Whole genome-wide sequence analysis of long-lived families (Long-Life Family Study) identifies MTUS2 gene associated with late-onset Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. METHODS: We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aß) levels. RESULTS: We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aß42/40 ratio compared to lower amyloid. DISCUSSION: MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology. HIGHLIGHTS: Long-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults.

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10-8; rs880179, p = 4.83 × 10-8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10-5 < p < 7.35 × 10-3), of which two were replicated (p < 3.10 × 10-3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.

A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants.

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609, p = 7.13 × 10-8) that almost reached genome-wide significance and four additional loci that were suggestively significant. Among these, a novel rare variant (rs145265196) on chromosome 11 had much higher longevity allele frequencies in cases of Ashkenazi Jewish and Southern Italian ancestry compared to cases of other European ancestries. We also correlated EL-associated SNPs with serum proteins to link our findings to potential biological mechanisms that may be related to EL and are under genetic regulation. The findings from the proteomic analyses suggested that longevity-promoting alleles of significant genetic variants either provided EL cases with more youthful molecular profiles compared to controls or provided some form of protection from other illnesses, such as Alzheimer's disease, and disease progressions.

17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single-nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13), to identify associations with histological features of NAFLD and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis but decreased inflammation, ballooning, Mallory-Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy-proven NAFLD and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice-site SNP in high linkage with rs6834314 (r2 = 0.94) generates splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6-skipping and G-nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation), is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9-fold higher (P = 0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved amino acid 22-28 sequence and amino acid 71-106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. Conclusion: We demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology and identify the enzyme as a lipid droplet-associated RDH; our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.

Leukocyte Telomere Length Is Unrelated to Cognitive Performance Among Non-Demented and Demented Persons: An Examination of Long Life Family Study Participants.

OBJECTIVE: Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient dementia. METHOD: Enrolled subjects belong to the Long Life Family Study (LLFS), a multi-generational cohort study, where enrollment was predicated upon exceptional family longevity. Included subjects had valid cognitive and telomere data at baseline. Exclusion criteria were age ≤ 60 years, outlying LTL, and missing sociodemographic/clinical information. Analyses were performed using linear regression with generalized estimating equations, adjusting for sex, age, education, country, generation, and lymphocyte percentage. RESULTS: Older age and male gender were associated with shorter LTL, and LTL was significantly longer in family members than spouse controls (p < 0.005). LTL was not associated with working or episodic memory, semantic processing, and information processing speed for 1613 cognitively unimpaired individuals as well as 597 individuals with dementia or incipient dementia (p < 0.005), who scored significantly lower on all cognitive domains (p < 0.005). CONCLUSIONS: Within this unique LLFS cohort, a group of families assembled on the basis of exceptional survival, LTL is unrelated to cognitive ability for individuals with and without cognitive impairment. LTL does not change in the context of degenerative disease for these individuals who are biologically younger than the general population.

Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium.

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P =1.27 × 10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

Genetic Variants Associated with Circulating Parathyroid Hormone.

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Greater skeletal muscle fat infiltration is associated with higher all-cause mortality among men of African ancestry.

BACKGROUND: fat infiltration within and around skeletal muscle (i.e. myosteatosis) increases with ageing, is greater in African versus European ancestry men and is associated with poor health. Myosteatosis studies of mortality are lacking, particularly among African ancestry populations. METHODS: in the Tobago Health study, a prospective longitudinal study, we evaluated the association of all-cause mortality with quantitative computed tomography (QCT) measured lower leg myosteatosis (intermuscular fat (IM fat) and muscle density) in 1,652 African ancestry men using Cox proportional hazards models. Date of death was abstracted from death certificates and/or proxy. RESULTS: one hundred and twelve deaths occurred during follow-up (mean 5.9 years). In all men (age range 40-91 years), higher all-cause mortality was associated with greater IM fat (HR (95% CI) per SD: 1.29 (1.06-1.57)) and lower muscle density (HR (95% CI) per SD lower: 1.37 (1.08-1.75)) in fully adjusted models. Similar mortality hazard rates were seen in the subset of elderly men (aged ≥65 years) with greater IM fat (1.40 (1.11-1.78) or lower muscle density (1.66 (1.24-2.21)) in fully adjusted models. CONCLUSIONS: our study identified a novel, independent association between myosteatosis and all-cause mortality in African ancestry men. Further studies are needed to establish whether this association is independent of other ectopic fat depots and to identify possible biological mechanisms underlying this relationship.

