scholarly journals Distribution of local ancestry and evidence of adaptation in admixed populations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rodrigo Secolin ◽  
Alex Mas-Sandoval ◽  
Lara R. Arauna ◽  
Fábio R. Torres ◽  
Tânia K. de Araujo ◽  
...  
Keyword(s):  
Native American ◽  
European Ancestry ◽  
Local Ancestry ◽  
Native American Ancestry ◽  
Increased Risk ◽  
Sub Saharan ◽  
First Time ◽  
Diabetes And Obesity ◽  
Selection Event

Abstract Admixed American populations have different global proportions of European, Sub-Saharan African, and Native-American ancestry. However, individuals who display the same global ancestry could exhibit remarkable differences in the distribution of local ancestry blocks. We studied for the first time the distribution of local ancestry across the genome of 264 Brazilian admixed individuals, ascertained within the scope of the Brazilian Initiative on Precision Medicine. We found a decreased proportion of European ancestry together with an excess of Native-American ancestry on chromosome 8p23.1 and showed that this is due to haplotypes created by chromosomal inversion events. Furthermore, Brazilian non-inverted haplotypes were more similar to Native-American haplotypes than to European haplotypes, in contrast to what was found in other American admixed populations. We also identified signals of recent positive selection on chromosome 8p23.1, and one gene within this locus, PPP1R3B, is related to glycogenesis and has been associated with an increased risk of type 2 diabetes and obesity. These findings point to a selection event after admixture, which is still not entirely understood in recent admixture events.

scholarly journals Differences in MTHFR and LRRK2 variant’s association with sporadic Parkinson’s disease in Mexican Mestizos correlated to Native American ancestry

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Elizabeth Romero-Gutiérrez ◽  
Paola Vázquez-Cárdenas ◽  
Hortensia Moreno-Macías ◽  
José Salas-Pacheco ◽  
Teresa Tusié-Luna ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Native American ◽  
Neurodegenerative Disorder ◽  
European Ancestry ◽  
Native American Ancestry ◽  
Risk Effect ◽  
Mexican Mestizos ◽  
Shared Risk

AbstractParkinson’s disease (PD), a common neurodegenerative disorder, has a complex etiology where environmental and genetic factors intervene. While a number of genes and variants have been identified in recent decades as causative or protective agents of this condition, a limited number of studies have been conducted in mixed populations, such as Mexican Mestizos. The historical convergence of two founding groups and three ethnicities, and the increasing north-to-south gradient of Native American ancestry in Mexico resulted in a subpopulation structure with considerable genetic diversity. In this work, we investigate the influence of 21 known susceptibility variants for PD. Our case–control study, with a cohort of 311 Mexican Mestizo subjects, found a significant risk association for the variant rs1491942 in LRRK2. However, when stratification by ancestry was performed, a risk effect for MTHFR rs1801133 was observed only in the group with the highest percentage of European ancestry, and the PD risk effect for LRRK2 rs1491942 was significant in subjects with a higher ratio of Native American ancestry. Meta-analyses of these SNP revealed the effect of LRRK2 rs1491942 to be even more significant than previously described in populations of European descent. Although corroboration is necessary, our findings suggest that polymorphism rs1491942 may be useful as a risk marker of PD in Mexican Mestizos with greater Native American ancestry. The absence of associations with the remaining known risk factors is, in itself, a relevant finding and invites further research into the shared risk factors’ role in the pathophysiological mechanisms of this neurodegenerative disorder.

FABP1 gene variant associated with risk of metabolic syndrome

2021 ◽  
Vol 24 ◽  
Author(s):  
Reza Zare-Feyzabadi ◽  
Majid Mozaffari ◽  
Majid Ghayour-Mobarhan ◽  
Mohsen Valizadeh
Keyword(s):  
Metabolic Syndrome ◽  
International Diabetes Federation ◽  
Amplification Refractory Mutation System ◽  
Study Cohort ◽  
Increased Risk ◽  
Mutation System ◽  
Polymerase Chain ◽  
The Relationship ◽  
Diabetes And Obesity

