Interactions between TNFAIP3, PTPN22, and TRAF1-C5 gene polymorphisms in patients with primary Sjögren's syndrome.

Objectives: The aim of our study was to investigate whether TNFAIP3, PTPN22, and TRAF1-5 single nucleotide polymorphisms (SNPs) are associated with susceptibility, severity, or serological markers in primary Sjögren's syndrome (pSS). Patients and methods: The cases and controls study was conducted between December 2021 and June 2022. TNFAIP3 rs10499194C/T, rs6920220G/A, and rs2230926T/G, PTPN22 rs2476601C/T and rs33996649G/A, and TRAF1-C5 rs10818488G/A polymorphisms were genotyped in 154 female pSS patients (mean age: 45.2±6.8 years) and 313 female control subjects (mean age: 50.3±7.5 years) using the TaqMan® SNP genotyping assay. An association analysis between TNFAIP3, PTPN22, and TRAF1-C5 SNPs and susceptibility, clinical characteristics, and serological markers of pSS was performed. Interactions between TNFAIP3, PTPN22, and TRAF1-C5 SNPs were also evaluated in patients and controls. Results: The genotype and allele frequencies showed no association with susceptibility, severity, or serological markers of pSS. Nevertheless, several interactions between TNFAIP3 and TRAF1-C5 or TNFAIP3, PTPN22, and TRAF1-C5 genotypes were associated with susceptibility to pSS (p<0.01). Conclusion: Individual TNFAIP3, PTPN22, and TRAF1-C5 SNPs are not associated with susceptibility, severity, or serological markers of pSS. However, genetic interactions between TRAF1-C5 and TNFAIP3 or TNFAIP3, PTPN22, and TRAF1-C5 SNPs are risk factors for pSS.

ELANE rs17223045C/T and rs3761007G/A variants: Protective factors against COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for causing coronavirus disease 2019 (COVID-19). The development and severity of this infectious disease is influenced by a combination of environmental and genetic factors. Angiotensin-converting enzyme 2 (ACE2) facilitates SARS-CoV-2 entry into human cells, with transmembrane serine protease 2 (TMPRSS2) playing a crucial role in S protein priming. Other proteases, such as cathepsin L and elastase, neutrophil-expressed (ELANE), have the capability to prime the S protein and contribute to SARS-CoV-2 infection. ELANE variants have not been previously examined in COVID-19 patients. We aimed to assess the association of single nucleotide variants (SNVs) within ELANE with COVID-19 and biochemical markers. The study included 319 SARS-CoV-2-infected patients and 288 controls. Genotyping of ELANE rs17216663C/T (Pro257Leu), rs17223045C/T (As1n30Asn), and rs3761007G/A was conducted using a 5'-nuclease allelic discrimination assay (TaqMan assay). Our findings indicate that ELANE rs17223045C/T (C vs T: odds ratio [OR] 0.08, P = 0.005, and CC vs CT: OR 0.08, P = 0.005) and rs3761007G/A (G vs A: OR 0.38, P = 0.009, and GG vs GA: OR 0.40, P = 0.008) confer protection against COVID-19. However, these variants were not associated with biochemical markers. In conclusion, our data suggests that ELANE rs17223045C/T and rs3761007G/A SNVs may play a protective role against COVID-19.

The functional TNFAIP3 rs2230926T/G (Phe127Cys) variant confers risk to systemic lupus erythematosus in a Latin American population.

TNFAIP3 is a classical systemic lupus erythematosus (SLE)-associated risk locus identified by genome-wide association studies (GWASs) and replicated by candidate gene association studies primarily in Caucasians and Asians. However, in Latin American populations, its role on SLE susceptibility is not known. We conducted a case-control study to evaluate whether the TNFAIP3 rs2230926T/G (Phe127Cys) variant is associated with risk of developing SLE in a cohort of Mexican patients. The TNFAIP3 rs2230926T/G variant was analyzed in 561 patients with SLE and 499 control subjects, using TaqMan probes. We found that the G allele was associated with susceptibility to SLE under the allelic (OR 2.09, p = 0.005) and genotypic (OR 2.14, p = 0.004) models. In conclusion, our results show that TNFAIP3 rs2230926T/G is a risk factor for the development of SLE in the Mexican population.

