Antonio Martinez

The BloodGen project: toward mass-scale comprehensive genotyping of blood donors in the European Union and beyond.

Neil D. Avent, Antonio Martinez, Willy A. Flegel, Martin L. Olsson, Marion L. Scott, Núria Nogués, Martin Písǎcka, Geoff Daniels, Ellen van der Schoot, Eduardo Muñiz-Diaz, Tracey E. Madgett, Jill R. Storry, Sigrid H. Beiboer, Petra A. Maaskant-van Wijk, Inge von Zabern, Elisa Jiménez, Diego Tejedor, Mónica López, Emma Camacho, Goedele Cheroutre, Anita Hacker, Pavel Jinoch, Irena Svobodova, and Masja de Haas

The Bloodgen Project of the European Union, 2003-2009

The Bloodgen project was funded by the European Commission between 2003 and 2006, and involved academic blood centres, universities, and Progenika Biopharma S.A., a commercial supplier of genotyping platforms that incorporate glass arrays. The project has led to the development of a commercially available product, BLOODchip, that can be used to comprehensively genotype an individual for all clinically significant blood groups. The intention of making this system available is that blood services and perhaps even hospital blood banks would be able to obtain extended information concerning the blood group of routine blood donors and vulnerable patient groups. This may be of significant use in the current management of multi-transfused patients who become alloimmunised due to incomplete matching of blood groups. In the future it can be envisaged that better matching of donor-patient blood could be achieved by comprehensive genotyping of every blood donor, especially regular ones. This situation could even be extended to genotyping every individual at birth, which may prove to have significant long-term health economic benefits as it may be coupled with detection of inborn errors of metabolism.

HLA-DRB1*1501 and Spinal Cord Magnetic Resonance Imaging Lesions in Multiple Sclerosis

BACKGROUND Multiple sclerosis (MS) is a heterogeneous neurologic disease with extensive variation with respect to the most affected central nervous system region (brain vs spinal cord). OBJECTIVE To test the hypothesis that this variation in lesion location (brain vs spinal cord) might be (partially) genetically determined. DESIGN Candidate gene study. SETTING Academic research. PATIENTS Patients were selected for the availability of DNA material, clinical variables, and brain and spinal cord magnetic resonance images (evaluating T2-weighted lesion load in the brain and the number of spinal cord lesions). MAIN OUTCOME MEASURES For genotyping, we used a DNA chip containing a set of genes mentioned in previous publications noting their relation to different phenotypes of MS. We assessed the association between brain and spinal cord abnormalities and the genotypes of the patients. RESULTS One hundred fifty patients were included in the analysis. Five single-nucleotide polymorphisms within the major histocompatibility complex region were associated with the number of focal abnormalities in the spinal cord. The most significant was rs3135388 (surrogate marker for the HLA-DRB1*1501 allele). Carriers of HLA-DRB1*1501 had a median of 4 spinal cord lesions compared with 2 lesions for noncarriers (P < .001). No significant association was noted between the single-nucleotide polymorphisms and T2-weighted lesion load in the brain. CONCLUSIONS Carriership of HLA-DRB1*1501 (via rs3135388) was associated with the extent of focal abnormalities in the spinal cord. Spinal cord lesions might be an explanation for increased MS disease severity in patients carrying HLA-DRB1*1501.

Can we predict top‐level sports performance in power vs endurance events? A genetic approach

The goal of our study was to discriminate potential genetic differences between humans who are in both endpoints of the sports performance continuum (i.e. world‐class endurance vs power athletes). We used DNA‐microarray technology that included 36 genetic variants (within 20 different genes) to compare the genetic profile obtained in two cohorts of world‐class endurance (N=100) and power male athletes (N=53) of the same ethnic origin. Stepwise multivariate logistic regression showed that the rs1800795 (IL6−174 G/C), rs1208 (NAT2 K268R) and rs2070744 (NOS3−786 T/C) polymorphisms significantly predicted sport performance (model χ2=25.3, df=3, P‐value <0.001). Receiver–operating characteristic (ROC) curve analysis showed a significant discriminating accuracy of the model, with an area under the ROC curve of 0.72 (95% confidence interval: 0.66–0.81). The contribution of the studied genetic factors to sports performance was 21.4%. In summary, although an individuals potential for excelling in endurance or power sports can be partly predicted based on specific genetic variants (many of which remain to be identified), the contribution of complex gene–gene interactions, environmental factors and epigenetic mechanisms are also important contributors to the “complex trait” of being an athletic champion. Such trait is likely not reducible to defined genetic polymorphisms.

Are elite endurance athletes genetically predisposed to lower disease risk

We compared a polygenic profile that combined 33 disease risk-related mutations and polymorphisms among nonathletic healthy control subjects and elite endurance athletes. The study sample comprised 100 healthy Spanish male nonathletic (sedentary) control subjects and 100 male elite endurance athletes. We analyzed 33 disease risk-related mutations and polymorphisms. We computed a health-related total genotype score (TGS, 0-100) from the accumulated combination of the 33 variants. We did not observe significant differences in genotype or allele distributions among groups, except for the rs4994 polymorphism (P < 0.001). The computed health-related TGS was similar among groups (23.8 +/- 1.0 vs. 24.2 +/- 0.8 in control subjects and athletes, respectively; P = 0.553). Similar results were obtained when computing specific TGSs for each main disease category (cardiovascular disease and cancer). We observed no evidence that male elite endurance athletes are genetically predisposed to have lower disease risk than matched nonathletic control subjects.

Genetic Correlations of Brain Lesion Distribution in Multiple Sclerosis: An Exploratory Study

BACKGROUND AND PURPOSE: In MS, the total brain lesion volume and spatial distribution of lesions across the brain vary widely among individual patients. We hypothesized that spatial distribution may be partially driven by genetic predisposition, and we aimed to explore relations among candidate genes and the spatial distribution of white matter brain lesions in MS. MATERIAL AND METHODS: Genotypes of 69 SNPs in 208 patients with MS were related to the spatial distribution of T2 brain lesions. Lesions were manually outlined on MR images, and binary lesion masks were produced and registered to a common space. With Randomise software, the lesion masks were related to genotype by using a voxelwise nonparametric GLM approach, followed by clusterwise analysis. We used a DNA chip with SNPs selected from the literature on MS susceptibility, severity, and phenotypes. RESULTS: For 11 of these SNPs, 1 of the genotypes expressed significant clusters of increased or decreased lesion probability in varying, predominantly periventricular, brain regions. When we statistically controlled the voxelwise analyses for effects of total brain lesion volume, only 1 SNP remained significant: rs2227139, located within the MHC class II region. This SNP retained its periventricular cluster of significantly increased lesion probability for the heterozygote genotype. CONCLUSIONS: Heterozygosity of rs2227139 (MHC class II region) is associated with increased right frontal periventricular lesion probability (P < .01). Ten other SNPs showed associations between genotype and spatial lesion distribution that are partly explained by total lesion volume.