Background: Metabolic Syndrome (MetS) is defined by a clustering of metabolic abnormalities associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. There has been an increasing interest in the associations of genetic variants involved in diabetes and obesity in the FABP1 pathway. The relationship between the rs2241883 polymorphism of FABP1 and risk of MetS remains unclear. Objective: We aimed to examine the association between this genetic polymorphism and the presence of MetS and its constituent factors. Methods: A total of 942 participants were recruited as part of the Mashhad Stroke and Heart Atherosclerosis Disorders (MASHAD study) Cohort. Patients with MetS were identified using the International Diabetes Federation (IDF) criteria (n=406) and those without MetS (n=536) were also recruited. DNA was extracted from peripheral blood samples and used for genotyping of the FABP1 rs2241883T/C polymorphism using Tetra-Amplification Refractory Mutation System Polymerase Chain Reaction (Tetra-ARMS PCR). Genetic analysis was confirmed by gel electrophoresis and DNA sequencing. Results: Using both univariate and multivariate analyses after adjusting for age, sex and physical activity, carriers of C allele (CT/CC genotypes) in FABP1 variant were related to an increased risk of MetS, compared to non-carriers (OR: 1.38, 95%CI: 1.04,1.82, p=0.026). Conclusion: The present study shows that C allele in the FABP1 variant can be associated with an increased risk of MetS. The evaluation of these factors in a larger population may help further confirm these findings.

scholarly journals Type 2 Diabetes Mellitus. From the start – combination therapy

2018 ◽  
Vol 21 (5) ◽  
pp. 386-394 ◽  
Author(s):  
Francesco Indovina ◽  
Pierpaolo Falcetta ◽  
Stefano Del Prato
Keyword(s):  
Type 2 Diabetes ◽  
Combination Therapy ◽  
Diabetes Diagnosis ◽  
Good Glycemic Control ◽  
Chronic Hyperglycemia ◽  
Increased Risk ◽  
History Of ◽  
First Time ◽  
Early Combination Therapy

Modern treatment of T2DM requires a shift in paradigm with appropriate intensification of therapy from the very first time of diabetes diagnosis. This is supported by data showing how even a moderate delay in achieving good glycemic control can translate into a later increased risk of developing diabetic complications. The recognition of the complexity of the pathogenesis of T2DM leads to the appreciation of the importance of attacking the disease from different angles, i.e. simultaneous tackling of multiple mechanisms contributing to hyperglycemia. From the turn of century a growing number of new anti-hyperglycemic agents have been made available. As compared to the older ones, these new medicines have a more targeted mechanism of action as they act at the level of the specific pathophysiologic disturbances accounting the development and progression of hyperglycemia. Because of that drugs can be use in combination taking advantage of their complementary mechanisms of action and synergistic. If introduced earlier in the natural history of the disease combination therapy may contribute avoiding undesirable exposure to even mild chronic hyperglycemia and provide early benefits. With respect to that in this review we will discuss advantages, disadvantages and still unanswered questions related to the use of early combination therapy in type 2 diabetes.

scholarly journals Placental Restriction of Fetal Growth Increases Insulin Action, Growth, and Adiposity in the Young Lamb

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1350-1358 ◽  
Author(s):  
Miles J. De Blasio ◽  
Kathryn L. Gatford ◽  
I. Caroline McMillen ◽  
Jeffrey S. Robinson ◽  
Julie A. Owens
Keyword(s):  
Insulin Sensitivity ◽  
Fetal Growth ◽  
Insulin Action ◽  
Visceral Obesity ◽  
Later Life ◽  
Anabolic Hormone ◽  
Increased Risk ◽  
Catch Up ◽  
Diabetes And Obesity

Most children who are short or light at birth due to intrauterine growth restriction (IUGR) exhibit accelerated growth in infancy, termed “catch-up” growth, which together with IUGR, predicts increased risk of type 2 diabetes and obesity later in life. Placental restriction (PR) in sheep reduces size at birth, and also causes catch-up growth and increased adiposity at 6 wk of age. The physiological mechanisms responsible for catch-up growth after IUGR and its links to these adverse sequelae are unknown. Because insulin is a major anabolic hormone of infancy and its actions are commonly perturbed in these related disorders, we hypothesized that restriction of fetal growth would alter insulin secretion and sensitivity in the juvenile sheep at 1 month, which would be related to their altered growth and adiposity. We show that PR impairs glucose-stimulated insulin production, but not fasting insulin abundance or production in the young sheep. However, PR increases insulin sensitivity of circulating free fatty acids (FFAs), and insulin disposition indices for glucose and FFAs. Catch-up growth is predicted by the insulin disposition indices for amino acids and FFAs, and adiposity by that for FFAs. This suggests that catch-up growth and early-onset visceral obesity after IUGR may have a common underlying cause, that of increased insulin action due primarily to enhanced insulin sensitivity, which could account in part for their links to adverse metabolic and related outcomes in later life.

