Association between blood aluminum and beta-2 receptor gene methylation with childhood asthma control.

Previous studies have shown that environmental exposure to heavy metals has been related to epigenetic changes, such as DNA methylation in receptors involved in pathogenesis of asthma. One of these receptors is beta-2 adrenergic receptor (ADRB2). We conducted this study to examine the association between blood aluminum concentration, blood ADRB2 5' untranslated region (5'-UTR) methylation level, and childhood asthma control level. Our results showed a significant positive association between high blood aluminum concentration (odds ratio, 16, 95% confidence interval (CI) [3.57 to 71.76], p < 0.001) and high blood ADRB2 5'-UTR methylation level (odds ratio, 4.75, 95% CI [1.39 to 16.2], p = 0.013), and risk of uncontrolled asthma. Multivariable logistic regression revealed that higher blood aluminum concentration was independently associated with increased risk of uncontrolled bronchial asthma (odds ratio, 9.10, 95% CI [2.38 to 34.85], p = 0.0013], after controlling for age, sex, and blood ADRB2 5'-UTR methylation level. In addition, blood ADRB2 5'-UTR methylation level significantly correlated with whole blood aluminum concentration in asthmatic children (r = 0.480, p < 0.001). We concluded that increasing blood aluminum concentration is an important independent correlate of risk for uncontrolled bronchial asthma as well as increased blood aluminum concentration caused ADRB2 5'-UTR hyper-methylation with increasing risk of uncontrolled bronchial asthma.

Association between CETP, MLXIPL, and TOMM40 polymorphisms and serum lipid levels in a Latvian population.

BACKGROUND: Abnormal lipid levels are considered one of the most significant risk factors for atherosclerosis and coronary artery disease, two of the main causes of death worldwide. Apart from monogenic cases of hypercholesterolemia, most of the common dyslipidemias are caused by a number of low-impact polymorphisms. It has recently been reported that frequent polymorphisms at a large number of loci are significantly associated with one or more blood lipid parameters in many populations. Identifying these associations in different populations and estimating the possible interactions between genetic models are necessary to explain the underlying genetic architecture of the associated loci and their ultimate impact on lipid-associated traits. METHODS: We estimated the association between 144 common single-nucleotide polymorphisms (SNPs) from published genome-wide association studies and the levels of total cholesterol, low- and high-density lipoprotein-cholesterol, and triglycerides in 1273 individuals from the Genome Database of the Latvian Population. We analyzed a panel of 144 common SNPs with Illumina GoldenGate Genotyping Assays on the Illumina BeadXpress System. RESULTS: Ten SNPs at the CETP locus and two at the MLXIPL locus were associated with reduced high-density lipoprotein-cholesterol levels; one SNP at the TOMM40 locus was associated with increased low-density lipoprotein-cholesterol; and four SNPs at the MLXIPL locus were associated with increased log triglyceride levels. There was also a significant correlation between the number of risk alleles and all the lipid parameters, suggesting that the coexistence of many low-impact SNPs has a greater effect on the dyslipidemia phenotype than the individual effects of found SNPs. CONCLUSION: We conclude that the CETP, MLXIPL, and TOMM40 loci are the strongest genetic factors underlying the variability in lipid traits in our population.

Stronger association of common variants in TCF7L2 gene with nonobese type 2 diabetes in the Latvian population.

Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the strongest common genetic risk factors for type 2 diabetes (T2D) across multiple ethnicities. This study was conducted to evaluate an association between TCF7L2 variants and diabetes susceptibility in the population of Latvia. We genotyped 4 single nucleotide polymorphisms (SNP) rs7901695, rs7903146, rs11196205 and rs12255372 in 1 093 controls and 1 043 diabetic subjects. Association with T2D was found for 3 SNPs rs7901695, rs7903146 and rs12255372 in the whole sample (under an additive genetic model, the adjusted odds ratios (OR) were 1.26, 95% CI [1.08-1.48], P=0.003; OR=1.32, 95% CI [1.12-1.55], P=0.001 and OR=1.35, 95% CI [1.15-1.60], P=0.0004 respectively). In addition observed effects on T2D susceptibility for analysed SNPs were higher among subjects with BMI under 30 kg/m². The impact of TCF7L2 variation on T2D risk in Latvian population is compatible with that demonstrated by a range of studies conducted in various ethnic groups.

Combination of KIR 2DL2 and HLA-C1 (Asn 80) confers susceptibility to type 1 diabetes in Latvians.

Killer immunoglobulin-like receptors (KIRs) are known to modulate natural killer (NK) and NK T-cell function by interacting with human leucocyte antigen (HLA) class I ligands on target cells. The aim of our study was to investigate the influence of KIR2D genes with their HLA-C ligands in susceptibility to type 1 diabetes. A total of 98 type 1 diabetes patients and 70 healthy subjects from Latvia were typed for KIR genes and HLA-C ligands using polymerase chain reaction-based genotyping. The HLA C1+/C2+ combination was positively, and C1-/C2+ combination was negatively, associated with type 1 diabetes. Stratification analysis of KIR/HLA-C ligand combinations showed 2DL2+/C1+, 2DL3+/C1+, and 2DS2+ /C1+ to be positively, and 2DL2-/C1- and 2DS2-/ C1- to be negatively, associated. The presence of 2DL2-HLA-C1 in the absence of 2DS1, 2DS2 confers maximum susceptibility. Absence of 2DL2 and HLA-C1 along with absence of 2DS1 and 2DS2 confer maximum protection. A hypothetical model of KIR/ligand combinations on immune responses and type 1 diabetes susceptibility is proposed. Our results suggest that a combination KIR2DL2- HLA-C1 plays a critical role in susceptibility or protection in Latvians against type 1 diabetes.

