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Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

Cynthia Al Hageh,1,&ast; Stephanie Chacar,2,&ast; Thenmozhi Venkatachalam,2 Dominique Gauguier,3,4 Antoine Abchee,5 Elie Chammas,6 Hamdan Hamdan,2 Siobhan O’Sullivan,1 Pierre Zalloua,1,7,8 Moni Nader2,7 1Department of Molecular Biology and Genetics, College of Medicine and Health Sciences, Khalifa University for Science and Technology, Abu Dhabi, United Arab Emirates; 2Department of Physiology and Immunology College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, UAE; 3McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1, Canada; 4Université Paris Cité, INSERM, Paris, France; 5Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates; 6School of Medicine, Lebanese University, Beirut, Lebanon; 7Biotechnology Center, Khalifa University for Science and Technology, Abu Dhabi, United Arab Emirates; 8Harvard T.H. Chan School of Public Health, Boston, MA, USA&ast;These authors contributed equally to this workCorrespondence: Pierre Zalloua; Moni Nader, College of Medicine and Health Sciences, Khalifa University for Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates, Email pierre.zalloua@ku.ac.ae; moni.nader@ku.ac.aeBackground and Objective: Coronary artery disease (CAD) is a major cause of death worldwide. Revascularization via stent placement or coronary artery bypass grafting (CABG) are standard treatments for CAD. Despite a high success rate, these approaches are associated with long-term failure due to restenosis. Risk factors associated with restenosis were investigated using a case-control association study design.Methods: Five thousand two hundred and forty-two patients were enrolled in this study and were assigned as follows: Stenosis Group: 3570 patients with CAD > 50% without a prior stent or CABG (1394 genotyped), and Restenosis Group: 1672 patients with CAD > 50% and prior stent deployment or CABG (705 genotyped). Binomial regression models were applied to investigate the association of restenosis with diabetes, hypertension, and dyslipidemia. The genetic association with restenosis was conducted using PLINK 1.9.Results: Dyslipidemia is a major risk factor (Odds Ratio (OR) = 2.14, P-value < 0.0001) for restenosis particularly among men (OR = 2.32, P < 0.0001), while type 2 diabetes (T2D) was associated with an increased risk of restenosis in women (OR = 1.36, P = 0.01). The rs9349379 (PHACTR1) and rs264 (LPL) were associated with an increased risk of restenosis in our patients. PHACTR1 variant was associated with increased risk of restenosis mainly in women and in diabetic patients, while the LPL variant was associated with increased risk of restenosis in men.Conclusion: The rs9349379 in PHACTR1 gene is significantly associated with restenosis, this association is more pronounced in women and in diabetic patients. The rs264 in LPL gene was associated with increased risk of restenosis in male patients.Keywords: PHACTR1, LPL, diabetes, restenosis

Yue Zhang,1 Jingyi Li,2 Chengzhang Liu,3 Hongxiang Yu,1 Chen Chen,1 Chonglei Bi,4 Chongqian Fang,4 Hai Ma,5 Aimin Li,6 Qing Dong,7 Lishun Liu,8 Binyan Wang,3 Xiao Huang,9 Xiaoshu Cheng,9 Pierre Zalloua,10 Xiping Xu,11 Yong Huo,12 Gang Li1 1Department of Neurology, East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Shenzhen Evergreen Medical Institute, Guangzhou, People’s Republic of China; 4People’s Hospital of Rongcheng, Rongcheng, Shandong, People’s Republic of China; 5Health and Family Planning Commission, Rongcheng, Shandong, People’s Republic of China; 6Department of Neurosurgery, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, People’s Republic of China; 7Lianyungang Health Committee, Lianyungang, Jiangsu, People’s Republic of China; 8Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, People’s Republic of China; 9Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 10School of Medicine, Lebanese American University, Beirut, Lebanon; 11Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangzhou, People’s Republic of China; 12Department of Cardiology, Peking University First Hospital, Beijing, People’s Republic of ChinaCorrespondence: Gang Li 1800 Yuntai Road, Shanghai, 200123, People’s Republic of ChinaTel +86-21-38804518-22107Fax +86-21-58798999Email ligang@tongji.edu.cnBackground and Purpose: Elevated high-density lipoprotein cholesterol (HDL-C) levels have displayed protection against cardiovascular disease. However, the association between specific lipoprotein classes and first ischemic stroke (IS) has not been well defined, particularly in higher-risk hypertensive populations. Our study evaluated the associations of HDL-C with first IS in a Chinese hypertensive population.Methods: The study population was obtained from a community-based cohort study of hypertension in Lianyungang and Rongcheng, China. A nested case-control design was used that included 2463 identified first IS cases and 2463 controls matched by age ± 1 year, sex, and region.Results: After adjusting for potential confounders, HDL-C was inversely associated with first IS (adjusted odds ratio [aOR]: 0.91; 95% confidence interval [CI]: 0.85– 0.98). HDL-C levels of at least 65.4 mg/dL displayed a significant protective effect for first IS (aOR: 0.82; 95% CI: 0.69– 0.98). Conversely, adverse effects of first IS were observed for low-density lipoprotein cholesterol (LDL-C) levels ≥ 138.1 mg/dL (aOR: 1.20; 95% CI: 1.02– 1.42) and triglyceride (TG) levels ≥ 140.8 mg/dL (aOR: 1.27; 95% CI: 1.09– 1.49). The risk associations of LDL-C and TG with first IS were attenuated in the presence of high HDL-C (≥ 53.0 mg/dL); an increased risk of first IS was only found in the presence of low HDL-C (< 53.0 mg/dL) when LDL-C (aOR: 1.66; 95% CI: 1.19– 2.31) and TG (aOR: 1.47; 95% CI: 1.17– 1.84) were combined with HDL-C for analysis.Conclusion: In this community-based Chinese hypertensive population, higher HDL-C was a significant protective factor of first IS. These data add to the evidence describing the relationship between lipids and IS and suggest that HDL-C maybe is a marker of IS risk in Chinses hypertensive population.Keywords: high-density lipoprotein cholesterol, lipids, ischemic stroke, epidemiology