scholarly journals A Novel Type 2 Diabetes Locus in sub-Saharan Africans, ZRANB3, is Implicated in Beta Cell Proliferation

2019 ◽  
Author(s):  
Adebowale A. Adeyemo ◽  
Guanjie Chen ◽  
Ayo P. Doumatey ◽  
Timothy L. Hostelley ◽  
Carmen C. Leitch ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
European Ancestry ◽  
Human Populations ◽  
Beta Cell Proliferation ◽  
Genome Wide ◽  
Significant Locus ◽  
Sub Saharan

AbstractGenome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report the largest genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyzed ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. TCF7L2 rs7903156 was the most significant locus (p=7.288 × 10−13). We identified a novel genome wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP chr2:136064024, T allele frequency=0.034, p=2.831×10−9). Knockdown of the zebrafish ortholog resulted in reduction in pancreatic beta cell number in the developing organism, suggesting a potential mechanism for its effect on glucose hemostasis. We also showed transferability in our study of 32 established T2D loci. Our findings provide evidence of a novel candidate T2D locus and advance understanding of the genetics of T2D in non-European ancestry populations.

scholarly journals Evidence for Natural Selection and Ethnic Diversity at the Adenylate cyclase 3 Gene Associated with Obesity and Type 2 Diabetes

2020 ◽  
Author(s):  
ISSEI YOSHIUCHI
Keyword(s):  
Type 2 Diabetes ◽  
Natural Selection ◽  
Adenylate Cyclase ◽  
Ethnic Diversity ◽  
European Ancestry ◽  
Loss Of Function ◽  
Obesity And Diabetes ◽  
African Populations ◽  
Diabetes And Obesity

Abstract Background: Diabetes and obesity cause serious complications worldwide, including stroke and cardiovascular disease, and are a global health burden. Diabetes is strongly related with obesity and both are significantly heritable. The prevalence of diabetes and obesity are higher in African populations than in European and Asian populations. In human evolution, natural selection is a key process of genetic survival over generations. Thus, the selection for diabetes- and obesity-related genes is a key mechanism for survival during times of feast and famine. Loss-of-function variations in the adenylate cyclase 3 ( ADCY3 ) gene are associated with obesity and diabetes, while mutations in ADCY3 are also associated with childhood obesity. ADCY3 -deficient mice showed severe obesity, impaired insulin sensitivity, and reduced physical activity. Here, we researched evidence for natural selection at ADCY3 . Methods: We used a three-step genetic method to identify natural selection at ADCY3 using data on four populations from the 1000 Genomes Project and HapMap: Utah residents with Northern and Western European ancestry (CEU), the Yoruba in Ibadan, Nigeria (YRI), Han Chinese in Beijing (CHB) and Japanese in Tokyo (JPT). First we used Wright’s F-statistics (Fst) as a measure of population differentiation to find ethnic diversity at ADCY3 . We then used a long-range haplotype (LRH) test to find significant long haplotypes, and then the integrated haplotype score (iHS) to find natural selection at ADCY3 . Results: We observed high Fst values and significant ethnic diversity at four ADCY3 body mass index (BMI)-associated variations (rs7586879, rs6545814, rs11676272 and rs10182181) between the non-African and African populations. Both LRH and iHS also provided evidence for natural selection at ADCY3 . Conclusions: These observations show evidence for natural selection and ethnic diversity at ADCY3 . Further exploration into the evolution of obesity- and Type 2 diabetes-associated genes is needed.

scholarly journals Outcome of COVID-19: Diabetes and Obesity

2021 ◽  
pp. 248-255
Author(s):  
Rithika Gunta
Keyword(s):  
Vascular Inflammation ◽  
Diabetic Patients ◽  
Vulnerable Group ◽  
Glucose Levels ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Lipid Aldehydes ◽  
Diabetes And Obesity ◽  
Corona Viruses

