Journal of Molecular Medicine

, Volume 85, Issue 7, pp 777–782 | Cite as

TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis

  • Stéphane Cauchi
  • Younes El Achhab
  • Hélène Choquet
  • Christian Dina
  • Franz Krempler
  • Raimund Weitgasser
  • Chakib Nejjari
  • Wolfgang Patsch
  • Mohamed Chikri
  • David Meyre
  • Philippe Froguel
Rapid Communication

Abstract

TCF7L2 variants have been consistently associated with type 2 diabetes (T2D) in populations of different ethnic descent. Among them, the rs7903146 T allele is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. In the present study, we investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects). Then, we systematically reviewed the association of this single nucleotide polymorphism (SNP) with T2D risk in a meta-analysis, combining our data with data from previous studies. The allelic odds ratios (ORs) for T2D were 1.56 [1.29–1.89] (p = 2.9 × 10−6) and 1.52 [1.29–1.78] (p = 3.0 × 10−7) in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test (χ2 = 0.04, df = 1, p = 0.84). We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. A meta-analysis was then performed on 29,195 control subjects and 17,202 cases. No heterogeneity in genotypic distribution was found (Woolf test: χ2 = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). A Mantel–Haenszel procedure was then performed to provide a pooled odds ratio (OR) of 1.46 [1.42–1.51] (p = 5.4 × 10−140). No publication bias was detected, using the conservative Egger’s regression asymmetry test (t = −1.6, df = 25, p = 0.11). Compared to any other gene variants previously confirmed by meta-analysis, TCF7L2 can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high. In the near future, large-scale genome-wide association studies will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2.

Introduction

TCF7L2 rs7903146 T allele has been consistently associated with type 2 diabetes (T2D) in individuals of European [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14], Asian [7, 15, 16, 17], and African descent [7, 18], so far. Despite comprehensive genotyping efforts across this gene locus [1, 2, 4, 18], this single nucleotide polymorphism (SNP) always showed the strongest association with T2D. Furthermore, Helgason et al. [18] reported that the rs7903146 T allele is probably the ancestral allele and concluded that if this allele is not itself the causative variant, then the unidentified functional variant it tags is likely to lie outside the screened locus. Thus, genotyping this polymorphism is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups, and combining data related to this SNP is likely to be sufficient for a meta-analysis of the global contribution of the gene on T2D. In the present study, we examined the association between the TCF7L2 rs7903146 polymorphism and T2D in two additional populations of different ethnic descents, Central Europeans and, for the first time, North Africans. Then, we systematically reviewed the association of this polymorphism with T2D risk in a meta-analysis combining our data with those from previous studies.

Results

The contribution of the rs7903146 T allele to T2D was assessed in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects) [19], and in Moroccans (406 normoglycemic individuals and 504 T2D subjects). Clinical characteristics and allelic distributions of both populations are reported in Tables 1 and 2. All genotypic distributions were in Hardy–Weinberg equilibrium. The allelic odds ratios (ORs) for T2D were 1.56[1.29–1.89] (p = 2.9 × 10−6) and 1.52[1.29–1.78] (p = 3.0 × 10−7) in Moroccans and Austrians, respectively (Table 2). No heterogeneity was found between these two different populations by Woolf test (χ2 = 0.04, df = 1, p = 0.84). The genetic models were found to be multiplicative in Moroccans (p = 4.1 × 10−5) and in Austrians (p = 3.2 × 10−7), rather than departing from linearity (p = 0.13 and p = 0.19, respectively).
Table 1

Clinical characteristics (means ± SD) of the T2D case-control studies

Status

Moroccan

Austrian

Control

T2D

Control

T2D

N

406

504

1,075

486

Sex ratio (male/female)

121/285

156/348

725/350

285/201

Age at examination (years)

55 ± 12

58 ± 11

51.5 ± 6.0

56.5 ± 9.6

Age at diagnosis (years)

na

51 ± 12

na

49.3 ± 9.5

BMI (kg/m2)

