To assess whether plasma neurofilament light chain (NfL) levels are elevated before amyotrophic lateral sclerosis (ALS) diagnosis and to evaluate whether prediagnostic NfL levels are associated with ...metabolic alterations.
We conducted a matched case-control study nested in 3 large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study) and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels.
Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 SD increase 2.68, 95% CI 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI 0.78-1.73). A total of 21 metabolites were correlated with prediagnostic NfL levels in ALS cases (
< 0.05), but none of these remained significant after multiple comparison adjustments.
Plasma NfL levels were elevated in prediagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease.
This study provides Class II evidence that plasma NfL levels are elevated in prediagnostic ALS.
The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content ...identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetic factors play an important role in the etiology of breast cancer. We carried out a multi-stage genome-wide association (GWA) study in over 28,000 cases and controls recruited from 12 studies ...conducted in Asian and European American women to identify genetic susceptibility loci for breast cancer. After analyzing 684,457 SNPs in 2,073 cases and 2,084 controls in Chinese women, we evaluated 53 SNPs for fast-track replication in an independent set of 4,425 cases and 1,915 controls of Chinese origin. Four replicated SNPs were further investigated in an independent set of 6,173 cases and 6,340 controls from seven other studies conducted in Asian women. SNP rs4784227 was consistently associated with breast cancer risk across all studies with adjusted odds ratios (95% confidence intervals) of 1.25 (1.20-1.31) per allele (P = 3.2 x 10(-25)) in the pooled analysis of samples from all Asian samples. This SNP was also associated with breast cancer risk among European Americans (per allele OR = 1.19, 95% CI = 1.09-1.31, P = 1.3 x 10(-4), 2,797 cases and 2,662 controls). SNP rs4784227 is located at 16q12.1, a region identified previously for breast cancer risk among Europeans. The association of this SNP with breast cancer risk remained highly statistically significant in Asians after adjusting for previously-reported SNPs in this region. In vitro experiments using both luciferase reporter and electrophoretic mobility shift assays demonstrated functional significance of this SNP. These results provide strong evidence implicating rs4784227 as a functional causal variant for breast cancer in the locus 16q12.1 and demonstrate the utility of conducting genetic association studies in populations with different genetic architectures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Metabolic syndrome (MetS) is associated with a high risk of cardiovascular disease, a leading cause of death among women. MetS is a diagnosis of at least 3 of the following: high blood ...pressure, high fasting glucose, high triglycerides, high waist circumference, and low high-density lipoprotein cholesterol. Epidemiological studies suggest that endocrine disrupting chemical (EDC) exposure is positively associated with individual components of MetS, but evidence of an association between EDCs and MetS remains inconsistent. In a cross-sectional analysis within the Multiethnic Cohort Study, we evaluated the association between 4 classes of urinary EDCs (bisphenol A BPA, triclosan, parabens, and phthalates) and MetS among 1728 women. Multivariable logistic regression was used to estimate odds ratios and 95% CI for the association between tertiles of each EDC and MetS adjusting for age, body mass index (BMI), racial and ethnic group, and breast cancer status. Stratified analyses by race and ethnicity and BMI were conducted. MetS was identified in 519 (30.0%) women. We did not detect statistically significant associations of MetS with BPA, triclosan, or phthalate metabolite excretion. MetS was inversely associated with total parabens (Ptrend = .002). Although there were suggestive inverse associations between EDCs and MetS among Latino and African American women, and women with BMI < 30 kg/m2, there was no statistically significant heterogeneity in associations by race and ethnicity or BMI. These findings suggest an inverse association between parabens and MetS in larger multiethnic studies. Prospective analyses to investigate suggested differences in associations by race, ethnicity, and BMI are warranted.
Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the ...effects of adiposity on CRC are not fully understood.
We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.
In sex-specific MR analyses, higher BMI (per 4.2 kg/m
) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m
) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.
Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association ...studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted.
We ...conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided.
We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003).
Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.
We report targeted sequencing of 63 known prostate cancer risk regions in a multi-ancestry study of 9,237 men and use the data to explore the contribution of low-frequency variation to disease risk. ...We show that SNPs with minor allele frequencies (MAFs) of 0.1-1% explain a substantial fraction of prostate cancer risk in men of African ancestry. We estimate that these SNPs account for 0.12 (standard error (s.e.) = 0.05) of variance in risk (∼42% of the variance contributed by SNPs with MAF of 0.1-50%). This contribution is much larger than the fraction of neutral variation due to SNPs in this class, implying that natural selection has driven down the frequency of many prostate cancer risk alleles; we estimate the coupling between selection and allelic effects at 0.48 (95% confidence interval 0.19, 0.78) under the Eyre-Walker model. Our results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits.
A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse ...causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival.
We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.
Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years;
= 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.
Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival.
Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
Dietary indices have been related to risk for type 2 diabetes (T2D) predominantly in white populations. The present study evaluated this association in the ethnically diverse Multiethnic Cohort and ...examined four diet quality indices in relation to T2D risk, homoeostatic model assessment-estimated insulin resistance (HOMA-IR) and biomarkers of dyslipidaemia, inflammation and adipokines. The T2D analysis included 166 550 white, African American, Native Hawaiian, Japanese American and Latino participants (9200 incident T2D cases). Dietary intake was assessed at baseline using a quantitative FFQ and T2D status was based on three self-reports and confirmed by administrative data. Biomarkers were assessed about 10 years later in a biomarker subcohort (n 10 060). Sex- and ethnicity-specific hazard ratios were calculated for the Healthy Eating Index-2010 (HEI-2010), the alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED) and the Dietary Approaches to Stop Hypertension (DASH). Multivariable-adjusted means of biomarkers were compared across dietary index tertiles in the biomarker subcohort. The AHEI-2010, aMED (in men only) and DASH scores were related to a 10–20 % lower T2D risk, with the strongest associations in whites and the direction of the relationships mostly consistent across ethnic groups. Higher scores on the four indices were related to lower HOMA-IR, TAG and C-reactive protein concentrations, not related to leptin, and the DASH score was directly associated with adiponectin. The AHEI-2010 and DASH were directly related to HDL-cholesterol in women. Potential underlying biological mechanisms linking diet quality and T2D risk are an improved lipid profile and reduced systemic inflammation and, with regards to DASH alone, an improved adiponectin profile.
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