Mammographic density (MD) is one of the strongest known breast cancer risk factors. Twin studies have suggested that a large part of the variation in MD is genetically determined. We hypothesized ...that breast cancer susceptibility variants may affect MD, and that their effects may be modified by nongenetic factors.
We assessed MD, using a computer-assisted method, on 2,348 postmenopausal Caucasian women (50-69 years) who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006-07. We used linear regression (additive models) to determine the association between each SNP and MD, adjusting for age, body mass index (BMI), and study. We evaluated MD associations with 17 established breast cancer SNPs, overall, and by strata defined by non-genetic factors.
Two variants, 6q25.1-rs9383938 and TXNRD2-rs8141691, were statistically significantly associated with percent MD (P = 0.019 and 0.03, respectively), with the 6q25.1-rs9383938 association being consistent with the SNP effect on breast cancer risk. The effect of 6q25.1-rs3734805 on percent MD varied between parous and nulliparous women (Pinteraction = 0.02), whereas the effects of 9q31.2-rs865686 and MRPS30:FGF10-rs4415084 differed across strata of BMI (Pinteraction = 0.01 and 0.005, respectively). There was no evidence of effect modification by estrogen and progestin therapy use or alcohol consumption.
This study provides novel evidence of shared genetic risk factors between MD and breast cancer and of possible MD genetic-environmental interactions.
Although the results may be chance findings, they nevertheless highlight the need to investigate interactions with nongenetic factors in studies on the genetics of MD.
Understanding the interplay between trauma-related psychological mechanisms and psychotic symptoms may improve the effectiveness of interventions for post-traumatic stress reactions in psychosis. ...Network theory assumes that mental health problems persist not because of a common latent variable, but from dynamic feedback loops between symptoms, thereby addressing the heterogeneous and overlapping nature of traumagenic and psychotic diagnoses. This is a proof-of-concept study examining interactions between post-traumatic stress symptoms, which were hypothesized to reflect trauma-related psychological mechanisms, and auditory hallucinations and delusions.
Baseline data from two randomised controlled trials (N = 216) of trauma-focused therapy in people with post-traumatic stress symptoms (87.5% met diagnostic criteria for PTSD) and psychotic disorder were analysed. Reexperiencing, hyperarousal, avoidance, trauma-related beliefs, auditory hallucinations and delusional beliefs were used to estimate a Gaussian graphical model along with expected node influence and predictability (proportion of explained variance).
Trauma-related beliefs had the largest direct influence on the network and, together with hypervigilance, were implicated in the shortest paths from flashbacks to delusions and auditory hallucinations.
These findings are in contrast to previous research suggesting a central role for re-experiencing, emotional numbing and interpersonal avoidance in psychosis. Trauma-related beliefs were the psychological mechanism most associated with psychotic symptoms, although not all relevant mechanisms were measured. This work demonstrates that investigating multiple putative mediators may clarify which processes are most relevant to trauma-related psychosis. Further research should use network modelling to investigate how the spectrum of traumatic stress reactions play a role in psychotic symptoms.
The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol ...consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case‐control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58‐1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20‐0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26‐0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self‐reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.
We observed a significant decreased risk among carriers of one or both Lys alleles of rs671 for invasive mucinous ovarian cancer and for invasive and borderline mucinous tumors. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype.
Summary
Little is known about the types and numbers of mutations that may accumulate in normal human cells with age. Such information would require obtaining enough DNA from a single cell to ...accurately carry out reliable analysis despite extensive amplification; and complete genomic coverage under these circumstances is difficult. We have compared colon crypts, which are putatively clonal and contain ~2000 cells each, to determine how much somatic genetic variation occurs in vivo (without ex vivo cell culturing). Using high‐density SNP microarrays, we find that chromosome deletions, duplications, and gene conversions were significantly more frequent in colons from the older individuals. These changes affected lengths ranging from 73 kb to 46 Mb. Although detection requires progeny of a single mutant stem cell to reach niche dominance over neighboring stem cells, none of the deletions appear likely to confer a selective advantage. Mutations can become fixed randomly during stem cell evolution through neutral drift in normal human crypts. The fact that chromosomal changes are detected in individual crypts with increasing age suggests that either such changes accumulate with age or single stem cell dominance increases with age, and the former is more likely. This progressive genome‐wide divergence of human somatic cells with age has implications for aging and disease in multicellular organisms.
Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell‐mediated chromosome transfer and expression microarray analysis ...identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty‐three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer HetOR = 1.42 (1.15–1.74) and the HomOR = 1.63 (1.10–1.42), p‐trend = 0.0002 and HetOR = 0.97 (0.80–1.17), HomOR = 0.74 (0.58–0.93), p‐trend = 0.009, respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele‐specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele‐specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.
In all, 80% of antenatal karyotypes are generated by Down's syndrome screening programmes (DSSP). After a positive screening, women are offered prenatal foetus karyotyping, the gold standard. ...Reliable molecular methods for rapid aneuploidy diagnosis (RAD: fluorescence in situ hybridization (FISH) and quantitative fluorescence PCR (QF-PCR)) can detect common aneuploidies, and are faster and less expensive than karyotyping.In the UK, RAD is recommended as a standalone approach in DSSP, whereas the US guidelines recommend that RAD be followed up by karyotyping. A cost-effectiveness (CE) analysis of RAD in various DSSP is lacking. There is a debate over the significance of chromosome abnormalities (CA) detected with karyotyping but not using RAD. Our objectives were to compare the CE of RAD versus karyotyping, to evaluate the clinically significant missed CA and to determine the impact of detecting the missed CA. We performed computer simulations to compare six screening options followed by FISH, PCR or karyotyping using a population of 110948 pregnancies. Among the safer screening strategies, the most cost-effective strategy was contingent screening with QF-PCR (CE ratio of $24084 per Down's syndrome (DS) detected). Using karyotyping, the CE ratio increased to $27898. QF-PCR missed only six clinically significant CA of which only one was expected to confer a high risk of an abnormal outcome. The incremental CE ratio (ICER) to find the CA missed by RAD was $66608 per CA. These costs are much higher than those involved for detecting DS cases. As the DSSP are mainly designed for DS detection, it may be relevant to question the additional costs of karyotyping.
Inducible nitric oxide (NO) synthase (iNOS, encoded by NOS2A) produces NO in response to environmental stimuli, which can result in nitrosative stress. Because nitrosative stress affects respiratory ...health, it was hypothesised that variants in NOS2A are associated with asthma incidence and lung function growth during adolescence.
In this prospective study, spirometric testing was performed at school and a presence or absence of asthma was ascertained annually by questionnaire among children participating in the Southern California Children's Health Study. 24 single nucleotide polymorphisms (SNPs) of the NOS2A region (with seven promoter SNPs in one haplotype block), spanning 20 kb upstream and 10 kb downstream were genotyped. Association between the NOS2A region and asthma or lung function growth was tested using genetic block-specific principal component and haplotype analyses. This study was restricted to children with Latino and Caucasian ancestry for analyses of both asthma (n=1596) and lung function growth (n=2108).
A pair of "yin-yang" haplotypes in the promoter region showed strong association with new-onset asthma and lung function growth. The "yin" haplotype (h0111101) was associated with 44% increased asthma risk (p=0.003) and reduced forced expiratory volume in 1 s (FEV(1)) growth from 10 to 18 years of age (-29.46 ml, p=0.07), whereas the "yang"(h1000010) haplotype was associated with 23% reduced asthma risk (p=0.13) and better FEV(1) growth (43.84 ml, p=0.01). Furthermore, the increased asthma risk associated with h0111101 was restricted to children with the GSTM1 "null" genotype (interaction p=0.002, HR 1.89, 95% CI 1.34 to 2.60).
Common haplotypes in the NOS2A promoter are associated with new-onset asthma and lung function growth. These effects are stronger in adolescents with the GSTM1 "null" genotype.
PDF