27.2 ± 5.3

28.0 ± 4.7

26.4 ± 4.0

30.7 ± 6.3

Data presented as means ± SD

na Not available

Table 2

Genotypic distributions of rs7903146 among Moroccan and Austrian populations

Parameters

Moroccan (control/T2D)

Austrian (control/T2D)

C/C

176/140

555/200

C/T

185/277

432/208

T/T

54/99

88/78

Hwe (control)

0.67

0.76

HWE (T2D)

0.08

0.07

MAF% (control)

35.3

28.3

MAF% (T2D)

46

37.4

Allelic OR [95% CI]

1.56 [1.92–1.89]

1.52 [1.29–1.78]

p value

2.9 × 10−6

3.0 × 10−7

HWE: p value for Hardy–Weinberg Equilibrium

We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. Unfortunately, the data available on Mexican-American population were not detailed enough to include them in the present analysis [14]. From these studies, a total of 27,705 control individuals and 16,200 subjects with T2D have been analyzed for disease association between T2D and the T allele variant. If we include our own study cohorts (Austrians and Moroccans),the overall total would add up to 29,195 control subjects and 17,202 cases. Considering that all publications were consistent with a multiplicative model of inheritance, the relative risk for T2D was only estimated by allelic odds ratios. No heterogeneity in genotypic distribution was found (Woolf test: χ2 = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%).

A Mantel–Haenszel procedure was then performed to provide a pooled odds ratio of 1.46[1.42–1.51] (p = 5.4 × 10−140) (Fig. 1). No publication bias was detected, using the conservative Egger’s regression asymmetry test (t = −1.6, df = 25, p = 0.11).
Fig. 1

Association of the TCF7L2 rs7903146 T allele with T2D: Data are shown for allelic odds ratios based on allele counts. MAF stands for minor allele frequency in controls. For each study, the point estimate is given by a square whose height is inversely proportional to the standard error of the estimate and the extent of the 95% around the estimate is given by the horizontal line. The summary odds ratio is drawn as a diamond with horizontal limits at the confidence limits and width inversely proportional to its standard error. In this meta-analysis, we were able to compare 29,195 control individuals with 17,202 subjects with T2D. No heterogeneity in genotypic distribution was found (Woolf test: χ2 = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). No publication bias was detected, using the conservative Egger’s regression asymmetry test (t = −1.6, df = 25, p = 0.11). A mantel-Haenszel (fixed effects) procedure was then performed to provide a pool odds ratio.

Several other genes have been previously associated with T2D by meta-analysis [20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. KCNJ11 and PPARG have reached genome-wide association levels of significance and the role of other genes have been under debate. The TCF7L2 gene can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high (Fig. 2).
Fig. 2

TCF7L2, the most reproducible risk for T2D by a gene variant so far: data are shown for allelic odds ratios based on meta-analyses previously published. The 95% CI for each meta-analysis is represented by a horizontal line. The square’s area is proportional to the statistical weight of each meta-analysis

Discussion

We positively replicated the association of TCF7L2 variation and T2D in two populations of different ethnic descent, Central Europeans and, for the first time, North Africans. The most striking result is the very stable relative risk (around 50%) conferred by the rs7903146 T allele in these two geographically, ethnically, and environmentally diverse populations. The meta-analysis of 27 different studies confirms this finding with a resulting global OR of 1.46 [1.42–1.51], suggesting that in any tested human population the effect of TCF7L2 is very similar. The absence of heterogeneity between studies is also indicative of a universal contribution of this gene to T2D, the population-attributable risk being only driven by the prevalence of the T allele in a specific ethnic group. This situation is unique as previous candidate genes for T2D have always shown some degree of discrepancy between populations [20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. TCF7L2 has moved rapidly from a novel positional candidate gene to a reference gene for T2D susceptibility [1, 30]. In most ethnic groups, except for Eastern Asians [16, 17], a highly frequent T allele (ranging from 18–35% for controls to 22–45% for cases) offers the possibility to get enough statistical power for association studies [18]. Consequently, almost all published case-control studies were able to detect an association with T2D, except for those with few participants or without clear ethnic belonging [4, 7]. However, even among Caucasian populations there are substantial differences in T allele frequency, e.g., 17% difference between Finns [2] and Moroccans (this study).

