Organ aging signatures in the plasma proteome track health and disease.

Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

Biological Age Acceleration and Motoric Cognitive Risk Syndrome.

OBJECTIVE: Motoric cognitive risk (MCR) syndrome, a predementia syndrome characterized by slow gait and subjective cognitive concerns, is associated with multiple age-related risk factors. We hypothesized that MCR is associated with biological age acceleration. We examined the associations of biological age acceleration with MCR, and mortality risk in MCR cases. METHODS: Biological age was determined using proteomic and epigenetic clocks in participants aged 65 years and older in the LonGenity study (N = 700, females = 57.9%) and Health and Retirement Study (HRS; N = 1,043, females = 57.1%) cohorts. Age acceleration (AgeAccel) was operationally defined as the residual from regressing predicted biological age (from both clocks separately) on chronological age. Association of AgeAccel with incident MCR in the overall sample as well as with mortality risk in MCR cases was examined using Cox models and reported as hazard ratios (HRs). RESULTS: AgeAccel scores derived from a proteomic clock were associated with prevalent MCR (odds ratio adjusted for age, gender, education years, and chronic illnesses [aOR] = 1.36, 95% confidence interval [CI] = 1.09-1.71) as well as predicted incident MCR (HR = 1.19, 95% CI = 1.00-1.41) in the LonGenity cohort. In HRS, the association of AgeAccel using an epigenetic clock with prevalent MCR was confirmed (aOR = 1.47, 95% CI = 1.16-1.85). Participants with MCR and accelerated aging (positive AgeAccel score) were at the highest risk for mortality in both LonGenity (HR = 3.38, 95% CI = 2.01-5.69) and HRS (HR = 2.47, 95% CI = 1.20-5.10). INTERPRETATION: Accelerated aging predicts risk for MCR, and is associated with higher mortality in MCR patients. ANN NEUROL 2023;93:1187-1197.

Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors.

BACKGROUND: Intracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture. METHODS: Functionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out. RESULTS: Pro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA. CONCLUSIONS: The study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture.

Plasma proteomic profile of abdominal obesity in older adults.

OBJECTIVE: This study examines the plasma proteomic profile of abdominal obesity in older adults. METHODS: The association of abdominal obesity (waist circumference [WC]) with 4265 plasma proteins identified using the SomaScan Assay was examined in 969 Ashkenazi Jewish participants (LonGenity cohort), aged 65 years and older (mean [SD] age 75.7 [6.7] years, 55.4% women), using regression models. Pathway analysis, as well as weighted correlation network analysis, was performed. WC was determined from the proteome using elastic net regression. RESULTS: A total of 480 out of 4265 proteins were associated with WC in the linear regression model. Leptin (ß [SE] = 12.363 [0.490]), inhibin ß C chain (INHBC; ß [SE] = 24.324 [1.448]), insulin-like growth factor-binding protein 2 (IGFBP-2; ß [SE] = -12.782 [0.841]), heparan-sulfate 6-O-sulfotransferase 3 (H6ST3; ß [SE] = -39.995 [2.729]), and matrix-remodeling-associated protein 8 (MXRA8; ß [SE] = -27.101 [1.850]) were the top proteins associated with WC. Cell adhesion, extracellular matrix remodeling, and IGF transport pathways were the top enriched pathways associated with WC. WC signature determined from plasma proteins was highly correlated with measured WC (r = 0.80) and was associated with various metabolic and physical traits. CONCLUSIONS: The study unveiled a multifaceted plasma proteomic profile of abdominal obesity in older adults, offering insights into its wide-ranging impact on the proteome. It also elucidated novel proteins, clusters of correlated proteins, and pathways that are intricately associated with abdominal obesity.

GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures.