The Levant is a region in the Near East with an impressive record of continuous human existence and major cultural developments since the Paleolithic period. Genetic and archeological studies present solid evidence placing the Middle East and the Arabian Peninsula as the first stepping-stone outside Africa. There is, however, little understanding of demographic changes in the Middle East, particularly the Levant, after the first Out-of-Africa expansion and how the Levantine peoples relate genetically to each other and to their neighbors. In this study we analyze more than 500,000 genome-wide SNPs in 1,341 new samples from the Levant and compare them to samples from 48 populations worldwide. Our results show recent genetic stratifications in the Levant are driven by the religious affiliations of the populations within the region. Cultural changes within the last two millennia appear to have facilitated/maintained admixture between culturally similar populations from the Levant, Arabian Peninsula, and Africa. The same cultural changes seem to have resulted in genetic isolation of other groups by limiting admixture with culturally different neighboring populations. Consequently, Levant populations today fall into two main groups: one sharing more genetic characteristics with modern-day Europeans and Central Asians, and the other with closer genetic affinities to other Middle Easterners and Africans. Finally, we identify a putative Levantine ancestral component that diverged from other Middle Easterners ∼23,700-15,500 years ago during the last glacial period, and diverged from Europeans ∼15,900-9,100 years ago between the last glacial warming and the start of the Neolithic.

North African populations are distinct from sub-Saharan Africans based on cultural, linguistic, and phenotypic attributes; however, the time and the extent of genetic divergence between populations north and south of the Sahara remain poorly understood. Here, we interrogate the multilayered history of North Africa by characterizing the effect of hypothesized migrations from the Near East, Europe, and sub-Saharan Africa on current genetic diversity. We present dense, genome-wide SNP genotyping array data (730,000 sites) from seven North African populations, spanning from Egypt to Morocco, and one Spanish population. We identify a gradient of likely autochthonous Maghrebi ancestry that increases from east to west across northern Africa; this ancestry is likely derived from "back-to-Africa" gene flow more than 12,000 years ago (ya), prior to the Holocene. The indigenous North African ancestry is more frequent in populations with historical Berber ethnicity. In most North African populations we also see substantial shared ancestry with the Near East, and to a lesser extent sub-Saharan Africa and Europe. To estimate the time of migration from sub-Saharan populations into North Africa, we implement a maximum likelihood dating method based on the distribution of migrant tracts. In order to first identify migrant tracts, we assign local ancestry to haplotypes using a novel, principal component-based analysis of three ancestral populations. We estimate that a migration of western African origin into Morocco began about 40 generations ago (approximately 1,200 ya); a migration of individuals with Nilotic ancestry into Egypt occurred about 25 generations ago (approximately 750 ya). Our genomic data reveal an extraordinarily complex history of migrations, involving at least five ancestral populations, into North Africa.

Background The relationship of osteoporosis and stroke is still not fully clarified. Apart from the well-known risk factors for stroke, bone mineral density (BMD) has gained more interest in recent years. Aim To further elucidate the relationship between BMD and stroke risk, a prospective cohort study in the Chinese rural population was conducted. Design Retrospective analysis of a family osteoporosis cohort. Methods Our subjects were selected from an osteoporosis cohort conducted in Anqing, China. All participants underwent a questionnaire assessment, clinical examinations and laboratory assessments. During the follow-up period, the number of people who had a stroke was recorded. Generalized estimating equation regression analysis was performed to determine the significance of the association between BMD and stroke. Results A total of 17868 people were included. A two-way interaction test of sex and BMD on stroke was significant (P  = 0.002). There was a significant difference in BMD and stroke morbidity in the male group (P  = 0.003). When BMD was assessed as quartiles and the lowest quartile was used as reference, a significantly lower risk for stroke was observed in Q2–4. Notably, no significant difference was observed in female participants with adjusted odds ratio (P  > 0.05). The P -value for interaction was calculated. The body mass index (P  = 0.014) and waist-to-hip ratio (P  = 0.027) were found to be significantly associated with BMD and stroke risk in female participants. Conclusions In Chinese rural areas, total BMD may negatively correlated with stroke, especially in men. [ABSTRACT FROM AUTHOR]