Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Insulins | Research article

GWAS in people of Middle Eastern descent reveals a locus protective of kidney function—a cross-sectional study

Authors: Siham A. Mohamed, Juan Fernadez-Tajes, Paul W. Franks, Louise Bennet

Published in: BMC Medicine | Issue 1/2022

Login to get access

Abstract

Background

Type 2 diabetes is one of the leading causes of chronic kidney failure, which increases globally and represents a significant threat to public health. People from the Middle East represent one of the largest immigrant groups in Europe today. Despite poor glucose regulation and high risk for early-onset insulin-deficient type 2 diabetes, they have better kidney function and lower rates of all-cause and cardiovascular-specific mortality compared with people of European ancestry. Here, we assessed the genetic basis of estimated glomerular filtration rate (eGFR) and other metabolic traits in people of Iraqi ancestry living in southern Sweden.

Methods

Genome-wide association study (GWAS) analyses were performed in 1201 Iraqi-born residents of the city of Malmö for eGFR and ten other metabolic traits using linear mixed-models to account for family structure.

Results

The strongest association signal was detected for eGFR in CST9 (rs13037490; P value = 2.4 × 10−13), a locus previously associated with cystatin C-based eGFR; importantly, the effect (major) allele here contrasts the effect (minor) allele in other populations, suggesting favorable selection at this locus. Additional novel genome-wide significant loci for eGFR (ERBB4), fasting glucose (CAMTA1, NDUFA10, TRIO, WWC1, TRAPPC9, SH3GL2, ABCC11), quantitative insulin-sensitivity check index (METTL16), and HbA1C (CAMTA1, ME1, PAK1, RORA) were identified.

