least a puff of a cigarette).

Adolescent↗
PubMed2002

Genetic predisposition to low bone mass is paralleled by an enhanced sensitivity to signals anabolic to the skeleton.

The structure of the adult skeleton is determined, in large part, by its genome. Whether genetic variations may influence the effectiveness of interventions to combat skeletal diseases remains unknown. The differential response of trabecular bone to an anabolic (low-level mechanical vibration) and a catabolic (disuse) mechanical stimulus were evaluated in three strains of adult mice. In low bone-mineral-density C57BL/6J mice, the low-level mechanical signal caused significantly larger bone formation rates (BFR) in the proximal tibia, but the removal of functional weight bearing did not significantly alter BFR. In mid-density BALB/cByJ mice, mechanical stimulation also increased BFR, whereas disuse significantly decreased BFR. In contrast, neither anabolic nor catabolic mechanical signals influenced any index of bone formation in high-density C3H/HeJ mice. Together, data from this study indicate that the sensitivity of trabecular tissue to both anabolic and catabolic stimuli is influenced by the genome. Extrapolated to humans, these results may explain in part why prophylaxes for low bone mass are not universally effective, yet also indicate that there may be a genotypic indication of people who are at reduced risk of suffering from bone loss.

Adaptation, Physiological↗
PubMed2006

Genetic predisposition to anxiety-related behavior determines coping style, neuroendocrine responses, and neuronal activation during social defeat.

Genetic background may influence an individual's susceptibility to, and subsequent coping strategy for, an acute stressor. When exposed to social defeat (SD), rats bred for high (HAB) or low (LAB) trait anxiety, which also differ in depression-like behavior, showed highly divergent passive and active coping behaviors, respectively. HABs spent more time freezing and emitted more ultrasound vocalization calls during SD than LABs, which spent more time rearing and grooming. Although the behavioral data confirmed the prediction that heightened trait anxiety would make rats more prone to experience stress, adrenocorticotropin and corticosterone were secreted to a higher extent in LABs than in HABs. In the latter, Fos expression upon SD was enhanced in the amygdala and hypothalamic areas compared with LABs, whereas it was diminished in prefrontal and brainstem areas.

Adaptation, Psychological↗
PubMed2003

Eye birth defects in humans may be caused by a recessively-inherited genetic predisposition to the effects of maternal vitamin A deficiency during pregnancy.

Congenital malformations of the eye can cause blindness in children. They occur throughout the world and in most cases the aetiology is unknown. Linkage studies have largely been unsuccessful and the risk to siblings is generally low. Epidemiological and laboratory evidence support a hypothesis that there may be genetic (recessive) predisposition to the teratogenetic effects of mild to moderate maternal vitamin A deficiency (VAD) during pregnancy. This may explain the higher prevalence of congenital eye anomalies in a part of Asian countries, where maternal VAD is common and consanguineous marriages are popular. Other congenital malformations commonly found in association with ocular coloboma (e.g. oesophageal fistulae and heart defects in CHARGE association) may also be VAD related. Mutations in a gene involved in the cellular access to vitamin A that normally protects the tissue or embryo from natural variation in dietary vitamin A intake, could render that individual intolerant of conditions of VAD. An interaction of this kind could also explain a proportion of "sporadic" cases in locations where VAD is uncommon. If this interaction is shown to be true, there are public health implications for the prevention of blindness due to congenital eye malformations. The hypotheses proposed above are reminiscent of the research leading to the discovery that folic acid supplementation could prevent neural tube defects. However, this form of intervention would be much more difficult with vitamin A, which is itself a powerful teratogen if present in excess.

Anophthalmos↗
PubMed2006

Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae.

The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness.

Genetic Predisposition to Disease↗
PubMed2002

Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis.

