A bloodâ based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial

IntroductionMultinutrient approaches may produce more robust effects on brain health through interactive qualities. We hypothesized that a bloodâ based nutritional risk index (NRI) including three biomarkers of diet quality can explain cognitive trajectories in the multidomain Alzheimer prevention trial (MAPT) over 3â years.MethodsThe NRI included erythrocyte nâ 3 polyunsaturated fatty acids (nâ 3 PUFA 22:6nâ 3 and 20:5nâ 3), serum 25â hydroxyvitamin D, and plasma homocysteine. The NRI scores reflect the number of nutritional risk factors (0â 3). The primary outcome in MAPT was a cognitive composite Z score within each participant that was fit with linear mixedâ effects models.ResultsEighty percent had at lease one nutritional risk factor for cognitive decline (NRI â ¥1: 573 of 712). Participants presenting without nutritional risk factors (NRI=0) exhibited cognitive enhancement (β = 0.03 standard units [SU]/y), whereas each NRI point increase corresponded to an incremental acceleration in rates of cognitive decline (NRIâ 1: β = â 0.04 SU/y, P = .03; NRIâ 2: β = â 0.08 SU/y, P < .0001; and NRIâ 3: β = â 0.11 SU/y, P = .0008).DiscussionIdentifying and addressing these wellâ established nutritional risk factors may reduce ageâ related cognitive decline in older adults; an observation that warrants further study.Highlightsâ ¢Multiâ nutrient approaches may produce more robust effects through interactive propertiesâ ¢Nutritional risk index can objectively quantify nutritionâ related cognitive changesâ ¢Optimum nutritional status associated with cognitive enhancement over 3â yearsâ ¢Suboptimum nutritional status associated with cognitive decline over 3â yearsâ ¢Optimizing this nutritional risk index may promote cognitive health in older adultsPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152935/1/trc2jtrci201911004.pd

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] ¼ 0.99, 95% confidence interval [CI] ¼ 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc¼ 0.79, 95% CI ¼ 0.69 to 0.91; HRc¼ 0.70, 95% CI ¼ 0.59 to 0.82; HRc¼ 0.50, 95% CI ¼ 0.40 to 0.63, for 2, 3, and 4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend ¼ .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] ¼ 1.69, 95% CI ¼ 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc ¼ 1.33, 95% CI ¼ 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc¼ 0.72, 95% CI ¼ 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Place de l'éducation thérapeutique, dans une approche dyadique, sur la qualité de vie du patient atteint de maladie d'Alzheimer et son aidant

