Ability of lipid accumulation product to identify metabolic syndrome in healthy men from Buenos Aires.

The metabolic syndrome is a constellation of cardiovascular and metabolic risk factors associated with insulin resistance, which predisposes individuals to diabetes, and appears to be a multifactorial risk factor for cardiovascular disease, although its clinical significance remains controversial (1). Since it may become useful to be able to predict who will develop metabolic syndrome, we explored the value of lipid accumulation product (LAP), a novel index of central lipid accumulation, which has been associated with cardiovascular disease (2) and diabetes (3). LAP is based on a combination of waist circumference and triglyceride: $$LAP = (WC − 65) × TG for men and (WC − 58) × TG for women$$ (2), where TG is triglyceride and WC is waist circumference. We conducted a cross-sectional population-based survey on metabolic syndrome in Argentinian healthy individuals in order to identify single

Genetic Structure of the Spanish Population

<p>Abstract</p> <p>Background</p> <p>Genetic admixture is a common caveat for genetic association analysis. Therefore, it is important to characterize the genetic structure of the population under study to control for this kind of potential bias.</p> <p>Results</p> <p>In this study we have sampled over 800 unrelated individuals from the population of Spain, and have genotyped them with a genome-wide coverage. We have carried out linkage disequilibrium, haplotype, population structure and copy-number variation (CNV) analyses, and have compared these estimates of the Spanish population with existing data from similar efforts.</p> <p>Conclusions</p> <p>In general, the Spanish population is similar to the Western and Northern Europeans, but has a more diverse haplotypic structure. Moreover, the Spanish population is also largely homogeneous within itself, although patterns of micro-structure may be able to predict locations of origin from distant regions. Finally, we also present the first characterization of a CNV map of the Spanish population. These results and original data are made available to the scientific community.</p

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

La epidemia de obesidad. El vínculo fisiopatológico: disfunción endocrina del adipocito, inflamación y resistencia a la insulina

Obesity is defined as an excessive of adipose tissue mass as a result of an energy imbalance. During the last decades have favoured the energy imbalance causing the energy intake exceeds energy expenditure. The worldwide obesity epidemic has become a major health concern, because it contributes to higher mortality due to an increased risk for diseases including cardiovascular diseases, type 2 diabetes mellitus, muscle skeletal disorders and some cancers. The lack of a complete understanding of the precise regulatory networks that control adipogenesis, energy expenditure, and inflammation is a fundamental problem in metabolic research. In our paper we discussed the already established systemic, cellular and molecular mechanisms following the expandability of the white adipose tissue exporting high levels concentrations of free fatty acids causing lipotoxicity in specific organs (e.g.: striated muscle, liver). Insulin resistance is, likely, the main physiopathological consequence and mediator of all features defining the “lipotoxic” state. Also many other cellular alterations including the excessive generation of free radical and hence oxidation of key proteins as well as mitochondrial dysfunction are major alterations. Similarly expandability of the obese white adipose tissue stimulate early in this process. Stimulate the activity of inflammation through the enhanced activity of macrophages from inside the adipose cell and from other sources hence excessive liberation to the blood (plasma / serum) of multiple species of pro-inflammatory cytokines (e.g.: TNFα, IL6). Overall it ends up by establishing a chronic non-clinically overt inflammation (or para-inflammation) at the cores of obesity pathogenesis. These new avenues of research still demand more research including then possibility of discovering new pharmacological approaches for the treatment of the obese patients.La obesidad se define como un exceso de masa de tejido adiposo blanco como resultado de un desequilibrio energético. Las últimas décadas han favorecido tal desequilibrio energético debido a que la ingesta de energía excede al gasto de energía. La epidemia mundial de obesidad se ha convertido en un importante problema de salud, que contribuye a una mayor mortalidad debido a un mayor riesgo de enfermedades: cardiovasculares, diabetes mellitus tipo 2, y algunos tipos de cáncer. En nuestro trabajo hemos discutido los mecanismos ya establecidos a nivel sistémico, celular y molecular después de que la “expansión” del tejido adiposo blanco exporte concentraciones elevadas de ácidos grasos libres causantes de lipotoxicidad a órganos específicos (p.ej.: músculo estriado, hígado). La resistencia a la insulina es la principal consecuencia fisiopatológica y mediadora de las características del estado lipotóxico. Otras alteraciones celulares incluyen la generación excesiva de radicales libres de oxígeno y por tanto la oxidación de las proteínas clave, así como la disfunción mitocondrial. La expansión del tejido adiposo blanco obeso estimula pronto el desarrollo de inflamación a través de una mayor actividad de los macrófagos situados en la célula adiposa y de otras fuentes, con liberación excesiva a la sangre (plasma / suero) de múltiples citocinas pro-inflamatorias (p.ej.: TNF, IL-6). Así se establece un estado de inflamación crónico y subclínico en la patogénesis de la obesidad. Estas nuevas vías de investigación todavía exigen más investigación, incluyendo la posibilidad de descubrir nuevos fármacos para el tratamiento de los pacientes obesos y el diseño de estrategias más eficaces de prevención de Obesidad, Diabetes Mellitus tipo 2 y otras de sus comorbilidades