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Diabetologia

, Volume 56, Issue 3, pp 492–496 | Cite as

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes

  • A. Bonnefond
  • L. Yengo
  • J. Philippe
  • A. Dechaume
  • I. Ezzidi
  • E. Vaillant
  • A. P. Gjesing
  • E. A. Andersson
  • S. Czernichow
  • S. Hercberg
  • S. Hadjadj
  • G. Charpentier
  • O. Lantieri
  • B. Balkau
  • M. Marre
  • O. Pedersen
  • T. Hansen
  • P. FroguelEmail author
  • M. VaxillaireEmail author
Short Communication

Abstract

Aims/hypothesis

MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits.

Methods

BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case–control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models.

Results

No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified.

Conclusions/interpretation

No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation.

Keywords

BLK Diabesity Genetics Low-frequency variant Maturity-onset diabetes of the young MODY Mutation Type 2 diabetes 

Abbreviation

DESIR

Data from an Epidemiological Study on the Insulin Resistance Syndrome

HOMA-B

Homeostasis model assessment of pancreatic beta cell function

HOMA-IR

Homeostasis model assessment of insulin resistance

SUVIMAX

Supplementation en Vitamines et Mineraux Antioxydants

Introduction

MODY is a genetically and clinically heterogeneous form of non-autoimmune diabetes that is characterised by a highly penetrant autosomal-dominant mode of inheritance, an early age of onset (usually before 25 years) and a primary dysfunction of the pancreatic beta cells [1, 2].

So far, 13 MODY genes have been identified [3]. Among these, BLK (MODY11) encodes a non-receptor tyrosine-kinase of the SRC family of proto-oncogenes, which is present in many tissues and cells including pancreatic beta cells [4]. Five rare mutations were shown to segregate with diabetes in three MODY families: four mutations are located in non-coding regions (at the end of the non-coding 3′ untranslated region or outside the gene) and only one non-synonymous mutation (p.A71T) was found in the fourth exon of BLK [4]. The p.A71T mutation is part of a haplotype including two of the non-coding mutations [4]. It was shown that BLK overexpression in the MIN6 pancreatic beta cell line enhanced insulin content and insulin secretion in response to glucose [4]. These actions were greatly attenuated by the BLK-p.A71T mutation [4]. Since this report, no study has attempted to replicate these data, in particular to confirm BLK firmly as a MODY susceptibility gene in other cohorts.

In the present study, we investigated the role of BLK in MODY in two European cohorts of unelucidated MODY patients (MODY-X). Furthermore, we assessed the contribution of the BLK-p.A71T mutation to type 2 diabetes risk and to the variation of related traits, as we found that this mutation is not rare in the general European population.

Methods

Patients selected for BLK sequencing

We studied 14 probands from MODY-X families recruited at the CNRS-UMR-8199 unit in Lille (France), who were diagnosed with diabetes before 36 years of age (10 of whom were diagnosed before 25 years of age). As previously published, these families are of French European origin, except one family from Mauritius [5]. We also studied 39 probands from Danish MODY-X families collected at the Steno Diabetes Center (Copenhagen, Denmark) (age at diagnosis 9–25 years) [6] and 11 additional patients from families with a vertical transmission of diabetes (at least one family member presented with diabetes diagnosed before 25 years of age). The clinical features of these patients are reported in Table 1 of the electronic supplementary material (ESM).

Sequencing protocol

BLK is located on human chromosome 8p23-p22 and encodes a 505-amino-acid protein (NM_001715.2; NP_001706.2 [NCBI36]). Genomic DNA was amplified by PCR with primers designed to cover the 13 exons and flanking intron–exon boundaries of BLK. A standard sequencing protocol was subsequently used [7].

