Lifestyle Genomics最新文献

Background: Breast cancer (BC) is the most frequent cancer in women, driven by a combination of genetic, environmental, and lifestyle factors. Whether modifiable sleep behaviors causally affect BC risk remains unclear.

Objective: To systematically assess the causal impact of sleep-related phenotypes on overall BC and its major subtypes using two-sample Mendelian randomization (MR), and to determine whether inflammatory proteins mediate these relationships.

Methods: Inverse-variance weighted (IVW) served as the main analysis, with sensitivity and reverse-MR analyses as supporting checks. Mediation was quantified with a two-step MR design.

Results: Morning chronotype significantly reduced the risk of overall BC (OR = 0.936, 95% CI: 0.893-0.980) and luminal A subtype (OR = 0.944, 95% CI: 0.894-0.996). Short sleep duration was associated with decreased risk of overall BC (OR = 0.482, 95% CI: 0.284-0.818) and luminal A subtype (OR = 0.385, 95% CI: 0.194-0.766), whereas long sleep duration increased the risk of triple-negative BC (OR = 9.433, 95% CI: 2.419-36.775) and luminal A subtype (OR = 2.186, 95% CI: 1.111-4.302). Mediation analysis indicated that CXCL11 accounted for 22.4% of the total causal effect of short sleep duration on luminal A BC.

Conclusions: Morning chronotype confers protection against BC, whereas prolonged sleep duration elevates the risk of triple-negative and luminal A BC. CXCL11 mediates part of the protective effect of short sleep on luminal A BC. These findings provide evidence-based support for BC prevention strategies focusing on sleep optimization.

Introduction: Previous studies have reported the impact of the hypoxia inducible factor-1α (HIF1α) gene on risk of renal cell carcinoma (RCC). However, the results of these previous studies were inconsistent. Hence, this study aimed to verify the influence of single-nucleotide polymorphisms (SNPs) in the HIF1α gene and their interaction with environmental factors on RCC risk.

Methods: PCR-based restriction fragment length polymorphism was used to genotype four SNPs. Logistic regression was utilized to test the association between HIF1α SNPs and RCC risk. A generalized multifactor dimensionality reduction model was employed to evaluate the potential interaction of the four SNPs in the HIF1α gene with environmental factors.

Results: The rs11549465-CT, rs11549465-TT, and rs11549465-CT+TT genotypes were all associated with increased risk of RCC; the adjusted ORs (95% CI) were 1.74 (1.38-2.12) (CT vs. CC), 1.93 (1.47-2.43) (TT vs. CC), and 1.78 (1.41-2.18) (CT+TT vs. CC), respectively. We also found that the rs11549467-GA and rs11549467-GA+AA genotypes were associated with increased RCC risk, and adjusted ORs (95% CI) were 1.81 (1.49-2.16) (GA vs. GG), 1.79 (1.47-2.13) (GA+AA vs. GG), respectively. We found a statistically significant combination (including rs11549465 and smoking). Compared to non-smokers with the rs11549465-CC genotype, current or ever smokers with rs11549465-CT+TT genotype had the highest RCC risk; the OR (95% CI) was 3.68 (1.97-5.41).

Conclusion: This study demonstrated a significant impact of HIF1α polymorphisms on RCC risk. Additionally, this impact could be influenced by environmental factors, such as smoking status.

Introduction: Type 2 diabetes (T2D) risk factors are associated with gut microbiota dysregulation that can alter circulating metabolite levels such as bile acids (BAs) and short-chain fatty acids (SCFAs). The objective was to investigate how the high dairy (HD) (≥4 servings/day) product intake compared to adequate dairy (AD) (≤2 servings/day) intake influences the correlations between Roseburia, Faecalibacterium, Flavonifractor, as well as Verrucomicrobia and circulating BAs and SCFAs in subjects at risk of T2D.