AP2 suppresses osteoblast differentiation and mineralization through down-regulation of Frizzled-1.

Transcription factor activating protein 2 (AP2) plays an important role in cellular differentiation. Although profound craniofacial and long bone developmental abnormalities have been observed in AP2-knockout mice, the molecular effects of AP2 on osteoblasts are poorly defined. We demonstrated that AP2 regulates the expression of human Frizzled 1 (FZD1), a co-receptor for the Wnt signalling pathway, in human osteoblast cell lines and primary bone marrow stromal cells (BMSCs). We also identified a putative AP2-binding site in the FZD1 proximal promoter in silico and characterized this binding element further in Saos2 in vitro by ChIP, electrophoretic mobility shift and promoter reporter assays. The transcriptional repression of the FZD1 promoter by AP2 was confirmed in normal human fetal osteoblasts (hFOB). Furthermore, overexpression of AP2 resulted in a significant reduction in both differentiation and mineralization of Saos2 cells. Knockdown of FZD1 expression before AP2 up-regulation diminished the AP2-dependent inhibition of Saos2 cell differentiation and mineralization. Similarly, overexpressing FZD1 before AP2 treatment in both Saos2 and BMSCs diminished the inhibitory effect of AP2 on osteoblast differentiation and mineralization. Taken together, these results demonstrate that AP2 is a negative regulator of osteoblast differentiation and mineralization, and its inhibitory effect may be mediated in part through down-regulation of FZD1 expression.

Heritability and genetics of serum dickkopf 1 levels in African ancestry families.

The aim of the study was to determine the heritability of serum dickkopf-1 (DKK1) and its association with DKK1 polymorphisms in African ancestry subjects. Serum DKK1 was measured in 422 Afro-Caribbean men and women aged 18+ from 7 large, multi-generational families (mean family size: 60; 3,215 relative pairs). Twenty-four common single nucleotide polymorphisms (SNPs) were genotyped within an 80 kilobase-pair region encompassing the DKK1 gene. Heritability was estimated and SNPs were tested for association with serum DKK1 using variance components analysis. DKK1 mRNA expression was tested in peripheral blood of 16 individuals from each of the rs7069912 genotypes. Mean serum DKK1 was 1724.1 pg/mL and was significantly lower in women than men (P = 0.043). Residual genetic heritability of serum DKK1 was 0.4460 (P < 0.0001). Six SNPs reached nominal significance with DKK1, with rs7069912 being significant after adjustment for multiple comparisons. Two of these six SNPs represented independent association signals (rs7069912 and rs16928725), which accounted for 4.6% of the phenotypic variation in DKK1. Additionally, carriers of the rs7069912 variant had significantly greater DKK1 expression than non-carriers (P = 0.036). Serum DKK1 levels are highly heritable in the African ancestry families. Two SNPs within the DKK1 region accounted for nearly 5% of the variation in serum DKK1.

Sex differences in Alzheimer's disease blood biomarkers in a Caribbean population of African ancestry: The Tobago Health Study.

INTRODUCTION: Alzheimer's disease (AD) is increasing in the Caribbean, especially for persons of African ancestry (PAA) and women. However, studies have mostly utilized surveys without AD biomarkers. METHODS: In the Tobago Health Study (n = 309; 109 women, mean age 70.3 ± 6.6), we assessed sex differences and risk factors for serum levels of phosphorylated tau-181 (p-tau181), amyloid-beta (Aß)42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Blood samples were from 2010 to 2013 for men and from 2019 to 2023 for women. RESULTS: Women were more obese, hypertensive, and sedentary but reported less smoking and alcohol use than men (age-adjusted p < 0.04). Compared to men, women had worse levels of AD biomarkers, with higher p-tau181 and lower Aß42/40, independent of covariates (p < 0.001). In sex-stratified analyses, higher p-tau181 was associated with older age in women and with hypertension in men. GFAP and NfL did not differ by sex. DISCUSSION: Women had worse AD biomarkers than men, unexplained by age, cardiometabolic diseases, or lifestyle. Studying risk factors for AD in PAA is warranted, especially for women earlier in life.

Novel Loci (EIF4A2, ADIPOQ, TPRG1) for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change (ΔTHR) among Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Heart Study (FHS) Offspring Cohort (OS).

