Abstract
Research into the genetic basis of cardiovascular-related diseases is moving at an extremely fast pace. Developments in technology such as whole-genome sequencing and massive resources of DNA collected from hundreds of thousands of people mean scientists have an unprecedented ability to discover the genetic variation that predisposes to disease. Before 2007, very little was known about the variation in the human DNA sequence and its influence on common diseases. We now know of hundreds of common variants that influence LDL cholesterol levels, type 2 diabetes, hypertension and heart disease to name a few. Attention has now turned to the discovery of the genetic variants that occur in between 1 in 20 and 1 in 1000 individuals. These variants are unlikely to cause disease in the same way that mutations in some genes cause a monogenic disorder with a particular pattern of inheritance. But variants in this frequency range will shed light on biological mechanisms of disease. In this review, we focus on these variants and discuss how a range of study designs have identified low-frequency genetic variants with stronger predisposing effects on type 2 diabetes and related traits than common genetic variants.
Similar content being viewed by others
References
Ntuk UE, Gill JM, Mackay DF, Sattar N, Pell JP. Ethnic-specific obesity cutoffs for diabetes risk: cross-sectional study of 490,288 UK biobank participants. Diabetes Care. 2014;37(9):2500–7.
Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, Steinthorsdottir V, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44(9):981–90.
Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME, Luan J, et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet. 2012;44(9):991–1005.
McCarthy MI. Dorothy Hodgkin lecture 2010. From hype to hope? A journey through the genetics of type 2 diabetes. Diabet Med. 2011;28(2):132–40.
McCarthy MI. Genomic medicine at the heart of diabetes management. Diabetologia. 2015.
Pal A, McCarthy MI. The genetics of type 2 diabetes and its clinical relevance. Clin Genet. 2013;83(4):297–306.
Yaghootkar H, Frayling TM. Recent progress in the use of genetics to understand links between type 2 diabetes and related metabolic traits. Genome Biol. 2013;14(3):203.
Bonnefond A, Froguel P. Rare and common genetic events in type 2 diabetes: what should biologists know? Cell Metab. 2015;21(3):357–68.
Steinthorsdottir V, Thorleifsson G, Sulem P, Helgason H, Grarup N, Sigurdsson A, et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat Genet. 2014;46(3):294–8.
Yaghootkar H, Stancakova A, Freathy RM, Vangipurapu J, Weedon MN, Xie W, et al. Association analysis of 29,956 individuals confirms that a low frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion. Diabetes. 2015.
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320–3.
Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest. 2004;114(7):963–8.
Kushner JA, Ciemerych MA, Sicinska E, Wartschow LM, Teta M, Long SY, et al. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol. 2005;25(9):3752–62.
Bonnefond A, Clement N, Fawcett K, Yengo L, Vaillant E, Guillaume JL, et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet. 2012;44(3):297–301.
Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014;46(4):357–63.
Majithia AR, Flannick J, Shahinian P, Guo M, Bray MA, Fontanillas P, et al. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc Natl Acad Sci U S A. 2014;111(36):13127–32.
Boden G, Chen X, Urbain JL. Evidence for a circadian rhythm of insulin sensitivity in patients with NIDDM caused by cyclic changes in hepatic glucose production. Diabetes. 1996;45(8):1044–50.
Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, Sparso T, Holmkvist J, Marchand M, et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet. 2009;41(1):89–94.
Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, et al. In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci. 2006;119(Pt 20):4199–206.
Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de Plas R, Granvik M, et al. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc Natl Acad Sci U S A. 2009;106(35):14872–7.
Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402(6764):880–3.
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26(1):76–80.
Consortium STD, Estrada K, Aukrust I, Bjorkhaug L, Burtt NP, Mercader JM, et al. Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA. 2014;311(22):2305–14.
Holmen OL, Zhang H, Zhou W, Schmidt E, Hovelson DH, Langhammer A, et al. No large-effect low-frequency coding variation found for myocardial infarction. Hum Mol Genet. 2014;23(17):4721–8.
Mahajan A, Sim X, Ng HJ, Manning A, Rivas MA, Highland HM, et al. Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus. PLoS Genet. 2015;11(1):e1004876.
Huyghe JR, Jackson AU, Fogarty MP, Buchkovich ML, Stancakova A, Stringham HM, et al. Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat Genet. 2013;45(2):197–201.
Wessel J, Chu AY, Willems SM, Wang S, Yaghootkar H, Brody JA, et al. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun. 2015;6:5897.
Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91(1):301–7.
Holmen OL, Zhang H, Fan Y, Hovelson DH, Schmidt EM, Zhou W, et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet. 2014;46(4):345–51.
Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–6.
Hegele RA, Cao H, Harris SB, Hanley AJ, Zinman B. The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab. 1999;84(3):1077–82.
Triggs-Raine BL, Kirkpatrick RD, Kelly SL, Norquay LD, Cattini PA, Yamagata K, et al. HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc Natl Acad Sci U S A. 2002;99(7):4614–9.
Harries LW, Sloman MJ, Sellers EA, Hattersley AT, Ellard S. Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts. Diabetes. 2008;57(7):1978–82.
Moltke I, Grarup N, Jorgensen ME, Bjerregaard P, Treebak JT, Fumagalli M, et al. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature. 2014;512(7513):190–3.
Compliance with Ethics Guidelines
Conflict of Interest
Lorena Boquete Vilarino reports grants from Diabetes UK, during the conduct of the study. Timothy Frayling reports grants from Diabetes UK, grants from European Research Council, personal fees from Boehringer Ingelheim, during the conduct of the study.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the author.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Diabetes + Insulin Resistance
Rights and permissions
About this article
Cite this article
Boquete Vilariño, L., Frayling, T.M. The Hunt for Low-Frequency Alleles Predisposing to Type 2 Diabetes and Related Cardiovascular Risk Factors. Curr Cardiovasc Risk Rep 9, 47 (2015). https://doi.org/10.1007/s12170-015-0475-0
Published:
DOI: https://doi.org/10.1007/s12170-015-0475-0