Methods: In a randomized crossover trial, 10 hyperinsulinemic adults were randomized to HD or AD for 6 weeks separated by a 6-week washout period. Gut microbiota were measured with 16S rRNA-based high-throughput sequencing. BA profiling in plasma was performed by high-performance liquid chromatography-tandem mass spectrometry. Serum SCFAs were determined using headspace gas chromatography.

Results: No significant differences were observed in mean circulating BA or SCFA levels between AD and HD consumption. Verrucomicrobia and Flavonifractor showed positive correlations with secondary BAs following HD and AD intake, respectively. Additionally, Flavonifractor correlated positively with acetic and propionic acids after HD intake. Roseburia correlated positively with primary BAs, propionate, and butyrate after HD intake. Faecalibacterium was positively correlated with cholic acid after AD intake and with hexanoic acid after HD intake.

Conclusion: These findings suggest that HD intake may modulate microbiota-metabolite interactions without altering circulating metabolite concentrations, highlighting a potential role for dietary patterns in shaping gut-derived metabolic signals in individuals at risk of T2D.

Background: Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) have strong triglyceride-lowering and anti-inflammatory properties, and high levels of these fatty acids have been associated with reduced risk of cardiovascular disease. The synthesis of n3-LCPUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and n6-LCPUFA, arachidonic acid, share a common pathway mediated by fatty acid desaturase genes, FADS1 and FADS2. LCPUFA synthesis is regulated by both modifiable and non-modifiable factors. Of particular interest is the role of genetic variants in the FADS gene cluster, which are associated with altered FADS1 and FADS2 expression, as well as LCPUFA levels. However, the specific functional variants and the precise molecular mechanisms by which these variants regulate FADS gene expression remain to be elucidated. Variation in the FADS gene cluster is thought to have arisen through natural selection and changing dietary patterns. Available evidence suggests these variants, either individually or as a haplotype, may alter FADS gene expression by modifying DNA methylation in regulatory regions, as well as microRNA and transcription factor binding sites.

Summary: This review explores the current state of knowledge regarding the functional roles of these variants on LCPUFA synthesis and how these new insights will help support precision nutrition strategies aimed at improving an individual's n3-LCPUFA status and health.

Key messages: Identifying specific functional variants in or near the FADS gene cluster and elucidating the mechanisms by which these variants impact LCPUFA synthesis requires further investigation. However, hypothesis generating in vitro studies have revealed roles for epigenetics, non-coding RNAs, and modification of transcription factor binding sites. This knowledge will generate new insights that will help improve our understanding of the genetic basis underlying LCPUFA synthesis and how this may differ across populations.

Introduction: The AMY1 gene, which encodes salivary amylase, exhibits copy number variation (CNV) that affects starch metabolism and may influence obesity risk. This study aimed to assess AMY1 CNV among selected participants of the 2018-2019 Expanded National Nutrition Survey (ENNS), using a validated digital PCR method.

Method: The method validation was initially performed using certified reference material. Whole blood DNA was isolated from selected nutrition survey respondents who had available daily rice intake data. The daily rice intake of participants was divided into tertiles. Chi-square tests were used to compare AMY1 CNV, age, BMI, smoking and alcohol status, and other variables across daily rice intake tertiles.

Results: Data from selected ENNS participants revealed AMY1 CNV ranging from 6 to 18 copies. Higher rice intake was significantly associated with increased AMY1 CNV (p = 0.035). Lower AMY1 CNV was more prevalent among overweight and obese individuals.

Conclusion: Findings highlight gene-diet interactions and support the relevance of personalized nutrition approaches in the Philippines.

Background: Klotho, a transmembrane protein with pleiotropic antiaging properties, is increasingly recognized as a central regulator of longevity and metabolic resilience. Primarily expressed in the kidneys and brain, Klotho governs phosphate and calcium homeostasis, modulates redox signaling, and influences key metabolic pathways, including PI3K/AKT and IGF-1. Declining Klotho expression is associated with both biological and chronological aging and has been mechanistically implicated in the pathogenesis of chronic kidney disease, cardiovascular disease, neurodegeneration, and metabolic dysfunction.