Les stratégies non pharmacologiques sont au devant de la prise en charge de la maladie d'Alzheimer (MA) et parmi elles, les interventions psychoeducationnelles. Nous avons émis l'hypothèse qu'une intervention d'Education Thérapeutique (ETP) adressée à la dyade pourrait avoir un impact positif sur la qualité de vie du patient et mené un essai pour la tester. Les objectifs généraux étaient d'évaluer l'efficacité d'une ETP adressée à la dyade sur la qualité de vie du patient atteint de MA et sur le bien-être de l'aidant (fardeau et qualité de vie) mais aussi de mieux caractériser les sous populations cibles et les particularités des dyades pour concevoir de futures interventions. Nous avons aussi souhaité identifier des facteurs associés à l'entrée en EHPAD, chez chaque membre de la dyade. THERAD est un essai monocentrique, randomisé et contrôlé évaluant l'impact de l'ETP sur la qualité de vie du patient atteint de MA à domicile, chez 196 dyades. L'intervention était un programme d'ETP. Le critère de jugement principal était la qualité de vie du patient heteroevaluée par l'aidant, à 2 mois sur l'échelle de qualité de vie QOL (Quality of life) de Logsdon. Les critères de jugement secondaires étaient la qualité de vie du patient autoévaluée, les troubles du comportement (NPI), le fardeau de l'aidant (Zarit), la qualité de vie de l'aidant (échelle NHP) à 6 mois. Nous avons réalisé une analyse en intention de traiter et per protocole dans THERAD. Des analyses en sous-groupes ont été faites pour cibler les sous-populations d'aidants d'intérêt (genre, statut, fardeau). Nous avons aussi caractérisé 153 aidants dans une cohorte de 1711 sujets âgés (> 65 ans) et identifié des facteurs associés à l'entrée en EHPAD dans THERAD à 24 mois, par une analyse multivariée. Nous ne mettons pas en évidence de différence significative sur la qualité de vie du patient rapportée par l'aidant à 2 mois mais une différence significative sur la qualité de vie autodéclarée à 2 mois et 6 mois, sans autres résultats significatifs (art1). Nous retrouvons un effet significatif de l'intervention sur la qualité de vie du patient évaluée par l'aidant à 6 et 12 mois dans le sous-groupes de fardeau élevé > 40 (vs < = 20) et sur la qualité de vie du patient évaluée par l'aidant à 2 mois dans le sous-groupe de fardeau modéré 20-40 (vs < = 20). Il n'y a pas d'autre résultat significatif dans les sous-groupes étudiés (art1). Chez 153 aidants parmi 1711 sujets âgés, l'âge moyen, les comorbidités et le score de fragilité ne sont pas signitifcativement différents entre aidants et non aidants Les hommes sont plus représentés chez les aidants, plus autonomes, avec de meilleures performances physiques, cognitives et nutritionnelles. Une plus importante consommation d'alcool est trouvée chez les aidants (art2). Dans ces dyades, 5 facteurs prédictifs d'entrée en EHPAD ont été trouvés : un haut niveau socio culturel du patient, un fardeau élevé de l'aidant, le statut d'aidant " enfant " et pour le patient, le fait d'être dépendant et une desinhinbition. L'intervention n'est identifiée comme un facteur prédictif. Certains facteurs modifiables pourraient être la cible d'interventions d'ETP ou permettre d'identifier des sous-groupes (aidants enfants) (art3). La qualité de vie du patient n'est pas améliorée par l'ETP, lorsqu'elle est évaluée par l'aidant mais significativement améliorée quand autoévaluée par le patient. Ce résultat souligne l'intérêt d'une double perspective et la nécessité d'efforts méthodologiques limitant les biais. Il invite à concevoir des interventions sur des populations ciblées de patients et d'aidants (selon le niveau de fardeau et/ou le statut aidant/enfant). Le fardeau pourrait être la cible d'interventions éducatives visant à l'amélioration de la qualité du malade mais aussi visant le maintien à domicile, car il associé à l'entrée en EHPAD. C'est le fait d'être un aidant enfant qui est associé à l'entrée en EHPAD, sous- groupe potentiel d'intérêt. Ce type d'intervention reste pertinent, à la condition, soit, de mieux cibler les sous populations d'intérêt et de choisir, pour elles, un critère de jugement pertinent, soit en l'intégrant à une offre multidimensionnelle, si l'on veut poursuivre l'amélioration de qualité de vie des deux membres de la dyade. L'approche dyadique qui permet de considérer le malade comme un sujet de soin, nous semble essentielle.The lack of pharmacological treatment leads nonpharmacological therapies at the forefront of therapeutic strategies in Neurodegenerative diseases such as Alzheimer's disease (AD). Among them psychoeducational interventions are efficient. We hypothesized that a Therapeutic Patient Education (TPE) programme, using a dyadic approach, could have a positive impact on the patient's quality of life (QOL) and conducted a trial to test it. Our objectives were to assess the efficacy of a TPE programme adressed to the dyad (caregiver/patient) on the AD patient's QOL proxy-reported by caregiver, its impact on the caregiver's well-being (QOL, burden), and to better characterize subgroups of caregivers and, lastly, identify predictors of nursing home placement (NHP) among dyads. THERAD is a monocentric, randomized, controlled trial assessing the effect of a 2-month educational programme in AD patients (MMSE 11-26) among 196 dyads on patient's QOL caregiver-reported at 2 months. The intervention was a TPE programme (validated tools, format and methods. The primary outcome was the patient's QOL caregiver reported at 2 months. Secondary outcomes were : self-reported patient QOL (same scale), autonomy, behavioural and psychological symptoms (NPI), and caregiver QOL (NHP) and burden (Zarit) were secondary outcomes at 6 months. We performed an intention to treat analysis and sensitivity analysis in the THERAD per protocol population. Sub-group analysis were made (on gender, status, burden) on every outcomes (primary and secondary). A descriptive analysis of 153 caregivers (> 65 years) was made in a cohort of 1711 older adults from an ambulatory unit. We identified predictors of NHP in THERAD at 24 months by a multivariate analysis. We did not report any significant difference in caregiver-reported patients' QOL at 2 months but a significant one in self-reported patients' QOL at 2 and 6 months. No significant results on secondary outcomes(art1). In the sub-group of exhausted caregivers (burden>40vs 65) the mean age, level of comorbidities and frailty scores were the same in caregivers and non-caregivers. Men were most represented among caregivers. Caregivers were more independent, with greater physical performance, cognitive and nutritional. A higher alcohol consumption was found among caregivers (art2). Five independent predictors of NHP from multivariate analysis: a higher patient education level, a high caregiver burden, being a child as caregiver status, loss of autonomy and disinhibition. No effect of the intervention. Some modifiable factors could be the target of future interventions (Burden), including TPE, or criteria to define sub-groups of interest (art3). The caregiver did not report any improvement in the patient's QOL after a dyadic TPE, however the patient perceived one. This contrasted result underlines the interest of a double perspective and the need of methodological strains to limit bias. Our results emphasize the need to design dyadic interventions on target subpopulations of patients and/or caregivers according to the level of burden, the status (child vs spouse) The caregiver burden could be the target of TPE interventions aiming at improving the patient's QOL but also pursuing the " home choice " of dyads, because a high burden is associated with NHP. Old caregivers are probably weakened by the caregiver role besides it is being a child that is associated with NHP. There is a need to target subpopulation or to include this intervention in a multicomponent strategy, to pursue the aim of improving the dyad's QOL. The dyadic approach is essential, the AD patient being considered as a subject of care