Aims/hypothesis: Triglyceride (TG) /High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark. Methods: Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Results: Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (p=1.58e-9) for ΔTHR; this gene locus has been reported before influencing baseline THR levels. Our GWLS found evidence for a significant linkage with a logarithm of the odds (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families (pedigree-specific LODs>0.1), we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2/ADIPOQ-rs114108468, p=5e-6, MAF=1.8%; TPRG1-rs16864075, p=3e-6, MAF=8%; accounted for ~28% and ~29% of the linkage, respectively, and 57% jointly). While the former variant was associated with EIF4A2 (p=7e-5) / ADIPOQ (p=3.49e-2) RNA transcriptional levels, the latter variant was not associated with TPRG1 (p=0.23) RNA transcriptional levels. Replication in FHS OS observed modest effect of these loci on ΔTHR. Of 188 metabolites from 13 compound classes assayed in LLFS, we observed multiple metabolites (e.g., DG.38.5, PE.36.4, TG.58.3) that were significantly associated with the variants (p<3e-4). Conclusions: our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes selected for exceptional survival and healthy aging.

Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta-analyses: The Long Life Family Study.

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10-8) and 17 TWAS genes (Bonferroni-p < 2.73 × 10-6) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA-KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer-promoter variants with kidney function-related phenotypes at p < 5 × 10-8. Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA-Europeans and TOPMed, suggesting better kidney function in healthy-aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging-related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney- and aging-related signaling pathways.

Whole Genome Linkage and Association Analyses Identify DLG Associated Protein-1 as a Novel Positional and Biological Candidate Gene for Muscle Strength: The Long Life Family Study.

BACKGROUND: Grip strength is a robust indicator of overall health, is moderately heritable, and predicts longevity in older adults. METHODS: Using genome-wide linkage analysis, we identified a novel locus on chromosome 18p (mega-basepair region: 3.4-4.0) linked to grip strength in 3 755 individuals from 582 families aged 64 ±â€…12 years (range 30-110 years; 55% women). There were 26 families that contributed to the linkage peak (cumulative logarithm of the odds [LOD] score = 10.94), with 6 families (119 individuals) accounting for most of the linkage signal (LOD = 6.4). In these 6 families, using whole genome sequencing data, we performed association analyses between the 7 312 single nucleotide (SNVs) and insertion deletion (INDELs) variants in the linkage region and grip strength. Models were adjusted for age, age2, sex, height, field center, and population substructure. RESULTS: We found significant associations between genetic variants (8 SNVs and 4 INDELs, p < 5 × 10-5) in the Disks Large-associated Protein 1 (DLGAP1) gene and grip strength. Haplotypes constructed using these variants explained up to 98.1% of the LOD score. Finally, RNAseq data showed that these variants were significantly associated with the expression of nearby Myosin Light Chain 12A (MYL12A), Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1), Erythrocyte Membrane Protein Band 4.1 Like 3 (EPB41L3) genes (p < .0004). CONCLUSIONS: The DLGAP1 gene plays an important role in the postsynaptic density of neurons; thus, it is both a novel positional and biological candidate gene for follow-up studies aimed at uncovering genetic determinants of muscle strength.

A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS).

Glycated hemoglobin (HbA1c) indicates average glucose levels over three months and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal changes in HbA1c (ΔHbA1c) are also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 non-diabetic Europeans from the Long Life Family Study to uncover gene variants influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis of this locus revealed a variant rs56340929 (explaining 27% of the linkage peak) in the ARHGAP44 gene that was significantly associated with ΔHbA1c. RNA transcription of ARHGAP44 was associated with ΔHbA1c. The Framingham Offspring Study data further supported these findings on the gene level. Together, we found a novel gene ARHGAP44 for ΔHbA1c in family members without T2D. Follow-up studies using longitudinal omics data in large independent cohorts are warranted.

Epidemiology of fractures in adults of African ancestry with diabetes mellitus: A systematic review and meta-analysis.