Study cohorts

The case–control study included 4,901 French type 2 diabetic individuals and 4,280 French normoglycaemic controls (age at examination ≥45 years) (ESM Table 2). Type 2 diabetic individuals were recruited by the CNRS-UMR-8199 unit (n = 335), Corbeil-Essonnes Hospital (n = 2,182), Diab2-Néphrogène study (n = 1,997), DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) (n = 304) and the SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) study (n = 83), as previously described [7]. Control individuals were recruited by the CNRS-UMR-8199 unit (n = 249), the DESIR (n = 3,118) and SUVIMAX (n = 913) cohorts [7].

All participants with type 2 diabetes or normoglycaemia were defined as such according to the 2003 American Diabetes Association criteria.

Non-diabetic participants in the DESIR (n = 4,760) and SUVIMAX (n = 1,758) cohorts were also analysed for metabolic quantitative traits (ESM Table 2).

All studies were approved by local ethics committees and were performed according to the principles of the Helsinki Declaration II. Written informed consent was obtained from all participants.

Genotyping of the p.A71T variant

Genotyping was performed using the high-resolution melting method on a LightCycler 480 PCR System (Roche Diagnostics, Meylan, France), as previously described [7]. Positive signals were confirmed by sequencing, with a concordance rate of 99% between genotyping and sequencing results. A genotype call rate of at least 96% was obtained in each cohort. No deviation from Hardy–Weinberg equilibrium (p > 0.05) was detected in any of the studied populations.

Statistical analyses

The association between the p.A71T variant and the risk of type 2 diabetes or the variation of related metabolic traits was assessed using logistic or linear regression models, respectively, which were adjusted for age, sex and BMI (when appropriate) under a dominant model. By applying a Bonferroni correction, a p value below 5.6 × 10−3 = 0.05/(6[metabolic traits] + 3[type 2 diabetes case–controls]) was considered significant, and between 0.05 and 5.6 × 10−3 was considered nominal (trend of association).

We assessed the power of our study using QUANTO software. The statistical power to detect an OR of 1.45 was 86% in the overall case–control analysis (all cases, n = 4,901) and 80% when the cases were stratified according to BMI <30 or ≥30 kg/m2. In the non-diabetic participants in the DESIR (n = 4,760) and SUVIMAX (n = 1,758) cohorts, the statistical power to detect an effect on BMI variation between 2 and 5 kg/m2 was higher than 99%. All statistical analyses were performed with SPSS (version 14.0,) and QUANTO (version 1.2.4, http://hydra.usc.edu/GxE/) software.

Homeostasis model assessment of pancreatic beta cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated as previously described [8].

Results

No rare non-synonymous BLK mutations were found in French and Danish MODY patients (n = 64); in particular, the c.211G>A/p.A71T mutation was not identified. Of note, the previously identified extragenic or non-coding mutations were not screened in these patients, because, first, two of these variants were reported to be unequivocally transmitted together with the missense p.A71T mutation; and, second, the effect of these mutations on pancreatic beta cell function was not investigated, contrary to the p.A71T mutation [4]. The 1000 Genomes Project and the NHLBI Exome Sequencing Project listed the BLK c.211G>A/p.A71T mutation as a low-frequency variant in Europeans (rs55758736; minor allele frequency 0.012–0.013). We genotyped this variant in the DESIR French general population (n = 5,064) and found 58 carriers of the A allele, including 52 normoglycaemic carriers (age at examination 31–65 years). We therefore concluded that the p.A71T variant was unlikely to cause MODY, which is a highly penetrant disorder.

The c.211G>A/p.A71T variant was further genotyped in French type 2 diabetic individuals (n = 4,901) and control samples (n = 4,280). We found a nominal effect of the A allele on increased type 2 diabetes risk (OR 1.47 [95% CI 1.03, 2.11], p = 0.035; Table 1). As most of the carriers of the BLK c.211G>A/p.A71T mutation in the MODY family reported by Borowiec et al were overweight or obese [4], we stratified the diabetic individuals according to BMI (BMI <30 kg/m2, n = 2,456; BMI ≥30 kg/m2, n = 2,445). We found an enrichment of the A allele in obese diabetic participants only (OR 2.44 [95% CI 1.32, 4.49], p = 4.29 × 10−3; Table 1), in contrast to non-obese diabetic participants (p = 0.145; Table 1).
Table 1

Effect of the BLK c.211G>A/p.A71T variant on type 2 diabetes risk

Group

A allele frequency (%)

n

Genotype counts (%)

ORa (95 % CI)

p dom

GG

GA

AA

Controls

0.95

4,280

4,198 (98.08)

82 (1.92)

0 (0.00)

Ref.