OBJECTIVE: Several antiepileptic drugs (AEDs) are known to target the GABA(A) receptor through positive allosteric modulation of the receptors, thereby enhancing GABA(A) receptor-mediated inhibition. The large diversity of GABA(A) receptors has been reported in the central nervous system; some of these have been implicated in epilepsy susceptibility and AED resistance, which we aimed to examine. MATERIALS AND METHODS: We investigated the association of single-nucleotide polymorphisms in GABA(A) receptor subunit subtype genes namely; rs2279020 (GABRA1), rs3219151 (GABRA6), rs2229944 (GABRB2), and rs211037 (GABRG2) with predisposition to epilepsy and AED resistance. This was assessed in three cohorts of ethnically matched South Indian ancestry: mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype of AED-resistant epilepsy syndrome), juvenile myoclonic epilepsy (prototype of AED-responsive epilepsy syndrome), and nonepilepsy controls. RESULTS: A significant allelic (P=0.0006, odds ratio=1.6, 95% confidence interval=1.22-2.08) and genotypic (P=0.001) association of a synonymous variant in GABRG2, rs211037 (Asn196Asn) was observed with epilepsy irrespective of its phenotype, that is, MTLE-HS or juvenile myoclonic epilepsy. However, this association was not retained in epilepsy patients with a history of febrile seizures. The GABA(A) receptor subunit subtype genes were not found to have any association with AED resistance. In-silico analysis indicated that rs211037 plays a significant role in the transcriptional regulation and splicing regulation. CONCLUSION: We could substantiate that among the GABA(A) receptor subunit gene cluster polymorphisms, the GABRG2, rs211037 predisposes susceptibility to epilepsy, irrespective of its phenotype, but not to AED resistance.

Lack of association of lysyl oxidase (LOX) gene polymorphisms with intracranial aneurysm in a south Indian population.

Intracranial aneurysm (IA) accounts for 85 % of haemorrhagic stroke and is mainly caused due to weakening of arterial wall. Lysyl oxidase (LOX) is a cuproenzyme involved in cross linking structural proteins collagen and elastin, thus providing structural stability to artery. Using a case-control study design, we tested the hypothesis whether the variants in LOX gene flanking the two LD block, can increase risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. SNPs were genotyped by fluorescence-based competitive allele-specific PCR (KASPar) chemistry. We selected 200 radiologically confirmed aneurysmal cases and 235 ethnically and age and gender matched controls from the Dravidian Malayalam speaking population of South India. We observed marked interethnic differences in the genotype distribution of LOX variants when compared to Japanese and African populations. However, there was no significant association with any of the LOX variants with IA. This study also could not observe any significant role of LOX polymorphisms in influencing IA either directly or indirectly through its confounding factors such as hypertension and gender in South Indian population.

Frailty Resilience Score: A Novel Measure of Frailty Resilience Associated With Protection From Frailty and Survival.

Frailty is characterized by increased vulnerability to disability and high risk for mortality in older adults. Identification of factors that contribute to frailty resilience is an important step in the development of effective therapies that protect against frailty. First, a reliable quantification of frailty resilience is needed. We developed a novel measure of frailty resilience, the Frailty Resilience Score (FRS), that integrates frailty genetic risk, age, and sex. Application of FRS to the LonGenity cohort (n = 467, mean age 74.4) demonstrated its validity compared to phenotypic frailty and its utility as a reliable predictor of overall survival. In a multivariable-adjusted analysis, 1-standard deviation increase in FRS predicted a 38% reduction in the hazard of mortality, independent of baseline frailty (p < .001). Additionally, FRS was used to identify a proteomic profile of frailty resilience. FRS was shown to be a reliable measure of frailty resilience that can be applied to biological studies of resilience.

Epidemiology of Motoric Cognitive Risk Syndrome in the Kerala Einstein Study: Protocol for a Prospective Cohort Study.

BACKGROUND: The southern India state of Kerala has among the highest proportion of older adults in its population in the country. An increase in chronic age-related diseases such as dementia is expected in the older Kerala population. Identifying older individuals early in the course of cognitive decline offers the best hope of introducing preventive measures early and planning management. However, the epidemiology and pathogenesis of predementia syndromes at the early stages of cognitive decline in older adults are not well established in India. OBJECTIVE: The Kerala Einstein Study (KES) is a community-based cohort study that was established in 2008 and is based in the Kozhikode district in Kerala state. KES aims to establish risk factors and brain substrates of motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by the presence of slow gait and subjective cognitive concerns in individuals without dementia or disability. This protocol describes the study design and procedures for this KES project. METHODS: KES is proposing to enroll a sample of 1000 adults ≥60 years old from urban and rural areas in the Kozhikode district of Kerala state: 200 recruited in the previous phase of KES and 800 new participants to be recruited in this project. MCR is the cognitive phenotype of primary interest. The associations between previously established risk factors for dementia as well as novel risk factors (apathy and traumatic brain injury) and MCR will be examined in KES. Risk factor profiles for MCR will be compared between urban and rural residents as well as with individuals who meet the criteria for mild cognitive impairment (MCI). Cognitive and physical function, medical history and medications, sociodemographic characteristics, lifestyle patterns, and activities of daily living will be evaluated. Participants will also undergo magnetic resonance imaging and electrocardiogram investigations. Longitudinal follow-up is planned in a subset of participants as a prelude to future longitudinal studies. RESULTS: KES (2R01AG039330-07) was funded by the US National Institutes of Health in September 2019 and received approval from the Indian Medical Council of Research to start the study in June 2021. We had recruited 433 new participants from urban and rural sites in Kozhikode as of May 2023: 41.1% (178/433) women, 67.7% (293/433) rural residents, and 13.4% (58/433) MCR cases. Enrollment is actively ongoing at all the KES recruitment sites. CONCLUSIONS: KES will provide new insights into risk factors and brain substrates associated with MCR in India and will help guide future development of regionally specific preventive interventions for dementia. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49933.