CD147 rs8259T>A Variant Confers Susceptibility to COVID-19 Infection within the Mexican Population.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical manifestations of COVID-19 range from mild flu-like symptoms to severe respiratory failure. Nowadays, extracellular matrix metalloproteinase inducer (EMMPRIN), also known as cluster of differentiation 147 (CD147) or BASIGIN, has been studied as enabling viral entry and replication within host cells. However, the impact of the CD147 rs8259T>A single nucleotide variant (SNV) on SARS-CoV-2 susceptibility remains poorly investigated. OBJECTIVE: To investigate the impact of rs8259T>A on the CD147 gene in individuals from Mexico with COVID-19 disease. METHODS: We genotyped the CD147 rs8359T>A SNV in 195 patients with COVID-19 and 185 healthy controls from Mexico. In addition, we also measured the expression levels of CD147 and TNF mRNA and miR-492 from whole blood of patients with COVID-19 through RT-q-PCR. RESULTS: We observed a significant association between the CD147 rs8259T>A SNV and susceptibility to COVID-19: T vs. A; OR 1.36, 95% CI 1.02-1.81; p = 0.037; and TT vs. AA; OR 1.77, 95% CI 1.01-3.09; p = 0.046. On the other hand, we did not find differences in CD147, TNF or miR-492 expression levels when considering the genotypes of the CD147 rs8259T>A SNV. CONCLUSIONS: Our results suggest that the CD147 rs8259T>A variant is a risk factor for COVID-19.

Importance of the SARS-CoV-2 genome and spike protein in the immunopathogenesis of COVID-19 and in the efficacy of vaccines.

Coronavirus (CoV) infections cause respiratory and enteric diseases with clinical manifestations ranging from faint to severe, even lead to death of patients. High connectivity between nations and infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represent a global health problem as the coronavirus disease 19 (COVID-19). This CoV-2 that cause SARS, which appeared in Wuhan, China, in December 2019 originated COVID-19 and declared as pandemic a few months posterior its appearance. In this review, the genomic and spike protein characteristics of SARS-CoV-2, the role of SARS-CoV-2 in the COVID-19 pathogenesis, cytokine storm, the role of cytotoxic T and B cells against SARS-CoV-2, as well as the vaccines efficacy (taking into account mutations in the spike protein) are described.

Los coronavirus (CoV) causan enfermedades respiratorias y entéricas leves, graves o críticas, pudiendo ocasionar la muerte del paciente. Debido a la alta conectividad entre naciones y a la transmisión, actualmente la COVID-19 representa un verdadero problema de salud pública en todo el mundo. El CoV-2 causante del síndrome respiratorio agudo grave (SARS-CoV-2) apareció a finales de diciembre de 2019 en Wuhan, China, y en marzo de 2020 la COVID-19 fue declarada pandemia. En esta revisión se describen las características del genoma y de la proteína espiga del SARS-CoV-2, su papel en la inmunopatogénesis de la COVID-19, la tormenta de citocinas, la actividad citotóxica inducida por células T y la producción de anticuerpos contra el SARS-CoV-2 mediada por células B, así como la eficacia de algunas vacunas, tomando en cuenta las mutaciones presentes en la proteína espiga.

TNFSF4 is a risk factor for rheumatoid arthritis but not for primary Sjögren's syndrome in the Mexican population.

PURPOSE: Rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) are autoimmune diseases (ADs) characterized by joint damage and involvement of the salivary glands, respectively. ADs share some susceptibility loci, such as TNFSF4, which is a classical susceptibility gene associated with systemic lupus erythematosus, but its role in RA and pSS is not yet clear. Thus, the aim of this study was to determine whether three TNFSFS4 polymorphisms are associated with RA and pSS. METHODS: Our case-control study included 500 controls, 459 patients with RA, and 210 patients with pSS from Mexico. TNFSF4 single nucleotide polymorphisms (SNPs) rs1234315C/T, rs2205960G/T, and rs704840T/G were genotyped using TaqMan probes and discrimination allelic assay. RESULTS: The three TNFSF4 SNPs were associated with susceptibility to RA (rs1234315C/T: odds ratio [OR] 1.4, p = 0.01; rs2205960G/T: OR 1.23, p = 0.03; rs704840T/G: OR 1.24, p = 0.02). An association between TNFSF4 rs1234315C/T and pSS was also observed (OR 1.28, p = 0.04), however, after Bonferroni correction, this association was lost. CONCLUSION: Our data suggest that TNFSF4 could be a risk factor in RA but not pSS in a Mexican population.

