Isela Parra-Rojas

Admixture and population structure in Mexican-Mestizos based on paternal lineages

In the nonrecombining region of the Y-chromosome, there are single-nucleotide polymorphisms (Y-SNPs) that establish haplogroups with particular geographical origins (European, African, Native American, etc.). The complex process of admixture that gave rise to the majority of the current Mexican population (∼93%), known as Mestizos, can be examined with Y-SNPs to establish their paternal ancestry and population structure. We analyzed 18 Y-SNPs in 659 individuals from 10 Mexican-Mestizo populations from different regions of the country. In the total population sample, paternal ancestry was predominately European (64.9%), followed by Native American (30.8%) and African (4.2%). However, the European ancestry was prevalent in the north and west (66.7–95%) and, conversely, Native American ancestry increased in the center and southeast (37–50%), whereas the African ancestry was low and relatively homogeneous (0–8.8%). Although this paternal landscape concurs with previous studies based on genome-wide SNPs and autosomal short tandem repeats (STRs), this pattern contrasts with the maternal ancestry, mainly of Native American origin, based on maternal lineages haplogroups. In agreement with historical records, these results confirm a strong gender-biased admixture history between European males and Native American females that gave rise to Mexican-Mestizos. Finally, pairwise comparisons and analysis of molecular variance tests demonstrated significant population structure (FST=4.68%; P<0.00005), delimiting clusters that were geographically defined as the following: north–west, center–south and southeast.

Macrophage migration inhibitory factor (MIF): Genetic evidence for participation in early onset and early stage rheumatoid arthritis

Macrophage migration inhibitory factor (MIF) is an upstream pro-inflammatory cytokine that is associated with the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis (RA). Two polymorphisms in the upstream region exist in the MIF gene and are associated with RA susceptibility or severity in different populations. In this case-control study, we investigated whether MIF polymorphisms are associated with RA susceptibility or activity in a western Mexican population .The relationship of MIF levels with clinical features of disease also was assessed. Genotyping of the -794 CATT5-8 (rs5844572) and the -173 G>C (rs755622) polymorphisms was performed by PCR and PCR-RFLP respectively on 226 RA patients and 210 healthy subjects. Serum MIF levels were determined by ELISA. We found a significant association between the -794 CATT5-8 6,7 MIF genotype with RA. Moreover, we detected an association between the -794 CATT7 allele with early onset RA. The -794 CATT7 and -173(*)C alleles, which are in linkage disequilibrium, were associated with high disease activity on RA patients. A positive correlation between circulating MIF levels and C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, anti-citrullinated protein/peptides antibodies and TNFα was detected. MIF levels appear to be associated with disease progression rather than disease activity, which is distinct from the established relationship between disease activity and TNFα levels. In conclusion, the MIF gene and protein are associated with RA in a western Mexican population, with a main contribution onto early onset and early stages of disease.

The +49A>G CTLA-4 polymorphism is associated with rheumatoid arthritis in Mexican population.

BACKGROUND The Cytotoxic T lymphocyte antigen (CTLA-4) is one of the major susceptibility genes associated with autoimmune diseases. Susceptibility to rheumatoid arthritis (RA) is determined by both environmental and genetic factors. The genetic contribution approaches 50-60%. The association between RA with the +49A>G CTLA-4 polymorphism in the Mexican population was investigated. METHODS The polymerase chain reaction-restriction fragment was used to amplify the +49A>G CTLA-4 polymorphism in RA patients and healthy subjects (HS). RESULTS We analyzed the association between the +49A>G CTLA-4 polymorphism and RA. The G allele frequency was higher in RA patients than HS (46.8 vs 37.7%, OR=1.45, p=0.01). RA patients carrying the A/G genotype were significantly more likely to be positive to CRP and RF. There was no evidence of an association between SNP genotypes and the clinical characteristics of rheumatoid arthritis. CONCLUSIONS The +49A>G CTLA-4 polymorphism is a genetic marker of susceptibility for RA in western Mexican population.

Comparative analysis of autoantibodies targeting peptidylarginine deiminase type 4, mutated citrullinated vimentin and cyclic citrullinated peptides in rheumatoid arthritis: associations with cytokine profiles, clinical and genetic features.