Association between matrix metalloproteinases-2 and -9 gene polymorphism with basement membrane disruption in oral lichen planus: A case-control pilot study.

Objectives: This study investigated genetic polymorphism of matrix metalloproteinases (MMP) -2 and -9 in oral lichen planus (OLP) and their association with the basement membrane status. Study design: This case-control study involved genotyping of peripheral blood sample of 32 OLP patients and 106 ethnically matched controls. Single nucleotide polymorphisms (SNP) that were assessed in the groups were- MMP9 rs3918242, MMP9 rs17576 and MMP2 rs865094. Basement membrane status of the OLP biopsy samples was microscopically assessed and recorded following Periodic acid Schiff staining. Results: MMP9 rs3918242 showed significant genotypic and allelic associations between OLP subjects and controls. It was also significantly associated with intact basement membranes in OLP cases with increased frequency of 'TT' genotype and 'T' allele. No association was found with regard to MMP9 rs17576 and MMP2 rs865094. Conclusion: Biallelic substitution at the promoter region of MMP9 (rs3918242) gene may be associated with increased risk of development of OLP. It may be involved in compromising the integrity of the basement membrane junction.

Trajectories of frailty in aging: Prospective cohort study.

BACKGROUND: Emerging evidence suggests that there is significant variability in the progression of frailty in aging. We aimed to identify latent subpopulations of frailty trajectories, and examine their clinical and biological correlates. METHODS: We characterized frailty using a 41-item cumulative deficit score at baseline and annual visits up to 12 years in 681 older adults (55% women, mean age 74·6 years). Clinical risk profile and walking while talking performance as a clinical marker of trajectories were examined. Mortality risk associated with trajectories was evaluated using Cox regression adjusted for established survival predictors, and reported as hazard ratios (HR). Proteome-wide analysis was done. FINDINGS: Latent class modeling identified 4 distinct frailty trajectories: relatively stable (34·4%) as well as mild (36·1%), moderate (24·1%) and severely frail (5·4%). Four distinct classes of frailty trajectories were also shown in an independent sample of 515 older adults (60% women, 68% White, 26% Black). The stable group took a median of 31 months to accumulate one additional deficit compared to 20 months in the severely frail group. The worst trajectories were associated with modifiable risk factors such as low education, living alone, obesity, and physical inactivity as well as slower walking while talking speed. In the pooled sample, mild (HR 2·33, 95% CI 1·30-4·18), moderate (HR 2·49, 95% CI 1·33-4·66), and severely frail trajectories (HR 5·28, 95% CI 2·68-10·41) had higher mortality compared to the stable group. Proteomic analysis showed 11 proteins in lipid metabolism and growth factor pathways associated with frailty trajectories. CONCLUSION: Frailty shows both stable and accelerated patterns in aging, which can be distinguished clinically and biologically.

Genetics of frailty: A longevity perspective.

Frailty is a complex late life phenotype characterized by cumulative declines in multiple physiological systems that increases the risk for disability and mortality. The biological changes associated with aging are risk factors for frailty as well as for complex diseases; whereas longevity is assumed to be an outcome of protective biological mechanisms. Understanding the interplay between biological alterations associated with aging and protective mechanisms associated with longevity in the context of frailty may help guide development of interventions to increase healthspan and promote successful aging. The complexity of these phenotypes and relatively low heritability in studies are the main roadblocks in deciphering genetic mechanisms of these age associated conditions. We review genetic research related to frailty, and discuss the possible intertwined biology of frailty and longevity.

Plasma proteomic profile of frailty.

Frailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan® assay, 4265 proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid-binding proteins, including fatty acid-binding protein (FABP) (p = 1.96 × 10-19 ) and FABPA (p = 8.10 × 10-16 ), leptin (p = 1.43 × 10-14 ), and ANTR2 (p = 7.95 × 10-20 ). Pathway analysis with the top 143 frailty-associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell-to-cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 × 10-16 ). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 × 10-16 ) than observed frailty (r = 0.37, p = 1.2 × 10-15 ). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction.