Ref.

All type 2 diabetes

1.27

4,901

4,779 (97.51)

120 (2.45)

2 (0.04)

1.47 (1.03, 2.11)

0.035

Non-obese type 2 diabetes (BMI <30 kg/m2)

1.22

2,456

2,396 (97.56)

60 (2.44)

0 (0.00)

1.32 (0.91, 1.93)

0.145

Obese type 2 diabetes (BMI ≥30 kg/m2)

1.31

2,445

2,383 (97.46)

60 (2.46)

2 (0.08)

2.44 (1.32, 4.49)

4.29 × 10−3

aOR was assessed by logistic regression adjusted for age, sex and BMI, under a dominant model

Despite high statistical power, no nominal or significant association was found between the c.211G>A/p.A71T variant and BMI variation in 6,518 non-diabetic participants (p = 0.576; Table 2). Surprisingly, in the 4,760 non-diabetic participants from DESIR, the reported MODY A allele was associated with decreased HbA1c levels (β [SE] = −0.139[0.050]%, p = 5.27 × 10−3; Table 2) and an increase in beta cell function modelled by HOMA-B (β = 0.185[0.066], p = 5.37 × 10−3; Table 2), which does not fit with a MODY phenotype. No association was found for fasting glucose levels, fasting insulin levels or HOMA-IR (Table 2).
Table 2

Effect of the BLK c.211G>A/p.A71T variant on the variation of metabolic traits in non-diabetic participants in the DESIR and SUVIMAX studies

Metabolic traits

n

Mean/median data level by genotype

βa (SE)

p dom

GG

GA

AA

BMI (kg/m2)

6,518

24.38 ± 3.69

23.93 ± 3.79

NA

−0.189 (0.34)

0.576

Fasting glucose (mmol/l)

4,760

5.28 ± 0.53

5.15 ± 0.58

NA

−0.108 (0.07)

0.102

Fasting insulin (pmol/l)

4,760

39.2 (28.6;55.8)

40.4 (26.5;61.4)

NA

0.034 (0.06)

0.587

HOMA-B

4,760

68.1 (48.9;94.6)

73.2 (53.7;107.4)

NA

0.185 (0.07)

5.37 × 10−3

HOMA-IR

4,760

9.1 (6.5;13.5)

9.2 (5.8;14.1)

NA

0.011 (0.07)

0.865

HbA1c (%)

4,760

5.43 ± 0.40

5.27 ± 0.46

NA

−0.139 (0.05)

5.27 × 10−3

HbA1c (mmol/mol)

4,760

34.10 ± 4.60

32.24 ± 5.22

NA

−1.589 (0.58)

5.27 × 10−3

Data are presented as mean ± standard deviation or median (interquartile range)

Data for fasting serum insulin, HOMA-B and HOMA-IR were loge transformed before statistical analysis

aPer A allele effect size: coefficient β from dominant linear regression models adjusted for age, sex and BMI, except for the analysis of BMI that was adjusted for age and sex

NA, not applicable

Discussion

In this study, we identified numerous elderly normoglycaemic carriers of the BLK-p.A71T mutation, which does not fit with either rarity and high penetrance of a MODY gene mutation or the usual clinical features [3, 9, 10]. Furthermore, we did not find any other coding mutations in two European cohorts that included 64 MODY patients.