The rs8176740 T/A and rs512770 T/C Genetic Variants of the ABO Gene Increased the Risk of COVID-19, as well as the Plasma Concentration Platelets.

We conducted a case-control study in order to evaluate whether ABO gene polymorphisms were associated with a high risk of developing COVID-19 in a cohort of patients. Six ABO gene polymorphisms (rs651007 T/C, rs579459 T/C, rs495828 T/G, rs8176746 A/C, rs8176740 T/A, and rs512770 T/C) were determined using TaqMan genotyping assays in a group of 415 COVID-19 patients and 288 healthy controls. The distribution of rs651007 T/C, rs579459 T/C, rs495828 T/G, and rs8176746 A/C polymorphisms was similar in patients and healthy controls. Nonetheless, under co-dominant (OR = 1.89, pCCo-dominant = 6 × 10-6), recessive (OR = 1.98, pCRecessive = 1 × 10-4), and additive (OR = 1.36, pCAdditive = 3 × 10-3) models, the TT genotype of the rs8176740 T/A polymorphism increased the risk of developing COVID-19. In the same way, under co-dominant, recessive, and additive models, the TT genotype of the rs512770 T/C polymorphism was associated with a high risk of developing COVID-19 (OR = 1.87, pCCo-dominant = 2 × 10-3; OR = 1.87, pCRecessive = 5 × 10-4; and OR = 1.35, pCAdditive = 4 × 10-3, respectively). On the other hand, the GTC and GAT haplotypes were associated with a high risk of COVID-19 (OR = 5.45, pC = 1 × 10-6 and OR = 6.33, pC = 1 × 10-6, respectively). In addition, the rs8176740 TT genotype was associated with high-platelet plasma concentrations in patients with COVID-19. Our data suggested that the ABO rs512770 T/C and rs8176740 T/A polymorphisms increased the risk of developing COVID-19 and the plasma concentration of platelets.

Polymorphisms in TNFAIP3, but not in STAT4, BANK1, BLK, and TNFSF4, are associated with susceptibility to Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TAK) is considered a rare disease characterized by nonspecific inflammation of the large arteries, especially the aorta and its major branches. Because TAK is an autoimmune disease (AD), it could share susceptibility loci with other pathologies such as systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), among others. Widely explored polymorphisms in non-HLA genes, including TNFAIP3, STAT4, TNFSF4, BANK1, and BLK have been consistently associated with both SLE and RA, but they have not been evaluated in TAK. OBJECTIVE: The aim of our study was to investigate whether TNFAIP3, STAT4, BANK1, BLK, and TNFSF4 polymorphisms are associated with susceptibility to TAK. METHODS: The TNFAIP3 rs2230926T/G and rs5029924C/T, STAT4 rs7574865G/T, BANK1 10516487G/A, BLK rs2736340T/C, rs13277113A/G, and TNFS4 rs2205960G/T polymorphisms were genotyped in 101 cases and 276 controls by using a TaqMan SNP genotyping assay. An association analysis was performed. RESULTS: The TNFAIP3 rs2230926T/G and rs5029924C/T polymorphisms were in complete linkage disequilibrium and turned out to be risk factors for TAK (OR = 4.88, p = 0.0001). The STAT4, BANK1, BLK, and TNFSF4 polymorphisms were not associated with the disease. CONCLUSIONS: This is the first study documenting an association of TNFAIP3 rs2230926T/G and rs5029924C/T with TAK. Our results provide new information on the genetic bases of TAK.

BLK and BANK1 variants and interactions are associated with susceptibility for primary Sjögren's syndrome and with some clinical features.

