Gilberto Vargas-Alarcón

Heat shock protein 70 gene polymorphisms in Mexican patients with spondyloarthropathies

Objective: To investigate the role of HSP70 genes as contributors to genetic susceptibility of the spondyloarthropathies (SpA) in the Mexican population. Methods: The study included 150 patients with SpA (undifferentiated spondyloarthropathy (uSpA) 68, ankylosing spondylitis (AS) 60, and reactive arthritis 22) and 158 healthy controls. HSP70-1, HSP70-2 and HSP70-hom genotypes were analysed by the polymerase chain reaction-restriction fragment length polymorphism technique. Statistical methods included the Mantel-Haenzel, χ2, Fishers exact test, and Woolfs method for odds ratio (OR). Results: HSP70-2 B/B genotype frequency was increased in the whole group of patients with SpA (pC<0.05, OR=4.3), as well as in the different clinical subgroups (pC<0.05, OR=4.2 for AS; pC<0.05, OR=4.4 for uSpA; and pC<0.05, OR=4.1 for ReA). This frequency remained significantly increased when the patients with B27 negative SpA were analysed. On the other hand, HSP70-hom locus analysis showed significantly increased frequency of A allele in the whole group of SpA (pC<0.05, OR=3.4), as well as in the groups with AS (pC<0.05, OR=5.6) and with uSpA (pC<0.05, OR=3.1), when compared with healthy controls. In this case, also, the genotype A/A was increased in the whole group of SpA (pC<0.05, OR=4.5), as well as in patients with AS (pC<0.05, OR=6.4) and with uSpA (pC<0.05, OR=3.7). When the patients with B27 negative SpA were analysed the frequencies of HSP70-hom A allele and A/A genotype remained significantly increased in the whole group of SpA (pC<0.05, OR=3.2 for the A allele and pC<0.05, OR=4.2 for the A/A genotype) and in the uSpA subgroup (pC<0.05, OR=3.8 for the A allele and pC<0.05, OR=4.3 for the A/A genotype). Conclusion: In addition to the association of SpA with HLA-B27, there is a significant association of HSP70-2 and HSP70-hom alleles with SpA in Mexicans. This association seems to be independent of the susceptibility conferred by HLA-B27 in the group of patients with uSpA.

HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever.

The human leukocyte antigen DRB1 locus (HLA-DRB1) was typed in genomic DNA extracted from whole blood samples of 34 Mexican dengue hemorrhagic fever (DHF) patients and 47 dengue fever (DF) patients, by polymerase chain reaction-sequence-specific oligonucleotide reverse dot blot. HLA-DRB1*04 was negatively associated with risk of DHF (OR 0.31, 95% CI 0.11-0.85). HLA-DR4 homozygous individuals were 11.6 times less likely to develop DHF in comparison to DR4 negative persons (OR 0.08, 95% CI 0.01-0.75). After adjusting for gender and infection type by logistic regression, DR4 positive individuals were 3.6 times less likely to develop DHF than DR4 negative persons (OR 0.28, 95% CI 0.12-0.66). A secondary dengue virus infection was also positively linked with DHF risk (OR 2.89, 95% CI 0.92-9.07). This data suggests that genes of the major histocompatibility complex play a major role in the susceptibility and/or resistance to develop DHF. In Mexicans, HLA-DR4 may be a genetic factor that is protective against DHF. Because HLA-DR4 has been positively selected in Latin American populations, these results may apply also to other similar ethnic groups, particularly those with high percentages of admixture with indigenous Amerindian genes.

Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with rheumatic heart disease

The major histocompatibility genes (MHC) have been associated with the genetic susceptibility to rheumatic heart disease (RHD). Results have been inconsistent and new genes located on the MHC region such as tumor necrosis factor (TNF-alpha) need to be analyzed. TNF-alpha polymorphisms (positions -238 and -308) were determined in 87 RHD Mexican Mestizo patients and 101 healthy controls. Patients were classified into mitral valve damage (MVD) and multivalvular lesion (MVL) categories. TNF-238 G allele and GG genotype were increased in patients when compared to healthy controls (pC=0.001, OR=14.1 and pC=0.003, OR=14.1, respectively). Also, decreased frequencies of TNF-238 A allele (pC=0.001) and AG genotype (pC=0.003) were found. TNF-308 polymorphism analysis showed increased frequencies of T2 (A) allele (pC<10(-3), OR=10.8) and T1T2 (AG) genotype (pC<10(-3), OR=9.85) and decreased frequencies of T1 (G) allele and T1T1 (GG) genotype (pC<10(-3)). When comparing valvular damage to healthy controls, patients with MVD showed increased frequencies of -238 GG (pC=0.03, OR=ND), -308 T1T2 (AG) (pC<10(-3), OR=14) and -308 T2 (A) (pC<10(-3), OR=11.7). Also, this group showed decreased frequencies of T1 (G) allele and T1T1 (GG) genotype (pC<10(-3)). Patients with MVL presented increased frequency of -308 T2 (A) allele (pC=0.0003, OR=8.65) and decreased frequencies of -308 T1 (G) allele and -308 T1T1 (GG) genotype (pC=0.0003 and pC=0.006, respectively). Distribution of -238 and -308 polymorphisms were similar between MVD and MVL. The data demonstrate that RHD is associated with TNF-alpha polymorphisms in the Mexican population; however, these polymorphisms do not have relation with the valve damage.