We observed a weak effect of the loss-of-function BLK-p.A71T mutation on increased type 2 diabetes risk, with an enrichment of the variant in obese diabetic cases, although no association with BMI was found. The BLK-p.A71T variant may therefore be ‘diabetogenic’ through obesity-related mechanisms, as previously described for some more frequent genetic variants such as the ENPP1-K121Q, PPARG-P12A or ADIPOQ polymorphisms [11, 12, 13, 14]. Twelve out of 13 carriers of the p.A71T variant in the MODY family reported by Borowiec et al were overweight, of whom eight were obese [4]. The only carrier presenting with a normal BMI was non-diabetic at age 71 years [4]. This is in line with our present results and may reflect a modulation of the p.A71T variant effect by adiposity on type 2 diabetes risk.

Of note, the meta-analyses of European genome-wide association studies performed by the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) or the Genetic Investigation of ANthropometric Traits (GIANT) Consortium, did not show any evidence of associations between variants at the BLK locus and risk of type 2 diabetes or variation of metabolic traits including BMI, fasting glucose, fasting insulin, HbA1c or HOMA-B (ESM Figure 1). Our present results on the contribution of the BLK-p.A71T variant to the risk of type 2 diabetes or the variation of HbA1c or HOMA-B are therefore likely to be nominal associations only.

In conclusion, we demonstrated that the loss-of-function BLK-p.A71T mutation is very unlikely to cause MODY. Instead, it may modestly influence type 2 diabetes risk through an interaction with obesity, although this will require further validation in additional studies.

Notes

Acknowledgements

We are sincerely indebted to all participants in the genetic studies. We thank F. Allegaert and M. Deweirder for their careful management of DNA samples, and P. Gallina for his help in family recruitment (all are members of the CNRS-UMR-8199 unit at Lille Pasteur Institute). We thank all members of the SUVIMAX Study Group and all scientists, dietitians, technicians and assistants who helped carry out the SUVIMAX study.

The DESIR Study Group is composed of Inserm-U1018 (Paris: B. Balkau, P. Ducimetière, E. Eschwège), Inserm-U367 (Paris: F. Alhenc-Gelas), CHU d’Angers (A. Girault), Bichat Hospital (Paris: F. Fumeron, M. Marre, R. Roussel); CHU de Rennes (F. Bonnet), CNRS-UMR-8199 (Lille: S. Cauchi, P. Froguel), Medical Examination Services (Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, Le Mans, Orléans and Tours), Research Institute for General Medicine (J. Cogneau), General practitioners of the region, and Cross-Regional Institute for Health (C. Born, E. Caces, M. Cailleau, N. Copin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol).

We thank the MAGIC, DIAGRAM and GIANT consortia for making their data available. Data on type 2 diabetes risk were contributed by DIAGRAM investigators and were downloaded from www.well.ox.ac.uk/DIAGRAM/. Data on glycaemia, insulinaemia and HbA1c traits were contributed by MAGIC investigators and were downloaded from www.magicinvestigators.org. Data on BMI traits were contributed by GIANT investigators and were downloaded from www.broadinstitute.org/collaboration/giant/index.php/Main_Page.

Funding

The study was supported by the French Agence Nationale de la Recherche through a transnational research grant on Rare Diseases (EuroGeBeta, ERANET-09 RARE-005 to MV), the Contrat de Projets Etat-Région Nord-Pas-De-Calais (CPER 2007-2013 ‘Axe Cardio-Diabète’ to MV and PF), the Danish Diabetes Association and the Danish Council for Independent Research (Medical Sciences). The Diab2-Néphrogène study was made possible with the financial support of AFD-Association Française des Diabétiques (Research Grant 2003), GEMMS-Poitiers, University of Poitiers (AO Recherche 2001) and French Ministry of Health (PHRC 2002-PHRC 2008). The DESIR study has been supported by Inserm contracts with CNAMTS, Lilly, Novartis Pharma and Sanofi-aventis, and by Inserm (Réseaux en Santé Publique, Interactions entre les déterminants de la santé, Cohortes Santé TGIR 2008), the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Société Francophone du Diabète, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche and Topcon.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

AB and MV conceived and designed the study, and wrote the paper; AB, LY and MV performed the genetic analyses and interpreted the data; AD and IE performed the sequencing and analysed the data; JP and EV performed the genotyping and analysed the data; APG, EAA, SC, SHer, SHad, GC, OL, BB, MM, OP, TH and PF contributed to cohort-study samples and clinical data; PF reviewed the manuscript and contributed to the discussion. LY, AD, IE, JP, EV, APG, EAA, SC, SHer, SHad, GC, OL, BB, MM, OP and TH revised the final version of the manuscript. MV is the guarantor of the manuscript. All authors have read and approved the final version of the article.