Antibodies against cyclic citrullinated peptides (anti‐CCP) are widely used for diagnosis of rheumatoid arthritis (RA). We performed a comparative analysis of antibodies targeting the citrullinating enzyme peptidylarginine deiminase type 4 (anti‐PAD4) and mutated citrullinated vimentin (anti‐MCV) with anti‐CCP autoantibodies in RA patients and examined their relationships with clinical parameters, cytokine profiles and the PADI4 gene. Autoantibodies were examined by enzyme‐linked immunosorbent assay (ELISA) in sera of 170 RA patients and 103 controls. Cytokine profiles were measured using a multiplex system. PADI4 polymorphisms (89G > A, 90T > C and 92G > C) were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Anti‐PAD4, anti‐MCV and anti‐CCP autoantibodies were detected in 24, 61 and 74% of RA patients, respectively. Positive correlations were observed between anti‐PAD4 and disease duration; anti‐CCP and erythrocyte sedimentation rate (ESR); anti‐MCV and ESR and C‐reactive protein. Anti‐MCV antibodies were associated with high disease activity score 28 (DAS‐28) in early RA. Concentrations of T helper type 1 (Th1) [tumour necrosis factor (TNF)‐α, interleukin (IL)‐12, IL‐2, IL‐1β], Th2 (IL‐4, IL‐6, IL‐10, IL‐13) and Th17 (IL‐17) cytokines were higher in RA than in controls. Th2 and, to a lesser extent, Th1‐related cytokines, showed positive correlations with anti‐MCV and anti‐CCP. The GTG haplotype in PADI4 was associated with anti‐CCP and anti‐MCV, but not anti‐PAD4 antibodies. In conclusion, anti‐PAD4 antibodies are detected mainly in established RA, which is in contrast to the early detection of antibodies against citrullinated peptide/proteins (ACPAs). Among autoantibodies, anti‐MCV appear to perform better as markers of disease activity. Furthermore, anti‐CCP and anti‐MCV are associated genetically with the citrullinating enzyme PAD4 and are related strongly to Th1 and Th2 cytokines, suggesting a feed‐forward loop between cytokines and ACPA production.

Adenovirus-36 Seropositivity and Its Relation with Obesity and Metabolic Profile in Children

The human adenovirus 36 (Ad-36) is causally and correlatively associated in animals and humans, respectively, with increased adiposity and altered metabolic profile. In previous studies, the relationship between Ad-36 seropositivity with obesity was established in adults and children. We evaluated the association of positive antibodies to Ad-36 with obesity and metabolic profile in Mexican children. Seventy-five children with normal-weight and 82 with obesity were studied in this research. All children had a clinic assessment which included weight, height, body circumferences, and skinfold thickness. Laboratory analyzes included triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, and glucose and insulin levels. An enzyme-linked immunosorbent assay (ELISA) was used to determine the antibodies to Ad-36 in the serum samples. The overall Ad-36 seroprevalence was 73.9%. Ad-36 seropositivity had a higher prevalence in obese children than in normal weight group (58.6 versus 41.4%, P = 0.007). Ad-36 seropositivity was associated with obesity (OR = 2.66, P = 0.01) and high-density lipoprotein <40 mg/dL (OR = 2.85, P = 0.03). The Ad-36 seropositive group had greater risk of 4 metabolic abnormalities compared with those children without none alteration. In summary, Ad-36 seropositivity was associated with obesity and low HDL-c levels in the sample of children studied.

Association of the HindIII and S447X polymorphisms in LPL gene with hypertension and type 2 diabetes in Mexican families

Lipoprotein lipase (LPL) is a key enzyme in lipid metabolismand is associatedwith obesity, dyslipidemias, hypertension (HTN) and type 2 diabetes mellitus (T2DM). LPL gene polymorphisms can be related with the development of cardiovascular risk factors. The present study was conducted to analyze the relationship of the HindIII and S447X polymorphisms in LPL gene with cardiovascular risk factors in Mexican families. The study population comprised ninety members of 30 Mexican families, in which an index case had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical parameters. Screening for both polymorphisms was made by PCR-RFLPs. In the parents, both polymorphisms were in Hardy-Weinberg’s equilibrium. We found that the genotype T/T of HindIII was associated with diastolic blood pressure ≧ 85 mmHg (OR = 1.1; p = 0.011), whereas the genotype C/C of S447X was associated with systolic blood pressure ≧ 130 mmHg (OR = 1.2; p < 0.001), diastolic blood pressure ≧ 85 mmHg (OR = 1.3; p < 0.001), T2DM (OR = 1.3; p < 0.001) and with increase of total cholesterol (β = 23.6 mg/mL; p = 0.03). These data suggest that the HindIII and S447X LPL gene polymorphisms can confer susceptibility for the development of hypertension and T2DM in Mexican families.