Genetic admixture and diversity estimations in the Mexican Mestizo population from Mexico City using 15 STR polymorphic markers

The 15 AmpFlSTR Identifiler loci D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818 and FGA were analyzed in a sample of 378 unrelated individuals from Mexico City, Mexico. Significant deviations from HW equilibrium in 14/15 STR loci alleles were not detected. The D18S51 locus had the highest power of discrimination (0.970). Genetic admixture estimations revealed a 69% of Amerindian, 26% of European and 5% of African contribution. Comparative analyses between Mexicans and other neighboring populations reveal significant differences in genetic diversity. Our results are important for future comparative genetic studies in different Latin American ethnic groups, particularly Mexican Mestizos and Amerindians. They should also be helpful in genetics, population evolution, forensic and paternity testing.

Clinical and genetic heterogeneity in Mexican patients with ulcerative colitis

Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology. Genetic factors implied on its onset and severity may include genes located within the class II major histocompatibility complex (MHC) region. The aim of this study was to determine the relationship between human leukocyte antigen (HLA)-DRB1 alleles with the clinical disease patterns of UC in Mexican Mestizo patients. High-resolution HLA typing was performed by polymerase chain reaction-sequence specific oligonucleotide (PCR)-SSO reverse dot blot and PCR-single-strand polymorphism in 67 patients with UC and 99 ethnically matched healthy controls. UC patients overall showed an increased frequency of HLA-DR1 as compared with healthy controls (17.1% versus 5%, [pC = 0.003, OR = 3.9]). Patients with extensive colitis showed increased frequencies of HLA-DR1 (pC = 1 x 10(-10), OR = 13.9), HLA-DRB1*0103 (pC = 1 x 10(-3), OR = 21.7), HLA-DRB1*0102 (pC = 0.007, OR = undetermined), and HLA-DR15 (pC = 1 x 10(-3), OR = 8.5) when compared with healthy controls. We also found a statistically increased frequency of HLA-DR15 in UC patients with extensive colitis compared with UC patients with only distal colitis (18.7% versus 1.8%, pC = 0.03; OR = 12.2). When patients who underwent proctocolectomy were compared with those who did not, an increased frequency of HLA-DRB1*0103 was observed (21.8% versus 4.9%; pC = 0.03; OR = 5.4; 95% confidence interval, 1.39-21.93). Also, patients with proctocolectomy showed increased frequencies of HLA-DR1 (pC = 1 x 10(-3), OR = 24.2) and HLA-DRB1*0103 (pC = 1 x 10(-3), OR = 50.6) when compared with healthy controls. We concluded that HLA-DR1 is associated with genetic susceptibility to UC in the Mexican Mestizo population. HLA-DR15 distinguishes a subgroup of patients with extensive colitis and the HLA-DRB1*0103 allele distinguishes a subgroup of severe form of disease that might require surgical management.

Further evidence of the role of HLA-DR4 in the genetic susceptibility to actinic prurigo

BACKGROUND Actinic prurigo (AP) is triggered by sun exposure. Its prevalence in Mexicans seems to be particularly high, which suggests a genetic susceptibility. OBJECTIVE Our purpose was to determine the role of major histocompatibility complex (MHC) genes in the genetic susceptibility to AP. METHODS Fifty-six Mexican Mestizo patients with AP underwent serologic typing for HLA class I and class II antigens. Class II MHC genes were also studied by DNA analysis. Findings in patients were compared with 100 ethnically matched healthy controls. RESULTS We found that 92.8% of patients with AP were HLA-DR4 positive (corrected p = 0.002; odds ratio [OR] = 10.1). The class I antigens HLA-A28 and HLA-B39 (B16) were also significantly increased (p < or = 0.000001, OR = 20.9 and p = 0.0001, OR = 6.7, respectively) compared with normal controls. Allele-specific oligonucleotide DR4 subtyping showed that 80.7% of HLA-DR4+ patients with AP were also positive for the DRB1*0407 allele. CONCLUSION These results confirm the role of HLA-DR4 (DRB1*0407) in the genetic susceptibility to AP and raise the possibility of a role for class I MHC antigens HLA-A28 and B16 in Mexican patients.

Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in Mexican patients

Objective: To investigate the role of HLA-B and HLA-DR genes as contributors to genetic susceptibility and clinical expression of the spondyloarthropathies (SpA) in the Mexican population. Methods: The study included 172 patients with SpA (undifferentiated SpA 83, ankylosing spondylitis (AS) 64, and reactive arthritis 25) and 99 healthy controls. The HLA-B and HLA-DR alleles were detected by the polymerase chain reaction with sequence-specific primers technique. Patient assessment included demographic data, diagnostic categories, and disease patterns. Statistical methods included the Mantel-Haenzel χ2 test, Fishers exact test, and Woolf method for odds ratio (OR). Differences of continuous variables between HLA allele groups were calculated by Students t test. Results: Increased frequencies of HLA-B27 (pCh10−3, OR=28.7), HLA-DR1 (pC=0.045, OR=2.77), and HLA-B15 (p=0.034, pC=NS, OR=2.04) alleles in the whole group were found. HLA-B27 strength of association (OR) was 41.4 in AS; 20.9 in undifferentiated SpA; 27.2 in reactive arthritis. HLA-DR1 and HLA-B15 were increased in undifferentiated SpA (pC=0.045, OR=2.98 and p=0.004, pC=NS, OR=2.75). By analysing 58 HLA-B27 negative patients it was found that HLA-B15 and HLA-DR1 associations with SpA were independent of HLA-B27; increased frequencies of HLA-B15 were found in the whole SpA group and in patients with undifferentiated SpA (pC=0.03, OR=3.09 and pCh0.01, OR=3.77) and of HLA-DR1 in the latter (p=0.04, pC=NS, OR=3.15). HLA-B27 positive patients were younger than HLA-B27 negative patients at onset (p=0.03), but HLA-DR1 positive patients were older than HLA-DR1 negative patients (p=0.03). Bath indices for disease activity and functioning were higher in HLA-B27 positive patients (p=0.006 and p=0.004 v HLA-B27 negative patients). In contrast, neither HLA-DR1 nor HLA-B15 influenced these indices. Conclusion: Apart from HLA-B27, there is a significant association of HLA-DR1 and HLA-B15 with SpA in Mexicans which is independent of B27. HLA-B27 is associated with younger age at onset and increased disease severity and HLA-DR1 with older age at onset. The strength of HLA-B15, HLA-B27, and HLA-DR1 associations varied in different forms of SpA.

HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations

Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/−B and -DRB1/−DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations.

The ABCA1 Gene R230C Variant Is Associated with Decreased Risk of Premature Coronary Artery Disease: The Genetics of Atherosclerotic Disease (GEA) Study

Background ABCA1 genetic variation is known to play a role in HDL-C levels and various studies have also implicated ABCA1 variation in cardiovascular risk. The functional ABCA1/R230C variant is frequent in the Mexican population and has been consistently associated with low HDL-C concentrations. Although it has been associated with other cardiovascular risk factors such as obesity and type 2 diabetes mellitus, it is not known whether it is associated with coronary artery disease (CAD). Aim The purpose of the study was to analyze whether the ABCA1/R230C variant is associated with premature CAD in a case-control association study (GEA or Genetics of Atherosclerotic Disease), and to explore whether BMI modulates the effect of the C230 allele on other metabolic traits using a population-based design. Results The C230 allele was significantly associated with both lower HDL-C levels and a lower risk of premature CAD as compared to controls (OR = 0.566; Padd = 1.499×10−5). In addition, BMI modulated the effect of R230C on body fat distribution, as the correlation between BMI and visceral to subcutaneous adipose tissue (a metric of the propensity to store fat viscerally as compared to subcutaneously) was negative in RR homozygous individuals, but positive in premenopausal women bearing the C230 allele, with a statistically significant interaction (P = 0.005). BMI-R230C interaction was also significant for triglyceride levels in women regardless of their menopausal status (P = 0.036). Conclusion This is the first study assessing the effect of the R230C/ABCA1 variant in remature CAD. C230 was associated with both decreased HDL-C levels and a lower risk of premature CAD, and gender-specific BMI-R230C interactions were observed for different metabolic traits. These interactions may help explain inconsistencies in associations, and underscore the need to further analyze interactions of this functional and frequent variant with diet, exercise and other environmental factors.

Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis

Metabolic syndrome (MetS) should be considered a clinical entity when its different symptoms share a common etiology: obesity/insulin resistance as a result of a multi-organ dysfunction. The main interest in treating MetS as a clinical entity is that the addition of its components drastically increases the risk of atherosclerosis. In MetS, the adipose tissue plays a central role along with an unbalanced gut microbiome, which has become relevant in recent years. Once visceral adipose tissue (VAT) increases, dyslipidemia and endothelial dysfunction follow as additive risk factors. However, when the nonalcoholic fatty liver is present, risk of a cardiovascular event is highly augmented. Epicardial adipose tissue (EAT) seems to increase simultaneously with the VAT. In this context, the former may play a more important role in the development of the atherosclerotic plaque than the latter. Hence, EAT may act as a paracrine tissue vis-à-vis the coronary arteries favoring the local inflammation and the atheroma calcification.