Plasma proteomic profile of age, health span, and all-cause mortality in older adults.

Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan® proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65-95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; ß[SE] = 0.0262 [0.0012]; p = 3.21 × 10-86 ), WNT1-inducible-signaling pathway protein 2 (WISP-2; ß[SE] = 0.0189 [0.0009]; p = 4.60 × 10-82 ), chordin-like protein 1 (CRDL1; ß[SE] = 0.0203[0.0010]; p = 1.45 × 10-77 ), transgelin (TAGL; ß[SE] = 0.0215 [0.0011]; p = 9.70 × 10-71 ), and R-spondin-1(RSPO1; ß[SE] = 0.0208 [0.0011]; p = 1.09 × 10-70 ), were the proteins most significantly associated with age. Weighted gene co-expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age-associated diseases and other age-related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E-16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity.

Methylation map genes can be critical in determining the methylome of intracranial aneurysm patients.

Aim: Intracranial aneurysm is often asymptomatic until the time of rupture. Elevated homocysteine is reported in vascular diseases. Identifying early events in homocysteine metabolism through methylation map genes may prevent fatality. Materials & methods: In the present study, we investigated the role of variants in methylation map genes in ethnically matched 480 individuals that can influence the homocysteine levels and promote development of aneurysm. Results: The study demonstrates that the genetic variants in folate cycle and methionine cycle genes such as MTHFR, MTRR, MTR, BHMT and DNMT1 are associated with the risk of aneurysm. Conclusion: The associated allelic variants in these genes have functional relevance and are predictive of decreased expression indicative of altered methylation levels that may result in elevated homocysteine.

Genetic basis of motoric cognitive risk syndrome in the Health and Retirement Study.

OBJECTIVE: To examine polygenic inheritance of motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by the presence of subjective cognitive complaints and slow gait. METHODS: We analyzed 4,915 individuals, age 65 years and above, with European ancestry (mean age 75.0 ± 6.8 years, 56.6% women) in the Health and Retirement Study. Polygenic scores (PGS) were calculated as weighted sums of the effect of single nucleotide polymorphisms, with effect sizes derived from genome-wide association studies. The association between PGSs of 9 phenotypes (general cognition, body mass index [BMI], mean arterial pressure, education, Alzheimer disease [AD], neuroticism, well-being, waist circumference, and depressive symptoms) and MCR as well as its key components (cognitive complaints and slow gait) were examined by logistic regression, adjusting for age, sex, education, and genetic ancestry, and reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: There were 260 prevalent MCR cases, 529 with slow gait, and 1,928 with subjective cognitive complaints. Higher PGSs for BMI (OR 1.22, 95% CI 1.07-1.39) and waist circumference (OR 1.23, 95% CI 1.07-1.40) were associated with MCR, and PGS of AD showed a suggestive association (OR 1.16, 95% CI 1.02-1.32). Higher PGS for neuroticism (OR 1.10, 95% CI 1.03-1.18) was associated with cognitive complaints, whereas higher well-being PGS (OR 0.92, 95% CI 0.87-0.98) was protective. PGS for BMI (OR 1.16, 95% CI 1.06-1.28), waist circumference (OR 1.19, 95% CI 1.08-1.31), and AD (OR 1.13, 95% CI 1.03-1.24) was associated with slow gait. CONCLUSION: Obesity-related genetic traits increase risk of MCR syndrome; further investigation is required to identify potential therapeutic targets.

Frailty and Risk of Incident Motoric Cognitive Risk Syndrome.

BACKGROUND: Frailty is highly prevalent among older adults, and associated with cognitive decline. Relationship between frailty and motoric cognitive risk syndrome (MCR), a pre-dementia syndrome characterized by the presence of subjective cognitive complaints and slow gait, is yet to be elucidated. OBJECTIVE: To examine whether frailty increases the risk of developing incident MCR. METHODS: We analyzed 641 adults, aged 65 and above, participating in the LonGenity study. Frailty was defined using a 41-point cumulative deficit frailty index (FI). MCR was diagnosed at baseline and annual follow-up visits using established criteria. Cox proportional hazard models were used to study the association of baseline frailty with incident MCR, and reported as hazard ratio (HR) with 95% confidence intervals (CI) adjusted for age, sex, and education. RESULTS: At baseline, 70 participants (10·9%) had prevalent MCR. Of the remaining 571 non-MCR participants (mean age 75.0, 57.3% women), 70 developed incident MCR (median follow-up 2.6 years). Higher frailty scores at baseline were associated with an increased risk of incident MCR (HR for each 0.01 increase in the FI: 1.07; 95% CI 1.03-1.11; p = 0.0002). The result was unchanged even after excluding mobility related or chronic illnesses items from the FI as well as accounting for reverse causation, competing risk of death, baseline cognitive status, social vulnerability, and excluding participants with mild cognitive impairment syndrome. CONCLUSIONS: Higher levels of frailty increase risk for developing MCR and suggest shared mechanisms. This association merits further study to identify strategies to prevent cognitive decline.