BLK and BANK1 in primary Sjögren's syndrome (pSS) have scarcely been evaluated and the results are inconclusive. The aim of our study was to determine whether single nucleotide variants (SNVs) located within BLK or BANK1 are associated with susceptibility, clinical and serological features, and smoking in pSS. BLK rs13277113A/G, BANK1 rs10516487G/A and rs3733197G/A were genotyped in 203 cases and 424 controls using a TaqMan® SNP genotyping assay. The BLK rs13277113A allele showed association with pSS under the allelic (OR 1.35, p = 0.02), and recessive (OR 1.83, p = 0.003) model, while, BANK1 rs3733197G/A showed association under the dominant model (OR 2.90, p = 0.043). Interactions between BANK1 and BLK genotypes also showed association (OR 2.36, p < 0.0001). In addition, BLK rs13277113A/G was associated with protection against arthritis and BANK1 rs10516487G/A with both arthritis and keratoconjunctivitis sicca, meanwhile, BANK1 rs3733197G/A was associated with smoking in patients with pSS. This is the first study to describe an association between BLK and susceptibility to pSS in a Latin-American population. Our data also shows a first evidence of association between interactions of BLK and BANK1 in pSS, and association of BLK and BANK1with arthritis, keratoconjunctivitis sicca and smoking in patients with pSS.

The AIRE Ser196Ser synonymous variant is a risk factor for systemic lupus erythematosus.

The AIRE gene influences the expression of a wide array of self-antigens in the thymus, and is essential to the negative selection of self-reactive T cells and establishment of central tolerance. Single nucleotide variants (SNVs) such as rs878081C/T (Ser196Ser) and rs2075876G/T at this locus have been associated with susceptibility to rheumatoid arthritis, mainly in Asian populations, but its role in systemic lupus erythematosus (SLE) has not been documented. We performed a case-control association study with 379 SLE patients and 460 controls from central Mexico. In addition, we replicated our finding in another group of 179 SLE patients and 97 controls from the same region of Mexico. In the first group, we identified that the AIRE Ser196Ser synonymous variant was associated with SLE (OR 1.4, p = 0.009), meanwhile, in the second group we observed the following: OR 1.7, p = 0.024. No association was found between these AIRE SNVs and lupus nephritis. Our results suggest that AIRE is a risk factor for SLE in our population. This study is the first to document an association between AIRE and SLE susceptibility.

BLK and BANK1 polymorphisms and interactions are associated in Mexican patients with systemic lupus erythematosus.

OBJECTIVES: The BLK and BANK1 genes have been consistently associated with systemic lupus erythematosus (SLE), primarily in European or Asian-derived populations. However, this finding has not been replicated in Latin-American patients. METHODS: Our study included 881 women from Mexico: 487 healthy controls and 394 SLE patients. The BLK rs13277113A/G-rs2736340T/C as well as BANK1 rs10516487G/A (R61H)-rs3733197G/A (A383T) single nucleotide polymorphisms (SNPs) were evaluated using a TaqMan® SNP genotyping assay. RESULTS: Our data showed that the BLK rs2736340T/C and rs13277113A/G polymorphisms are associated with susceptibility to SLE (C vs T, OR 1.60, p = 2×10-5; G vs A, OR 1.53, p = 9 × 10-5, respectively). We also identified an association between the functional BANK1 R61H polymorphism and SLE (A vs G, OR 1.56, p = 0.002). In addition, we observed a genetic interaction between BLK (rs2736340T/C, rs13277113A/G) and BANK1 (R61H and A383T) associated with susceptibility to SLE. CONCLUSION: This is the first study documenting an association between BLK and BANK1 and SLE in a Latin-American population. Our data confirm previous reports: BLK and BANK1 are factors associated with SLE. Thus, both genes are universal loci for this autoimmune disease.

An association study in PTPN22 suggests that is a risk factor to Takayasu's arteritis.

OBJECTIVES: Takayasu's arteritis (TA) represents a rare autoimmune disease (AD) characterized by systemic vasculitis that primarily affects large arteries, especially the aorta and the aortic arch and its main branches. Genetic components in TA are largely unknown. PTPN22 is a susceptibility loci for different ADs; however, the role of different PTPN22 single-nucleotide polymorphisms (SNPs) in the susceptibility to TA is not clear. METHODS: We evaluated the PTPN22 R620W (C1858T), R263Q (G788A), and - 123G/C SNPs in a group of patients with TA and in healthy individuals from Mexico. Our study included 111 patients with TA and 314 healthy individuals. Genotyping was performed with the 5' exonuclease (TaqMan®) assay. RESULTS: Our data showed that the PTPN22 R620W polymorphism is a risk factor for TA (CC vs. CT: OR 4.3, p = 0.002, and C vs. T: OR 4.1, p = 0.003); however, the PTPN22 R263Q and - 1123G/C polymorphisms are not associated with this AD. In addition, the PTPN22 CGT haplotype, which carries the minor allele of the PTPN22 C1858T variant, was also associated with TA susceptibility. CONCLUSION: This is the first report documenting an association between PTPN22 R620W and TA.