Summary: Klotho expression is modifiable through diet, in preclinical and observational studies, offering a promising avenue for delaying cellular aging and preserving physiological function. Micronutrients such as magnesium, vitamin D, folate, and vitamin B12, as well as phytochemicals including sulforaphane and curcumin, have been shown to modulate Klotho expression through redox-sensitive and transcriptional mechanisms. Macronutrient balance, particularly carbohydrate quality and saturated fat intake, also plays a critical role in maintaining Klotho activity via insulin sensitivity, mitochondrial integrity, and inflammatory signaling. Inflammatory dietary profiles, quantified through tools such as the Dietary Inflammatory Index (DII), have been inversely associated with serum α-Klotho concentrations and biological age acceleration. This review critically synthesizes current knowledge on nutrient-specific and dietary pattern-level influences on Klotho, with emphasis on antioxidant, anti-inflammatory, and epigenetically active compounds. In parallel, the Klotho-FGF23 axis is examined regarding dietary calcium and phosphate regulation, highlighting the distinct effects of whole food-derived versus supplemental calcium on mineral metabolism and vascular health.

Key messages: Klotho emerges as a potential modifiable determinant with current limitations as a potential biomarker within precision nutrition strategies aimed at extending health span and attenuating age-related disease risk. Key concepts discussed include dietary factors in Klotho modulation and chronic disease prevention. Opportunities and limitations of soluble Klotho as a multifaceted biomarker of human health and longevity are highlighted.

Malignant hyperthermia (MH) is a rare but serious pharmacogenetic disorder triggered by specific anesthetic agents, leading to a rapid and often fatal hypermetabolic response. While its genetic roots-primarily involving RYR1 and CACNA1S mutations-are well documented, many susceptible individuals remain undiagnosed until they are exposed to the triggering anesthetic. Despite dantrolene being an instrumental drug in combatting MH mortality, global access remains inconsistent, and morbidity rates remains high. Current diagnostic tools are invasive and limited to specialized centers, and routine screening is rarely feasible. This review explores how recent advances in multi-omics-genomics, proteomics, metabolomics, transcriptomics, and radiomics-are reshaping our understanding of MH pathophysiology. From chronic calcium dysregulation and mitochondrial dysfunction to shifts in energy metabolism and subtle muscle changes, a complex picture is emerging. Integrative analyses reveal promising biomarkers for early detection, while CRISPR-based gene editing and machine learning offer potential pathways for future targeted interventions. Non-invasive imaging, blood-based metabolic profiling, and genomic risk prediction may soon offer safer, more effective screening tools for anesthesia planning. Ultimately, a shift from reactive crisis management to proactive risk identification could redefine how we approach MH-potentially improving patient outcomes and saving lives.

Background: Creatine is a conditionally essential nutrient integral to cellular energy homeostasis, with emerging evidence suggesting its potential role in modulating biological aging. However, associations between dietary creatine intake and epigenetic biomarkers of mortality remain unexplored.

Objective: This study investigates the relationship between dietary creatine intake and DNA methylation-derived mortality indices in U.S. adults aged 50 years and older.

Methods: Data from the NHANES 1999-2002 cycles were analyzed, including dietary creatine intake estimated from 24-hour recall interviews and DNA methylation profiles measured using the Illumina EPIC array. Epigenetic mortality predictors GrimAgeMort and GrimAge2Mort were examined in relation to creatine intake.

Results: Among 4,983 participants (mean age 67.6 ± 10.7 years), a significant inverse correlation was observed between dietary creatine and both GrimAgeMort (r = -0.041, P = 0.045) and GrimAge2Mort (r = -0.047, P = 0.019), indicating that higher creatine consumption was associated with lower epigenetic mortality risk scores. These associations persisted as statistically significant after adjustment for demographic variables and pertinent dietary factors.

Conclusions: Higher dietary creatine intake is linked to reduced biological age acceleration and mortality risk as estimated by epigenetic biomarkers. These findings highlight creatine's potential as a modifiable dietary factor promoting healthy aging and longevity. Further research is warranted to elucidate underlying mechanisms.