Diabetes mellitus (DM) is associated with increased fracture risk in White adults. However, the impact of DM on fractures in Black adults is unknown. This systematic review and meta-analysis investigated the association between DM and fractures in adults of African ancestry. MEDLINE, Scopus, CINAHL and Embase databases were searched from their inception up to November 2023 for all studies in the English language investigating the epidemiology of fractures (prevalence, incidence, or risk) in Black men and women (age ≥ 18 years) with type 1 or type 2 DM. Effect sizes for prevalence of previous fractures (%) and incident fracture risk (hazard ratio [HR]) were calculated using a random-effects model on Stata (version 18.0). There were 13 eligible studies, of which 12 were conducted in Black adults from the United States, while one was conducted in adults of West African ancestry from Trinidad and Tobago. We found no fracture data in Black adults with DM living in Africa. Five studies were included in a meta-analysis of incident fracture risk, reporting data from 2926 Black and 6531 White adults with DM. There was increased risk of fractures in Black adults with DM compared to non-DM (HR = 1.65; 95 % confidence interval [CI]: 1.14, 2.39). The risk of fractures was also higher in White adults with DM compared to non-DM (HR = 1.31; 95 % CI: 1.06, 1.61) among these studies. Five studies were included in a meta-analysis of fracture prevalence, of which three also reported fracture prevalence in White adults. There were 175 previous fractures among 993 Black adults with DM and 384 previous fractures among 1467 White adults with DM, with a pooled prevalence of 17.5 % (95 % CI: 15.4, 19.6) and 25.8 % (95 % CI: 4.8, 46.8), respectively. Our results indicate a high burden of fractures in Black adults with DM.

Associations of Fecal Microbiota with Ectopic Fat in African Caribbean Men.

OBJECTIVE: The gut microbiome has been associated with visceral fat (VAT) in European and Asian populations; however, associations with VAT and with ectopic fats among African-ancestry individuals are not known. Our objective was to investigate cross-sectional associations of fecal microbiota diversity and composition with VAT and ectopic fat, as well as body mass index (BMI), among middle-aged and older African Caribbean men. METHODS: We included in our analysis n = 193 men (mean age = 62.2 ± 7.6 years; mean BMI = 28.3 ± 4.9 kg/m2) from the Tobago Health Study. We assessed fecal microbiota using V4 16s rRNA gene sequencing. We evaluated multivariable-adjusted associations of microbiota features (alpha diversity, beta diversity, microbiota differential abundance) with BMI and with computed tomography-measured VAT and ectopic fats (pericardial and intermuscular fat; muscle and liver attenuation). RESULTS: Lower alpha diversity was associated with higher VAT and BMI, and somewhat with higher pericardial and liver fat. VAT, BMI, and pericardial fat each explained similar levels of variance in beta diversity. Gram-negative Prevotellaceae and Negativicutes microbiota showed positive associations, while gram-positive Ruminococcaceae microbiota showed inverse associations, with ectopic fats. CONCLUSIONS: Fecal microbiota features associated with measures of general adiposity also extend to metabolically pernicious VAT and ectopic fat accumulation in older African-ancestry men.

Systemic inflammation in relation to exceptional memory in the Long Life Family Study (LLFS).

Background and objectives: We previously found a substantial familial aggregation of healthy aging phenotypes, including exceptional memory (EM) in long-lived persons. In the current study, we aim to assess whether long-lived families with EM and without EM (non-EM) differ in systemic inflammation status and trajectory. Methods: The current study included 4333 participants of the multi-center Long Life Family Study (LLFS). LLFS families were classified as EM (556 individuals from 28 families) or non-EM (3777 individuals from 416 families), with 2 or more offspring exhibiting exceptional memory performance (i.e. having baseline composite z-score representing immediate and delayed story memory being 1.5 SD above the mean in the nondemented offspring sample) considered as EM. Blood samples from baseline were used to measure inflammatory biomarkers including total white blood cell (WBC) and its subtypes (neutrophils, lymphocytes, monocytes) count, platelet count, high sensitivity C-reactive protein, and interleukin-6. Generalized linear models were used to examine cross-sectional differences in inflammatory biomarkers at baseline. In a sub-sample of 2227 participants (338 subjects from 24 EM families and 1889 from 328 non-EM families) with repeated measures of immune cell counts, we examined whether the rate of biomarker change differed between EM and non-EM families. All models were adjusted for family size, relatedness, age, sex, education, field center, APOE genotype, and body mass index. Results: LLFS participants from EM families had a marginally higher monocyte count at baseline (b = 0.028, SE = 0.0110, p = 0.010) after adjusting for age, sex, education, and field site, particularly in men (p < 0.0001) but not in women (p = 0.493) (p-interaction = 0.003). Over time, monocyte counts increased (p < 0.0001) in both EM and non-EM families, while lymphocytes and platelet counts decreased over time in the non-EM families (p < 0.0001) but not in the EM families. After adjusting for multiple variables, there was no significant difference in biomarker change over time between the EM and non-EM families. Discussion: Compared with non-EM families, EM families had significantly higher monocyte count at baseline but had similar change over time. Our study suggests that differences in monocyte counts may be a pathway through which EM emerges in some long-lived families, especially among men.