Association of matrix metalloproteinase 2 and matrix metalloproteinase 9 gene polymorphism in aggressive and nonaggressive odontogenic lesions: A pilot study.

CONTEXT: The exact factors that determine the biological behavior of odontogenic lesions have not been thoroughly established yet. The influence of the matrix metalloproteinases (MMPs) on the clinical behavior of these lesions was recently brought to light. AIMS: We did a pioneer study to investigate the association of MMP9 (rs3918242 [-1562 C/T] and rs17576) and MMP2 (rs243865 [-1306 C/T] and rs865094) gene polymorphisms and aggressiveness of ameloblastomas, keratocystic odontogenic tumors (KCOT) and dentigerous cysts (DC). SETTINGS AND DESIGN: A case-control study conducted in the Department of Oral Pathology and Microbiology, Government Dental College, Trivandrum and Human Molecular Genetics Laboratory, Rajiv Gandhi Institute of Biotechnology and Poojappura, Trivandrum, Kerala. SUBJECTS AND METHODS: DNA from the blood samples of histopathologically proven ameloblastoma (n = 15), KCOT (n = 11) and DC (n = 13) patients were extracted using standard protocols. Primers were designed based on the functionality and relevance for polymerase chain reaction (PCR). PCR products were analyzed by PCR-restriction fragment length polymorphism and sequencing. STATISTICAL ANALYSIS USED: Chi-square analysis was done to assess the association of gene polymorphisms among the cases and controls. RESULTS: Ameloblastomas showed a higher frequency of mutant allele (T = 0.43; P = 0.05) of MMP9 rs3918242 (-1562C/T) compared to the control population. All the cases showed a statistically significant difference in the distribution of genotype (P = 0.046) and allele (P = 0.03; odds ratio [OR] = 2.06 [1.08-3.95]) frequency of MMP2 rs2438659 (-1306C/T). KCOT samples also showed a significant association in distribution of both genotype (P = 0.01) and allele (P = 0.01 with an OR at 3.42 [1.31-8.92]) frequency, on comparison with control population. CONCLUSIONS: MMP2 rs243865 polymorphism has a plausible role in increasing the aggressiveness of ameloblastomas and KCOT compared to that of the control population. Furthermore, MMP9 rs3918242 polymorphism may contribute to the aggressive behavior of ameloblastomas.

Undulating changes in human plasma proteome profiles across the lifespan.

Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.

Genetic Insights Into Frailty: Association of 9p21-23 Locus With Frailty.

Frailty is a complex aging phenotype associated with increased vulnerability to disability and death. Understanding the biological antecedents of frailty may provide clues to healthy aging. The genome-wide association study hotspot, 9p21-23 region, is a risk locus for a number of age-related complex disorders associated with frailty. Hence, we conducted an association study to examine whether variations in 9p21-23 locus plays a role in the pathogenesis of frailty in 637 community-dwelling Ashkenazi Jewish adults aged 65 and older enrolled in the LonGenity study. The strongest association with frailty (adjusted for age and gender) was found with the SNP rs518054 (odds ratio: 1.635, 95% CI = 1.241-2.154; p-value: 4.81 × 10-04) intergenic and located between LOC105375977 and C9orf146. The prevalence of four SNPs (rs1324192, rs7019262, rs518054, and rs571221) risk alleles haplotype in this region was significantly higher (compared with other haplotypes) in frail older adults compared with non-frail older adults (29.7 vs. 20.8%, p = 0.0005, respectively). Functional analyses using in silico approaches placed rs518054 in the CTCF binding site as well as DNase hypersensitive region. Furthermore, rs518054 was found to be in an enhancer site of NFIB gene located downstream. NFIB is a transcription factor that promotes cell differentiation during development, has antiapoptotic effect, maintains stem cell populations in adult tissues, and also acts as epigenetic regulators. Our study found novel association of SNPs in the regulatory region in the 9p21-23 region with the frailty phenotype; signifying the importance of this locus in aging.