MHC class I chain-related gene alleles 5 and 5.1 are transmitted more frequently to type 1 diabetes offspring in HBDI families.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by autoimmune destruction of pancreatic beta cells. Genetic and environmental factors contribute in this disease. There is evidence that MHC class I chain-related gene (MIC-A) plays a role in the susceptibility to this and other autoimmune diseases. There are five alleles of the MIC-A gene, which consist of different repetitions of GCT. In particular, MIC-A alleles 5 and 5.1 (the former with five repetitions of GCT, the latter with five repetitions and one additional insertion of nucleotide G) have been found to be associated with susceptibility to and age at onset of T1DM. The aim of our study was to analyze the transmission of these MIC-A alleles to T1DM-affected offsprings in HBDI families. These are multiplex families with affected offsprings and unaffected parents. DNA samples were amplified for MIC-A using fluorescence-labeled primers and analyzed on an ABI prism DNA sequencer. The transmission of alleles was then analyzed using pedigrees of families also obtained from HBDI. We analyzed 78 families and found that MIC-A alleles 5 and 5.1 are present and transmitted more frequently than expected. Heterozygotic parents for MIC-A alleles 5 and 5.1 were excluded from the study. Our results suggest that MIC-A alleles 5 and 5.1 are associated with susceptibility to T1DM in family studies.

HLA class I and class II association with ankylosing spondylitis in a southern Indian population.

Ankylosing spondylitis (AS) is a chronic inflammatory condition associated with HLA B27. But the association is not absolute. Hence association with other HLA class I antigens and class II alleles was studied in a southern Indian population. Sixty-five patients with primary AS were typed serologically for HLA class I antigens. Age- and sex-matched disease controls (37 with enterogenic reactive arthritis [ReA] and 25 with undifferentiated spondyloarthropathy [UnSpA]) and 124 healthy controls were studied. PCR-based DNA-SSO typing for DQA1 and DQB1 was performed on 20 patients with AS and 38 healthy controls. Twenty-three patients with AS and 39 controls were typed for DRB1 alleles. HLA B27 was positive in 76.9 % of the cases of AS (RR 811), 59.5% of those with ReA (RR 9.3), and 40% of the patients with UnSpA (RR 9.3), while none of the controls were B27 positive. The P value for positive association was highly significant for B27 in all the three groups. B27 positivity was associated with earlier age of onset of disease in all the diseases compared to the B27-negative group. HLA Cw2 was positively associated with AS (P highly significant; OR 52) and ReA (P = 0.0003; OR 14.2). HLA A1 and CW6 were significantly negatively associated only with AS (P = 0.0001 and 0.00004 and OR 0.25 and 0.02, respectively). None of the HLA class II alleles were significantly associated with AS. The apparent association with DRB1*11 (P = 0.03) was lost after Yates correction.

Class II MHC alleles in rheumatoid arthritis in Tamilnadu, India: is there an association?

Rheumatoid arthritis (RA) was reported to be associated with class II MHC alleles in different ethnic populations. A similar study was undertaken to determine the association of class II MHC with RA patients of Tamilnadu (Tamil-speaking Hindus), India. Thirty patients with RA and 39 healthy controls were included. Polymorphic second exons of the DRB1, DQA1, and DQB1 genes were amplified and subjected to SSOP typing. No allele was found to be significantly associated with RA. However DRB1*11 (P = 0.01) and DQB1*0302 (P = 0.02) were significantly associated with rheumatoid factor-positive RA patients. (All the DRB1*11-positive RA patients had either *04 or *10 allele as their second allele. This study is first of its kind in this population.

Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer.

Human papillomaviruses type 16 and 18 are the major cause of cervical cancer. However, genetic factors contribute to the propensity of persistent HPV infection and cervical carcinoma. Allelic variants of the human leukocyte genes have shown to be associated with cervical neoplasia. The strongest associations have been found with the genes in the HLA class II region. The aim of this study was to analyze the association of two non-HLA class II markers with invasive cervical cancer. Microsatellite polymorphism of the TNFA gene located in the class III region and a short tandem repeat polymorphism of the MICA gene located in the centromeric end of the HLA class I region were analyzed. Eighty-five patients and 120 matched control individuals from a population-based cohort from Northern Sweden participated in this nested case-control study. MICA was not associated with cervical carcinoma. TNFa-11 frequency was increased in the HPV18 DNA positive patients (OR = 2.84, p = 0.0481, CI = 1.04-7.78, pc = NS). TNFa-11 was not associated with susceptibility to HPV16 infection, but it increased the risk for cervical cancer with the HLA DQ6 (DQA 1*0102-DQB 1*0602) haplotype. Our findings indicate that the association of TNFA with cervical cancer is different with CIN. The extended HLA DQ6-TNFa-11 haplotype is increasing the risk for development of cervical cancer significantly (OR = 3.08, p = 0.0104, CI = 1.30-7.31).