Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.

Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population.

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10-6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10-10). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.

Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications.

Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.

High frequency of Parkin exon rearrangements in Mexican-mestizo patients with early-onset Parkinson's disease.

BACKGROUND: Parkin mutations in patients with early-onset Parkinson's disease (EOPD) are estimated to occur in 49% of familial cases and 18% of sporadic cases. METHODS: We analyzed the entire sequence-coding region and dosage mutations of parkin in 63 Mexican-mestizo EOPD patients and 120 controls. RESULTS: Parkin mutations were present in 34 patients (54.0%). Exon rearrangements, predominantly spanning exons 9 and 12 (31.7% and 19.0%, respectively) were present in 32 patients, with 17.5% carrying simple heterozygous and 25.4% carrying compound heterozygous parkin mutations. CONCLUSIONS: A higher frequency of parkin exon rearrangements than of sequence mutations was observed. Patients with parkin exons 9 and 12 rearrangements showed a later age at onset than did cases with other regions affected (40.3 ± 4.5 vs 30.1 ± 8.8; P = .005), suggesting a mutational hot spot in the etiology of Mexican-mestizo patients with EOPD. To our knowledge, this study represents the largest sampling of Mexican-mestizo patients with EOPD cases for which parkin sequence and dosage alterations were analyzed. .

[Frequency of apolipoprotein E in a Nahua population]. / Frecuencia de la apolipoproteína E en una población Nahua.

The presence of different ethnic groups in Mexico may give rise to genetic diversity between the native Indian population and the Mestizos. It is therefore of medical and anthropological interest to analyze the genotypes of disease-associated loci, such as polymorphism in the apolipoprotein E gene, whose 4/4 allele increases the risk of Alzheimer's disease and coronary heart disease in other populations. We studied a Nahua Indian-population in the State of Morelos (Santo Domingo Ocotitlan). The ABO blood type of all individuals was determined and compared with the findings of other Nahua group from the State of Puebla. Without statistical significant differences in O, A and AB groups between both populations (p > 0.05). The allelic and genotypic frequency of apolipoprotein E was similar to that observed in other Mexican indian (Mazatecans, Mayans) and Mestizo populations, however there was a statistically significant difference when the results were compared to the allelic frequencies of other Amerinds: The Cayapa (Ecuador) for the epsilon 3 and epsilon 4 alleles (p < 0.002); the Nuuk (Greenland) for epsilon 3 and epsilon 4 alleles (p < 0.0001 and p < 0.002 respectively); and the Ammssalik (Greenland) for both alleles with p < 0.0001 and p = 0.04 respectively. In the case of the genotypes, there was statistically significant difference for the 4/3 genotypes, but a non significant difference for the 4/4 genotype. This is a descriptive study which contributes to the knowledge of the genetic structure of Mexican population.