Conclusions

The genetic effects discovered here may help explain why people from the Middle East have better kidney function than those of European descent. Genetic predisposition to preserved kidney function may also underlie the observed survival benefits in Middle Eastern immigrants with type 2 diabetes.
Appendix
Available only for authorised users
Literature
1.
Lv JC, Zhang LX. Prevalence and disease burden of chronic kidney disease. Adv Exp Med Biol. 2019;1165:3–15.PubMedCrossRef
2.
Kazancioglu R. Risk factors for chronic kidney disease: an update. Kidney Int Suppl (2011). 2013;3(4):368-71.
3.
van Dieren S, Beulens JW, van der Schouw YT, Grobbee DE, Neal B. The global burden of diabetes and its complications: an emerging pandemic. Eur J Cardiovasc Prev Rehabil. 2010;17(Suppl 1):S3–8.PubMed
4.
5.
Corredor Z, Filho M, Rodriguez-Ribera L, Velazquez A, Hernandez A, Catalano C, et al. Genetic variants associated with chronic kidney disease in a Spanish population. Sci Rep. 2020;10(1):144.PubMedPubMedCentralCrossRef
6.
7.
Genovese G, Friedman DJ, Pollak MR. APOL1 variants and kidney disease in people of recent African ancestry. Nat Rev Nephrol. 2013;9(4):240–4.PubMedCrossRef
8.
9.
Bennet L, Groop L, Franks PW. Ethnic differences in the contribution of insulin action and secretion to type 2 diabetes in immigrants from the Middle East compared to native Swedes. Diabetes Res Clin Pract. 2014;105(1):79–87.PubMedCrossRef
10.
Bennet L, Franks PW, Zoller B, Groop L. Family history of diabetes and its relationship with insulin secretion and insulin sensitivity in Iraqi immigrants and native Swedes: a population-based cohort study. Acta Diabetol. 2018;55(3):233–42.PubMedCrossRef
11.
Nilsson C, Christensson A, Nilsson PM, Bennet L. Renal function and its association with blood pressure in Middle Eastern immigrants and native Swedes. J Hypertens. 2017;35(12):2493–500.PubMedCrossRef
12.
Pranavchand R, Reddy BM. Genomics era and complex disorders: implications of GWAS with special reference to coronary artery disease, type 2 diabetes mellitus, and cancers. J Postgrad Med. 2016;62(3):188–98.PubMedPubMedCentralCrossRef
13.
Genetics for all. Nat Genet. 2019;51(4):579.
14.
Bennet L, Johansson SE, Agardh CD, Groop L, Sundquist J, Rastam L, et al. High prevalence of type 2 diabetes in Iraqi and Swedish residents in a deprived Swedish neighbourhood - a population based study. BMC public health. 2011;11(1):303.PubMedPubMedCentralCrossRef
15.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70.PubMedCrossRef
16.
17.
Loh PR, Tucker G, Bulik-Sullivan BK, Vilhjalmsson BJ, Finucane HK, Salem RM, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47(3):284–90.PubMedPubMedCentralCrossRef
18.
19.
20.
Buniello A, MacArthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47(D1):D1005–D12.PubMedCrossRef
21.
Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet. 2009;41(6):712–7.PubMedPubMedCentralCrossRef
22.
Gorski M, van der Most PJ, Teumer A, Chu AY, Li M, Mijatovic V, et al. 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. Sci Rep. 2017;7:45040.PubMedPubMedCentralCrossRef
23.
Witasp A, Ekstrom TJ, Lindholm B, Stenvinkel P, Schalling M, Nordfors L. Novel insights from genetic and epigenetic studies in understanding the complex uraemic phenotype. Nephrol Dial Transplant. 2014;29(5):964–71.PubMedCrossRef
24.
Hwang SJ, Yang Q, Meigs JB, Pearce EN, Fox CS. A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study. BMC Med Genet. 2007;8 Suppl 1:S10.
25.
Veikkolainen V, Naillat F, Railo A, Chi L, Manninen A, Hohenstein P, et al. ErbB4 modulates tubular cell polarity and lumen diameter during kidney development. J Am Soc Nephrol. 2012;23(1):112–22.PubMedCrossRef
26.
Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, et al. New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet. 2012;8(9):e1002921.PubMedPubMedCentralCrossRef
27.
Bennet L, Udumyan R, Ostgren CJ, Rolandsson O, Jansson SPO, Wandell P. Mortality in first- and second-generation immigrants to Sweden diagnosed with type 2 diabetes: a 10 year nationwide cohort study. Diabetologia. 2021;64(1):95–108. https://​doi.​org/​10.​1007/​s00125-020-05279-1. Epub 2020 Sep 26. PMID: 32979073; PMCID: PMC7716891.
28.
Franks PW, McCarthy MI. Exposing the exposures responsible for type 2 diabetes and obesity. Science. 2016;354(6308):69–73.PubMedCrossRef
29.
Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT, et al. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia. 2007;50(1):63–7.PubMedCrossRef
30.
Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S. Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia. 2007;50(5):980–4.PubMedCrossRef
31.
Humphries SE, Gable D, Cooper JA, Ireland H, Stephens JW, Hurel SJ, et al. Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women. J Mol Med (Berl). 2006;84(12):1005–14.PubMedCrossRef
32.
Rees SD, Bellary S, Britten AC, O'Hare JP, Kumar S, Barnett AH, et al. Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population. BMC Med Genet. 2008;9:8.PubMedPubMedCentralCrossRef
33.