So far, few other SNPs have been reproducibly associated with T2D [20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. The comparison between meta-analyses (shown in Fig. 2) clearly illustrates that the magnitude of the TCF7L2 effect is much higher than any other confirmed T2D candidate. The individual effects of the other variants are modest, ranging from 10 to 30%. Interestingly, no major interactions with the T allele have been found to strongly modulate T2D susceptibility, even if body mass index [5, 7, 9, 16, 18], gender [10], drugs [9], or lifestyle interventions [9] may modulate TCF7L2 effects. No functional significance has been attributed to the TCF7L2 T allele so far, which is also different from most T2D SNPs listed in Fig. 2. In rodents, the Wnt/β-catenin signaling pathway is important for the development of pancreas [31, 32], but the pathophysiology of the TCF7L2-associated T2D remains to be clarified in humans.

The binding of transcription factors and alternative splicing events should be studied in the intronic region where the T allele is located. Recent theoretical studies have emphasized that as few as 20 susceptibility variants on the scale of those in TCF7L2 may suffice to explain as much as 50% of the burden of the disease [33]. In the near future, large-scale genome-wide association data will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2 [34].

Materials and methods

Subjects

Two populations with different ethnic backgrounds were analyzed: white Austrians from central Europe [19] and Moroccans from North Africa.

Moroccan subjects were recruited by the Faculty of Medicine (Fes) and were subject to a standardized clinical examination at the Hassan II Hospital. Inclusion criteria for cases were: (1) T2D according to 1997 American Diabetes Association (ADA) criteria; (2) family history of diabetes in first degree relatives; (3) BMI <30 kg/m2. Inclusion criteria for controls were: (1) age at examination over 45 yr.; (2) normal fasting glucose according to 1997 ADA criteria; (3) BMI <27 kg/m2.

Austrian subjects with T2D were recruited from diabetes outpatient clinics of the Landeskliniken Salzburg and the Hallein Hospital. Patients who were <73 years of age and <63 years of age at diagnosis were included. Participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (Saphir) who were not using hypoglycemic medications and had fasting blood glucose levels <110 mg/dl served as control subjects. Study populations comprised only white Europeans, mainly of Bavarian or Austrian-German descent, living in the same geographic region.

The main clinical characteristics were reported in Table 1. The genetic study was approved by local Ethical Committees and informed consent was obtained from all participants.Participants were considered as normoglycemic controls when their fasting glucose concentration was lower than 6.1 mmol/l.

Genotyping methods

High-throughput genotyping for the rs7903146 variant was performed using the TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA). The polymerase chain reaction (PCR) primers and TaqMan probes were designed by Primer Express and optimized according to the manufacturer’s protocol. There was a 98% genotyping success rate and the genotyping error rate was assessed by sequencing 384 control and 384 T2D individuals and by re-genotyping a random 10% sample. No difference was found with the first genotyping results, thus the genotyping error rate was 0%.

Statistical methods

Tests for deviation from Hardy–Weinberg equilibrium (HWE) and for association were performed with the De Finetti program (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). All P values were two-tailed. Meta-analysis was performed using the packages “rmeta” and “meta” of the R-Project (http://www.r-project.org).The Woolf test was first applied to test the genotypic heterogeneity between studied groups [35], then the Mantel–Haenszel procedure was performed to provide a pooled odds ratio with a 95% confidence interval. We performed the Higgins statistic (I2) to quantify the amount of between-study variability in effect attributable to true heterogeneity rather than chance [36]. We also used the Egger’s regression method to test for publication bias [37].

To assess whether the model of inheritance was multiplicative or departing from linearity, we applied a logistic regression test with two variables corresponding to genotypes v1 (coded 0, 1, 2), reflecting a linear increase in risk, and v2 (coded 0, 1, 0), reflecting a departure from linearity. Different meta-analyses of T2D association studies are discussed in Fig. 2: PPARG [20, 21], KCNJ11[22, 23], CAPN10 [24, 25], HNF1A [26], ENPP1 [27], and IL6 [28, 29]. We only reported studies with allelic odds ratios, based on diverse ethnic groups. SPSS 14.1 software (SPSS, Chicago, IL, USA) was used for general statistical analyses.