Supplementary material

125_2012_2794_MOESM1_ESM.pdf (13 kb)
ESM Table 1 PDF 12 kb
125_2012_2794_MOESM2_ESM.pdf (10 kb)
ESM Table 2 PDF 9 kb
125_2012_2794_MOESM3_ESM.pdf (253 kb)
ESM Fig. 1 PDF 253 kb

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • A. Bonnefond
    • 1
    • 2
  • L. Yengo
    • 1
    • 2
  • J. Philippe
    • 1
    • 2
  • A. Dechaume
    • 1
    • 2
  • I. Ezzidi
    • 3
  • E. Vaillant
    • 1
    • 2
  • A. P. Gjesing
    • 4
  • E. A. Andersson
    • 4
  • S. Czernichow
    • 5
    • 6
  • S. Hercberg
    • 7
    • 8
  • S. Hadjadj
    • 9
    • 10
  • G. Charpentier
    • 11
  • O. Lantieri
    • 12
  • B. Balkau
    • 13
    • 14
  • M. Marre
    • 15
    • 16
  • O. Pedersen
    • 4
    • 17
    • 18
  • T. Hansen
    • 4
    • 17
    • 19
  • P. Froguel
    • 1
    • 2
    • 20
    Email author
  • M. Vaxillaire
    • 1
    • 2
    Email author
  1. 1.CNRS-UMR-8199, Lille Pasteur InstituteLille CedexFrance
  2. 2.Lille Nord de France UniversityLilleFrance
  3. 3.Research Unit of Biology and Genetics of Hematological and Auto-immune Diseases, Faculty of Pharmacy of MonastirUniversity of MonastirMonastirTunisia
  4. 4.The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
  5. 5.University Versailles St-Quentin and Department of Nutrition, Ambroise Paré HospitalBoulogne-BillancourtFrance
  6. 6.Inserm-U1018, Centre for Research in Epidemiology and Population HealthVillejuifFrance
  7. 7.Inserm-U557, Institut National de la Recherche Agronomique-1125 Unit, Conservatoire National des Arts et Métiers, Centre de Recherches en Nutrition HumaineParis 13 UniversityBobignyFrance
  8. 8.Department of Public HealthAvicenne Hospital, AP-HPBobignyFrance
  9. 9.Centre Hospitalier Universitaire Poitiers, Department of Endocrinology and DiabetologyPoitiersFrance
  10. 10.Inserm-U927 and Biotheque of the Clinical Investigation Centre of Poitiers (CIC0802)PoitiersFrance
  11. 11.Department of Endocrinology and Diabetology, Corbeil-Essonnes HospitalCorbeil-EssonnesFrance
  12. 12.Institut Inter-Régional pour la Santé (IRSA)La RicheFrance
  13. 13.Inserm-U780, Centre for Research in Epidemiology and Population HealthVillejuifFrance
  14. 14.Paris-Sud 11 UniversityOrsayFrance
  15. 15.Department of Endocrinology, Diabetology and NutritionBichat-Claude Bernard University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP)ParisFrance
  16. 16.Inserm-U695Paris 7 UniversityParisFrance
  17. 17.Steno Diabetes Center and Hagedorn Research InstituteGentofteDenmark
  18. 18.Faculty of Health SciencesUniversity of AarhusAarhusDenmark
  19. 19.Faculty of Health SciencesUniversity of Southern DenmarkOdenseDenmark
  20. 20.Department of Genomic MedicineSchool Of Public Health, Hammersmith Hospital, Imperial College LondonLondonUK

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