Melzer D, Murray A, Hurst AJ, Weedon MN, Bandinelli S, Corsi AM, et al. Effects of the diabetes linked TCF7L2 polymorphism in a representative older population. BMC Med. 2006;4:34.PubMedPubMedCentralCrossRef
34.
Alsmadi O, Al-Rubeaan K, Mohamed G, Alkayal F, Al-Saud H, Al-Saud NA, et al. Weak or no association of TCF7L2 variants with type 2 diabetes risk in an Arab population. BMC Med Genet. 2008;9:72.PubMedPubMedCentralCrossRef
35.
Hebbar P, Abubaker JA, Abu-Farha M, Alsmadi O, Elkum N, Alkayal F, et al. Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population. Hum Genet. 2021;140(3):505–28.PubMedCrossRef
36.
37.
Ghassibe-Sabbagh M, Haber M, Salloum AK, Al-Sarraj Y, Akle Y, Hirbli K, et al. T2DM GWAS in the Lebanese population confirms the role of TCF7L2 and CDKAL1 in disease susceptibility. Sci Rep. 2014;4:7351.PubMedPubMedCentralCrossRef
38.
39.
Cauchi S, Proenca C, Choquet H, Gaget S, De Graeve F, Marre M, et al. Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study. J Mol Med (Berl). 2008;86(3):341-8.
40.
Olsson AH, Yang BT, Hall E, Taneera J, Salehi A, Nitert MD, et al. Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes. Eur J Endocrinol. 2011;165(4):589–95.PubMedPubMedCentralCrossRef
41.
Wu C, Xu G, Tsai SA, Freed WJ, Lee CT. Transcriptional profiles of type 2 diabetes in human skeletal muscle reveal insulin resistance, metabolic defects, apoptosis, and molecular signatures of immune activation in response to infections. Biochem Biophys Res Commun. 2017;482(2):282–8.PubMedCrossRef
42.
Dufurrena Q. Back N. Hodgson L, Tanowitz H, Mandela P, et al. Kalirin/Trio Rho GDP/GTP exchange factors regulate proinsulin and insulin secretion. J Mol Endocrinol: Mains RE; 2018.
43.
Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, et al. A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab. 2012;16(1):122–34.PubMedCrossRef
44.
Hwang JY, Sim X, Wu Y, Liang J, Tabara Y, Hu C, et al. Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians. Diabetes. 2015;64(1):291–8.PubMedCrossRef
45.
Heart E, Cline GW, Collis LP, Pongratz RL, Gray JP, Smith PJ. Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab. 2009;296(6):E1354–62.PubMedPubMedCentralCrossRef
46.
Hasan NM, Longacre MJ, Stoker SW, Kendrick MA, MacDonald MJ. Mitochondrial malic enzyme 3 is important for insulin secretion in pancreatic beta-cells. Mol Endocrinol. 2015;29(3):396–410.PubMedPubMedCentralCrossRef
47.
Veluthakal R, Chepurny OG, Leech CA, Schwede F, Holz GG, Thurmond DC. Restoration of glucose-stimulated Cdc42-Pak1 activation and insulin secretion by a selective epac activator in type 2 diabetic human islets. Diabetes. 2018;67(10):1999–2011.PubMedPubMedCentralCrossRef
48.
Wang Z, Oh E, Clapp DW, Chernoff J, Thurmond DC. Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo. J Biol Chem. 2011;286(48):41359–67.PubMedPubMedCentralCrossRef
49.
Kalwat MA, Yoder SM, Wang Z, Thurmond DC. A p21-activated kinase (PAK1) signaling cascade coordinately regulates F-actin remodeling and insulin granule exocytosis in pancreatic beta cells. Biochem Pharmacol. 2013;85(6):808–16.PubMedCrossRef
50.
Kuang J, Hou X, Zhang J, Chen Y, Su Z. Identification of insulin as a novel retinoic acid receptor-related orphan receptor alpha target gene. FEBS Lett. 2014;588(6):1071–9.PubMedCrossRef
51.
Zhang Y, Liu Y, Liu Y, Zhang Y, Su Z. Genetic variants of retinoic acid receptor-related orphan receptor alpha determine susceptibility to type 2 diabetes mellitus in Han Chinese. Genes (Basel). 2016;7(8):54. https://​doi.​org/​10.​3390/​genes7080054. PMID: 27556492; PMCID: PMC4999842.
52.
Metadata
Title
GWAS in people of Middle Eastern descent reveals a locus protective of kidney function—a cross-sectional study
Authors
Siham A. Mohamed
Juan Fernadez-Tajes
Paul W. Franks
Louise Bennet
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02267-7

Other articles of this Issue 1/2022

BMC Medicine 1/2022 Go to the issue

Opinion

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development

Research article

Head-to-head comparison of the accuracy of saliva and nasal rapid antigen SARS-CoV-2 self-testing: cross-sectional study

Research article

The impact of medication reviews by general practitioners on psychotropic drug use and behavioral and psychological symptoms in home-dwelling people with dementia: results from the multicomponent cluster randomized controlled LIVE@Home.Path trial

Research article

Length of initial prescription at hospital discharge and long-term medication adherence for elderly, post-myocardial infarction patients: a population-based interrupted time series study

Research article

Longitudinal patterns and predictors of healthcare utilization among cancer patients on home-based palliative care in Singapore: a group-based multi-trajectory analysis

Research article

Rapid intrapartum test for maternal group B streptococcal colonisation and its effect on antibiotic use in labouring women with risk factors for early-onset neonatal infection (GBS2): cluster randomised trial with nested test accuracy study