Notes

Acknowledgments

This work was partly supported by the French Governmental “Agence Nationale de la Recherche”, by the French-Moroccan convention “CNRST-CNRS”, and the charities: “Association Française des Diabétiques” and “Programme national de recherche sur le diabète” and “Association des diabétiques de la Wilaya de Fès”. We thank Marianne Deweider and Frederic Allegaert for the DNA bank management and Stefan Gaget for his help on phenotype databases. We are indebted to all subjects who participated to this study.

References

  1. 1.
    Grant SF, Thorleifsson G, Reynisdottir I et al (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323PubMedCrossRefGoogle Scholar
  2. 2.
    Scott LJ, Bonnycastle LL, Willer CJ et al (2006) Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes 55:2649–2653PubMedCrossRefGoogle Scholar
  3. 3.
    Groves CJ, Zeggini E, Minton J et al (2006) Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes 55:2640–2644PubMedCrossRefGoogle Scholar
  4. 4.
    Saxena R, Gianniny L, Burtt NP et al (2006) Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 55:2890–2895PubMedCrossRefGoogle Scholar
  5. 5.
    Cauchi S, Meyre D, Dina C et al (2006) Transcription factor TCF7L2 genetic study in the french population: expression in human {beta}—cells and adipose tissue and strong association with type 2 diabetes. Diabetes 55:2903–2908PubMedCrossRefGoogle Scholar
  6. 6.
    van Vliet-Ostaptchouk JV, Shiri-Sverdlov R, Zhernakova A et al (2007) Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort. Diabetologia 50:59–62PubMedCrossRefGoogle Scholar
  7. 7.
    Humphries SE, Gable D, Cooper JA et al (2006) 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 84:1–10PubMedCrossRefGoogle Scholar
  8. 8.
    Damcott CM, Pollin TI, Reinhart LJ et al (2006) Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes 55:2654–2659PubMedCrossRefGoogle Scholar
  9. 9.
    Florez JC, Jablonski KA, Bayley N et al (2006) TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355:241–250PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang C, Qi L, Hunter DJ et al (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of U.S. women and men. Diabetes 55:2645–2648PubMedCrossRefGoogle Scholar
  11. 11.
    Marzi C, Huth C, Kolz M et al (2007) Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA Surveys. Horm Metab Res 39:46–52PubMedCrossRefGoogle Scholar
  12. 12.
    Melzer D, Murray A, Hurst AJ et al (2006) Effects of the diabetes linked TCF7L2 polymorphism in a representative older population. BMC Med 4:34 DOI 10.1186/1741-7015-4-34
  13. 13.
    Mayans S, Lackovic K, Lindgren P et al (2007) TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden. Eur J Hum Genet 15:342–346PubMedCrossRefGoogle Scholar
  14. 14.
    Lehman DM, Hunt KJ, Leach RJ et al (2007) Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans. Diabetes 56:389–393PubMedCrossRefGoogle Scholar
  15. 15.
    Chandak GR, Janipalli CS, Bhaskar S et al (2007) Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 50:63–67PubMedCrossRefGoogle Scholar
  16. 16.
    Horikoshi M, Hara K, Ito C et al (2007) A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population. Diabetologia 50:747–751PubMedCrossRefGoogle Scholar
  17. 17.
    Hayashi T, Iwamoto Y, Kaku K et al (2007) Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia 50:980–984 (Electronic publication ahead of print)Google Scholar
  18. 18.
    Helgason A, Palsson S, Thorleifsson G et al (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39:218–225PubMedCrossRefGoogle Scholar
  19. 19.
    Oberkofler H, Linnemayr V, Weitgasser R et al (2004) Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes. Diabetes 53:1385–1393PubMedCrossRefGoogle Scholar
  20. 20.