Macrophage migration inhibitory factor: Association of -794 CATT5-8 and -173 G>C polymorphisms with TNF-α in systemic lupus erythematosus

Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive feedback loop with TNF-α that could perpetuate the inflammatory process in systemic lupus erythematosus (SLE). In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with SLE as well as with MIF and TNF-α serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms was performed by PCR and PCR-RFLP, respectively in 186 SLE patients and 200 healthy subjects. MIF and TNF-α serum levels were determined by ELISA. A significant increase of MIF and TNF-α levels was found in SLE patients. According to a genetic model, we found a significant association of genotypes carrying the -794 CATT7 and -173(∗)C risk alleles with susceptibility to SLE and with a significant increase of TNF-α. In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population.

Body Fat Distribution and Its Association With Hypertension in a Sample of Mexican Children

Background The association between elevated blood pressure and childhood overweight and obesity has been documented in several studies. However, the linkage of blood pressure with body fat distribution in children is not well established. We investigated the relationship between both central and subcutaneous adiposity with BP in the 95th percentile or higher in Mexican children. Methods and Results Our study, using a sample of children from the State of Guerrero, Mexico was comprised of 252 children, 124 girls and 128 boys, with an age range of 6 to 13 years. Resting blood pressure was measured in duplicate with an aneroid sphygmomanometer. Hypertension was classified as systolic or diastolic BP in the 95th percentile or higher. Additional measures included weight, height, body mass index, body circumferences, and skinfold thickness. The prevalence of obesity (26.5%) was higher than overweight (15.8%), but the prevalence of hypertension was moderate (4.7%). Both systolic and diastolic blood pressures correlated strongly with age, weight, height, and all measurements of central and subcutaneous adiposity. Interestingly, after being adjusted by age, sex, and body mass index, the BP in the 95th percentile or higher was associated with suprailiac skinfold, third tertile (OR = 11.83, P = 0.023); triceps skinfold, third tertile (OR = 6.02; P = 0.034); and biceps skinfold, third tertile (OR = 4.71; P = 0.038). Conclusions Our data indicate that the prevalence of hypertension in children is moderate. In addition, the skinfold thickness was a better predictor of hypertension than central adiposity in the sample of children studied.

Haplotypes in the CRP Gene Associated with Increased BMI and Levels of CRP in Subjects with Type 2 Diabetes or Obesity from Southwestern Mexico

Objective. We evaluated the association between four polymorphisms in the CRP gene with circulating levels of C-reactive protein (CRP), type 2 diabetes (T2D), obesity, and risk score of coronary heart disease. Methods. We studied 402 individuals and classified them into four groups: healthy, obese, T2D obese, and T2D without obesity, from Guerrero, Southwestern Mexico. Blood levels of CRP, glucose, cholesterol, triglycerides, and leukocytes were measured. Genotyping was performed by PCR/RFLP, and the risk score for coronary heart disease was determined by the Framinghams methodology. Results. The TT genotype of SNP rs1130864 was associated with increased body mass index and T2D patients with obesity. We found that the haplotype 2 (TGAG) was associated with increased levels of CRP (β = 0.3; 95%CI: 0.1, 0.5; P = 0.005) and haplotype 7 (TGGG) with higher body mass index (BMI) (β = 0.2; 95%CI: 0.1, 0.3; P < 0.001). The risk score for coronary heart disease was associated with increased levels of CRP, but not with any polymorphism or haplotype. Conclusions. The association between the TT genotype of SNP rs1130864 with obesity and the haplotype 7 with BMI may explain how obesity and genetic predisposition increase the risk of diseases such as T2D in the population of Southwestern Mexico.

Common variants in the CRP gene are associated with serum C-reactive protein levels and body mass index in healthy individuals in Mexico.

Variants in the C-reactive protein (CRP) gene have been found to be associated with various phenotypic traits. We evaluated the effect of four SNPs in the CRP gene on serum levels of protein and body mass index (BMI) in 150 unrelated Mexican subjects from 18 to 25 years old, without hypertension, non-overweight, and without inflammatory diseases, non-smoking and non-consumers of alcohol. Subjects were measured for BMI, waist circumference, blood pressure, and serum glucose and triglycerides. The identification of SNPs was performed by PCR-RFLP. Three of the four SNPs were associated with variation in serum levels of CRP, increased in TT (rs1130864) and GG (rs2794521) genotypes, and decreased in the AA genotype of rs1205. The TT genotype was associated with a significant increase in BMI (β = 1.1 kg/m², P = 0.04). Two haplotypes were significantly associated with increased serum levels of CRP, but not with BMI. We conclude that variation in the CRP gene affects serum protein levels.