Detailed Investigation of the Role of Common and Low-frequency WFS1 Variants in Type 2 Diabetes Risk

Overview

Journal Diabetes

Specialty Endocrinology

Date 2009 Dec 24

PMID 20028947

Citations 21

Authors

Katherine A Fawcett

Eleanor Wheeler

Andrew P Morris

Sally L Ricketts

Goran Hallmans

Olov Rolandsson

Allan Daly

Jon Wasson

Alan Permutt

Andrew T Hattersley

Benjamin Glaser

Paul W Franks

Mark I McCarthy

Nicholas J Wareham

Manjinder S Sandhu

Ines Barroso

Affiliations

Soon will be listed here.

Abstract

Objective: Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk.

Research Design And Methods: For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects.

Results: Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x 10(-7) on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01-0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes.

Conclusions: We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.

Citing Articles

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Gong M, Fang Y, Yang K, Yuan F, Hu R, Su Y Adv Sci (Weinh). 2024; 11(41):e2403405.

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The miR-668 binding site variant rs1046322 on is associated with obesity in Southeast Asians.

Hammad M, Abu-Farha M, Hebbar P, Anoop E, Chandy B, Melhem M Front Endocrinol (Lausanne). 2023; 14:1185956.

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Jan A, Saeed M, Zakiullah , Akbar R, Khan H J ASEAN Fed Endocr Soc. 2023; 38(1):48-54.

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Ustianowski P, Malinowski D, Safranow K, Dziedziejko V, Tarnowski M, Pawlik A J Pers Med. 2022; 12(2).

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SNPs in miRNAs and Target Sequences: Role in Cancer and Diabetes.

Chhichholiya Y, Suryan A, Suman P, Munshi A, Singh S Front Genet. 2021; 12:793523.

PMID: 34925466 PMC: 8673831. DOI: 10.3389/fgene.2021.793523.

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