    Altshuler D, Hirschhorn JN, Klannemark M et al (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80PubMedCrossRefGoogle Scholar
  21. 21.
    Barroso I, Luan J, Sandhu MS et al (2006) Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia 49:501–505PubMedCrossRefGoogle Scholar
  22. 22.
    Gloyn AL, Weedon MN, Owen KR et al (2003) Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52:568–572PubMedCrossRefGoogle Scholar
  23. 23.
    Love-Gregory L, Wasson J, Lin J et al (2003) E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of Type II diabetes in Caucasians as the PPARgamma Pro12Ala variant. Diabetologia 46:136–137PubMedGoogle Scholar
  24. 24.
    Weedon MN, Schwarz PE, Horikawa Y et al (2003) Meta-analysis and a large association study confirm a role for calpain-10 variation in type 2 diabetes susceptibility. Am J Hum Genet 73:1208–1212PubMedCrossRefGoogle Scholar
  25. 25.
    Tsuchiya T, Schwarz PE, Bosque-Plata LD et al (2006) Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses. Mol Genet Metab 89:174–184PubMedCrossRefGoogle Scholar
  26. 26.
    Weedon MN, Owen KR, Shields B et al (2005) A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population. Diabetes 54:2487–2491PubMedCrossRefGoogle Scholar
  27. 27.
    Weedon MN, Shields B, Hitman G et al (2006) No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians. Diabetes 55:3175–3179PubMedCrossRefGoogle Scholar
  28. 28.
    Qi L, van Dam RM, Meigs1 JB et al (2006) Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis. Hum Mol Genet 15:1914–1920PubMedCrossRefGoogle Scholar
  29. 29.
    Huth C, Heid IM, Vollmert C et al (2006) IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants’ data from 21 studies. Diabetes 55:2915–2921PubMedCrossRefGoogle Scholar
  30. 30.
    Zeggini E, McCarthy MI (2007) TCF7L2: the biggest story in diabetes genetics since HLA? Diabetologia 50:1–4PubMedCrossRefGoogle Scholar
  31. 31.
    Wang QM, Zhang Y, Yang KM et al (2006) Wnt/beta-catenin signaling pathway is active in pancreatic development of rat embryo. World J Gastroenterol 12:2615–2619PubMedGoogle Scholar
  32. 32.
    Wells JM, Esni F, Boivin GP et al (2007) Wnt/Beta-catenin signaling is required for development of the exocrine pancreas. BMC Dev Biol 7:4PubMedCrossRefGoogle Scholar
  33. 33.
    Yang Q, Khoury MJ, Friedman J et al (2005) How many genes underlie the occurrence of common complex diseases in the population? Int J Epidemiol 34:1129–1137PubMedCrossRefGoogle Scholar
  34. 34.
    Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885PubMedCrossRefGoogle Scholar
  35. 35.
    Agresti A (2002) Categorical data analysis. Wiley, New YorkGoogle Scholar
  36. 36.
    Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560PubMedCrossRefGoogle Scholar
  37. 37.
    Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Stéphane Cauchi
    • 1
  • Younes El Achhab
    • 2
  • Hélène Choquet
    • 1
  • Christian Dina
    • 1
  • Franz Krempler
    • 3
  • Raimund Weitgasser
    • 4
  • Chakib Nejjari
    • 2
  • Wolfgang Patsch
    • 5
  • Mohamed Chikri
    • 6
  • David Meyre
    • 1
  • Philippe Froguel
    • 1
    • 7
  1. 1.CNRS, 8090, Institute of BiologyPasteur InstituteLilleFrance
  2. 2.Laboratory of EpidemiologyFaculty of Medicine and Pharmacy of FezFezMorocco
  3. 3.Department of Internal MedicineKrankenhaus HalleinHalleinAustria
  4. 4.Department of Internal MedicineParacelsus Medical University and Landeskliniken SalzburgSalzburgAustria
  5. 5.Department of Laboratory MedicineParacelsus Medical University and Landeskrankenhaus SalzburgSalzburgAustria
  6. 6.Laboratory of BiochemistryFaculty of Medicine and Pharmacy of FezFezMorocco
  7. 7.Section of Genomic Medicine, Imperial College LondonHammersmith HospitalLondonUK

Personalised recommendations