Preneoplastic and neoplastic hepatocytes undergo c-Myc up-regulation and overgrowth in rats genetically susceptible to hepatocarcinogenesis, but not in resistant rats. Because c-Myc regulates the pRb-E2F pathway, we evaluated cell cycle gene expression in neoplastic nodules and hepatocellular carcinomas (HCCs), induced by initiation/selection (IS) protocols 40 and 70 weeks after diethylnitrosamine treatment, in susceptible Fisher 344 (F344) rats, and resistant Wistar and Brown Norway (BN) rats. No interstrain differences in gene expression occurred in normal liver. Overexpression of c-myc, Cyclins D1, E, and A, and E2F1 genes, at messenger RNA (mRNA) and protein levels, rise in Cyclin D1-CDK4, Cyclin E-CDK2, and E2F1-DP1 complexes, and pRb hyperphosphorylation occurred in nodules and HCCs of F344 rats. Expression of Cdk4, Cdk2, p16(INK4A), and p27(KIP1) did not change. In nodules and/or HCCs of Wistar and BN rats, low or no increases in c-myc, Cyclins D1, E, and A, and E2F1 expression, and Cyclin-CDKs complex formation were associated with p16(INK4A) overexpression and pRb hypophosphorylation. In conclusion, these results suggest deregulation of G1 and S phases in liver lesions of susceptible rats and block of G1-S transition in lesions of resistant strains, which explains their low progression capacity.

Animals↗
PubMed1994

Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I--converting enzyme gene.

In search of genetic determinants of susceptibility to diabetic nephropathy, we examined the association between DNA sequence differences at the locus of angiotensin I-converting enzyme (ACE) and renal complications in 151 insulin-dependent diabetes mellitus (IDDM) patients with a diabetes duration of 16-21 years. This nested case-control study included 77 normoalbuminuric control subjects (albumin excretion rate < 30 micrograms/min) and 74 cases with evidence of nephropathy ranging from microalbuminuria to overt proteinuria. DNA from each of these patients was genotyped at the ACE locus by a three-allele restriction fragment-melting polymorphism (RFMP) (Dde I), which we described recently, and a two-allele insertion/deletion recognized as an Xba I restriction fragment-length polymorphism, which has been shown by other investigators to be associated with serum levels of ACE and with risk of myocardial infarction. The least common allele of the Dde I RFMP was significantly more frequent among cases with nephropathy than among normoalbuminuric control subjects (12.8 vs. 4.5%, P < 0.05). The deletion in the ACE gene was also more frequent in case than in control subjects (56.1 vs. 47.4%), but the difference was not statistically significant (P < 0.25) with this sample size. To determine the independence of these associations, the two polymorphisms were analyzed jointly to identify Xba I/Dde I haplotypes. As might be expected, carriers of the Xba I/Dde I '+ =' haplotype had a fourfold risk of developing diabetic nephropathy (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.5-11.0). However, this did not explain all of the excess Xba I '+' allele among cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Screening for genetic predisposition to mutagens in cancer patients.

Both genetic and environmental factors are known to play an important role in the development of cancer. To determine whether, among individuals who develop cancers, some may have been more susceptible to the mutagenic effects of environmental agents, skin biopsies were taken from 79 cancer patients with different common types of cancers (e.g., lung, breast, bladder, colon, cervix, ovary, brain, vocal cord, uterus, skin, testis, stomach, basal cell carcinoma, leukemia, etc.). Fibroblast cultures have been established from skin explants from nearly all of the patients. The sensitivity of some of these cells as well as a number of other fibroblast strains established from "clinically normal" individuals to a battery of mutagenic agents (e.g., ethylmethane sulfonate, methylmethane sulfonate, ethidium bromide, actinomycin D, mitomycin C, bleomycin, camptothecin), which induce different kinds of DNA damage was examined. For the control group of fibroblasts, a normal range of toxicity for all of the above agents have been established. In contrast to other mutagens for which sensitivity of all of the control cell strains lay within a narrow range, large and interesting differences in sensitivity were observed for ethidium bromide. The fibroblast strains established from fetal tissue were found to be highly resistant to ethidium bromide, whereas fibroblasts from two clinically normal persons exhibited greatly enhanced sensitivity to this agent. The genetic or biochemical basis of increased sensitivity or resistance to ethidium bromide remains to be determined. The sensitivity of cells from 28 cancer patients to a number of the mutagenic agents was also examined. Most of these strains exhibited normal range of sensitivity to the mutagens; however, a few showed small but noticeable differences in sensitivity to specific agents. The fibroblast strains from cancer patients provide a useful resource to examine the genetic and metabolic factors that may be important determinants in cancer susceptibility.

Adolescent↗