Today the world is facing one of the biggest crisis, due to a new beta-corona virus emerged from Wuhan in China, on December 2019. WHO declared ‘acute respiratory syndrome COVID-19 (SARS Co-2)’as a pandemic on March 12, 2020. Corona viruses are enveloped positive single stranded RNA viruses, causing severe acute respiratory syndrome in the infected individuals. The risk of getting infected by covid-19 is similar in all the individuals across the nation. But the outcome of the infection varies from one individual to another, depending on the comorbidities present in them. The most vulnerable group of patients in respect to severity of outcome of the infection are the once with unbalanced heath conditions like age (>65 years), immune-compromised, hypertension, type 2 diabetes, increased insulin resistance, cardiovascular diseases, chronic kidney disease, chronic liver disease, vasculitis(vascular inflammation)and obesity. It is now a public knowledge that diabetes and obesity are a risk factor for any individual as these conditions can exacerbate the manifestations of COVID-19 infections thus increasing the severity of the condition, that may require hospitalization of the patient, later may even require intensive care unit or/and mechanical ventilation, with increased risk of mortality rates. In diabetic patients it is mainly due to failure in controlling the glucose levels and the risk of ketoacidosis. In patients with obesity lipid peroxidase creates reactive lipid aldehydes leading to poor prognosis.

Maternal Hypertension Increases Risk of Preeclampsia and Low Fetal Birthweight: Genetic Evidence From a Mendelian Randomization Study

Hypertension ◽  
2022 ◽  
Author(s):  
Maddalena Ardissino ◽  
Eric A.W. Slob ◽  
Ophelia Millar ◽  
Rohin K. Reddy ◽  
Laura Lazzari ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Body Mass ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Increased Risk

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight. Methods: Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Results: Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45–2.49]; P =3.23×10 −6 ) and reduced birthweight (OR=0.83 [95% CI=0.79–0.86]; P =3.96×10 −18 ), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44–1.94]; P =7.45×10 −12 ; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04–1.19]; P =1.19×10 −3 ), but not with reduced birthweight. Conclusions: Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Polymorphic variant rs4430796 at HNF1B gene: sex-specific, BMI-dependent associations with parameters of glucose metabolism, redox homeostasis and risk of type 2 diabetes

2021 ◽  
pp. 25-36
Author(s):  
Ю.Э. Азарова ◽  
Е.Ю. Клёсова ◽  
А.В. Полоников
Keyword(s):  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Body Mass ◽  
Redox Homeostasis ◽  
Russian Population ◽  
Polymorphic Variant ◽  
Pancreatic Islets Of Langerhans ◽  
Increased Risk ◽  
First Time