IL-17A haplotype confers susceptibility to systemic lupus erythematosus but not to rheumatoid arthritis in Mexican patients.

AIM: Recent studies highlight the importance of the interleukin (IL)-17A cytokine in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). There are also reports of associations between some single nucleotide polymorphisms (SNPs) in IL-17A and RA but not SLE. Notably, these findings have not been replicated in all studied populations. The aim of this study was to investigate whether the IL-17A -737 T/C (rs8193036), -444A/G (rs3819024), -197G/A (rs2275913), and -121G/A (rs8193037) SNPs conferred susceptibility to SLE (or lupus nephritis) or to RA in a Mexican population. METHODS: The study included 1367 Mexican subjects, 501 with RA, 367 with SLE, and 499 healthy controls. IL-17A was genotyped using a TaqMan 5' allelic discrimination assay. RESULTS: Our results showed that the IL-17A -737 T/C, -444A/G, -197G/A, and -121G/A SNPs had similar genotype and allele frequencies in patients with SLE (or lupus nephritis) or RA and in controls. However, an IL-17A haplotype (TAGA) showed an association with SLE susceptibility (odds ratio 2.43, P = 0.004) but not with RA susceptibility. CONCLUSIONS: These results confirm that the IL-17A -737T/C, -444A/G, -197G/A, and -121G/A SNPs are not risk factors for RA, but the IL-17A TAGA haplotype is a risk factor for SLE. This is the first report to document an association between IL-17A and SLE susceptibility in adults.

[Micronutrients and diabetes, the case of minerals]. / Micronutrientes y diabetes, el caso de los minerales.

Minerals are essential nutrients for the body, are of inorganic nature which gives them the characteristic of being resistant to heat, are involved in a lot of chemical reactions in metabolism, regulating electrolyte balance, in maintaining bone, in the process of blood clotting and the transmission of nerve impulses, particularly its role as enzyme cofactors confers a key role in various physiological processes. Glucose homeostasis involves a fine coordination of events where hormonal control by insulin plays a key role. However, the role of minerals like magnesium, zinc, chromium, iron and selenium in the diabetes is less obvious and in some cases may be controversial. This review shows the knowledge of these five elements and their correlation with diabetes.

Los minerales son nutrientes esenciales para el organismo, de naturaleza inorgánica que les confiere, entre otras características, ser resistentes al calor, participan en diversas reacciones químicas del metabolismo en donde regulan el equilibrio hidroelectrolítico, el mantenimiento óseo, en la trasmisión de los impulsos nerviosos, y durante el proceso de coagulación sanguínea, particularmente por su función como cofactores enzimáticos, tienen un papel clave en varios procesos fisiológicos. La homeostasis de la glucosa involucra una fina coordinación de eventos en donde el control hormonal por la insulina tiene un papel primordial. Sin embargo, la función de los minerales, como el magnesio, el zinc, el cromo, el hierro y el selenio en la diabetes es menos evidente y puede ser, en algún caso, controversial. Esta revisión muestra el conocimiento acerca de estos cinco elementos y su correlación con la diabetes.

LOC387761 polymorphism is associated with type 2 diabetes in the Mexican population.

Worldwide researchers have invested time, effort, and money during the last years to find new genes associated with diabetes susceptibility, such as LOC387761, HHEX, EXT2, and SLC30A8. The aim of the present study was to evaluate whether single-nucleotide polymorphisms (SNPs) of these genes are associated with type 2 diabetes (T2D) and metabolic traits in the Mexican population. We also assessed these SNPs in Mexican indigenous groups to identify a possible inherited susceptibility. Seven SNPs were analyzed in 789 Mexicans (234 control subjects, 455 type 2 diabetic patients, and 100 of indigenous origin), using the KASPar assay (KBioscience Company). Analysis of the data showed an association of the LOC387761 SNP rs7480010 with T2D (p = 0.019). The risk allele A of rs7480010 increased body mass index in diabetic patients (p = 0.01). In addition, there was no association between T2D and the SNPs of HHEX, EXT2, and SLC30A8. Our findings suggest that the SNP rs7480010 (LOC387761) can contribute to a failure in insulin secretion, thus increasing the susceptibility to T2D in Mexicans.

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.