Ожирение является важнейшим фактором риска развития сахарного диабета 2 типа (СД2). Гепатоцитарный ядерный фактор 1 β (HNF1B) контролирует глюкостатическую функцию островков Лангерганса поджелудочной железы и ассоциирован с развитием СД2 в европейской и азиатской популяциях. Однако исследований, оценивающих роль генетических вариантов HNF1B в формировании предрасположенности к СД2 в русской популяции, на сегодняшний день не проводилось. Целью настоящей работы стало изучение ассоциации полиморфного варианта rs4430796 (A>G) в интроне гена HNF1B с показателями гликемического профиля и редокс-гомеостаза, а также риском развития СД2 у жителей Центральной России, с учетом их пола и индекса массы тела. В исследование включено 3206 человек, из них 1579 больных СД2 и 1627 условно здоровых добровольцев. Генотипирование проводили с использованиеми технологии iPLEX на геномном времяпролетном масс-спектрометре MassArray 4 (Agena Bioscience). Впервые в русской популяции установлена взаимосвязь полиморфизма rs4430796 гена HNF1B с повышенным риском развития СД2 (OR 1,24, 95CI 1,05-1,47, р=0,011). Стратифицированный анализ по полу обнаружил, что выявленная ассоциация характерна только для женщин с избыточной массой тела (OR 1,54, 95CI 1,06-2,22, р=0,02) и ожирением (OR 2,07, 95CI 1,14-3,77, р=0,047) и отсутствует у лиц с нормальной массой тела вне зависимости от пола. Изучаемый SNP ассоциирован с повышенным содержанием перекиси водорода (р=0,012) и более низким уровнем общего глутатиона плазмы (р=0,041) у женщин, тогда как у мужчин с СД2 генотип G/G связан со снижением концентрации С-пептида (р=0,004) и повышением концентрации глюкозы крови (р=0,015). Биоинформатический анализ подтвердил отрицательный эффект аллеля G на экспрессию HNF1B, а также выявил его связь с гиперметилированием гена в различные периоды жизни, что обусловливает низкую экспрессию гена HNF1B у носителей минорного аллеля rs4430796-G. Таким образом, нами впервые установлено, что полиморфный вариант гена HNF1B rs4430796 ассоциирован с предрасположенностью к СД2 в русской популяции, при этом его связь с заболеванием имеет пол-специфический характер и зависит от индекса массы тела. Obesity is a critical risk factor for type 2 diabetes mellitus (T2D). Hepatic nuclear factor 1 β (HNF1B) controls the glucostatic function of pancreatic islets of Langerhans and is associated with the development of T2D in the European and Asian populations. However, studies evaluating the contribution of genetic variants at HNF1B to the pathogenesis of the disease in Russian population have not been conducted to date. The aim of this work was to study the association of the polymorphic variant rs4430796 (A>G) in the intron of the HNF1B gene with parameters of glycemic profile and redox homeostasis, as well as the risk of developing T2D in citizens of Central Russia, taking into account their gender and body mass index. The study included 3206 participants, 1579 patients with T2D and 1627 healthy volunteers. Genotyping was performed using iPLEX technology on a genomic time-of-flight mass spectrometer MassArray 4 (Agena Bioscience). For the first time in the Russian population, the relationship of the rs4430796 polymorphism at the HNF1B gene with an increased risk of developing T2D (OR 1,24, 95CI 1,05-1,47, p=0,011) was established. A gender-stratified analysis found that the association is characteristic only for females with overweight (OR 1,54, 95CI 1,06-2,22, p=0,02) and obesity (OR 2.07, 95CI 1,14-3,77, p=0.047) and is absent in individuals with normal body weight, regardless from the gender. The studied SNP is associated with an increased content of hydrogen peroxide (p=0,012) and a lower level of total plasma glutathione (p=0,041) in females, whereas in diabetic males the G/G genotype is associated with a decrease in the concentration of C-peptide (p=0,004) and an increase in blood glucose concentration (p=0,015). Bioinformatic analysis confirmed the negative effect of the alternative G allele on the expression of the HNF1B gene, as well as its relationship with hypermethylation of the gene at different periods of life, which leads to low expression of HNF1B in carriers of variant rs4430796. Conclusions: It was found for the first time that the polymorphic variant rs4430796 of the HNF1B gene is associated with a predisposition to T2D, whereas its relationship with the disease is sex-specific and depends on body mass index.

scholarly journals Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer’s disease in Caribbean Hispanics

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Andréa R. V. R. Horimoto ◽  
Diane Xue ◽  
Timothy A. Thornton ◽  
Elizabeth E. Blue
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Native American ◽  
Late Onset ◽  
European Ancestry ◽  
Admixture Mapping ◽  
Native American Ancestry ◽  
Genome Wide ◽  
A Genome ◽  
The Brain

Abstract Background Genetic studies have primarily been conducted in European ancestry populations, identifying dozens of loci associated with late-onset Alzheimer’s disease (AD). However, much of AD’s heritability remains unexplained; as the prevalence of AD varies across populations, the genetic architecture of the disease may also vary by population with the presence of novel variants or loci. Methods We conducted genome-wide analyses of AD in a sample of 2565 Caribbean Hispanics to better understand the genetic contribution to AD in this population. Statistical analysis included both admixture mapping and association testing. Evidence for differential gene expression within regions of interest was collected from independent transcriptomic studies comparing AD cases and controls in samples with primarily European ancestry. Results Our genome-wide association study of AD identified no loci reaching genome-wide significance. However, a genome-wide admixture mapping analysis that tests for association between a haplotype’s ancestral origin and AD status detected a genome-wide significant association with chromosome 3q13.11 (103.7–107.7Mb, P = 8.76E−07), driven by a protective effect conferred by the Native American ancestry (OR = 0.58, 95%CI = 0.47−0.73). Within this region, two variants were significantly associated with AD after accounting for the number of independent tests (rs12494162, P = 2.33E−06; rs1731642, P = 6.36E−05). The significant admixture mapping signal is composed of 15 haplotype blocks spanning 5 protein-coding genes (ALCAM, BBX, CBLB, CCDC54, CD47) and four brain-derived topologically associated domains, and includes markers significantly associated with the expression of ALCAM, BBX, CBLB, and CD47 in the brain. ALCAM and BBX were also significantly differentially expressed in the brain between AD cases and controls with European ancestry. Conclusion These results provide multiethnic evidence for a relationship between AD and multiple genes at 3q13.11 and illustrate the utility of leveraging genetic ancestry diversity via admixture mapping for new insights into AD.

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