Haplotype analysis of the apolipoprotein A5 gene in patients with the metabolic syndrome.

BACKGROUND AND AIMS: In recent studies, the T-1131C variant of apolipoprotein A5 (APOA5) gene was found to confer a risk for metabolic syndrome (MS). Here we determined four haplotype-tagging polymorphisms (T-1131C, IVS3+G476A, T1259C, and C56G), and studied the distribution of the naturally occurring major haplotype profiles in MS. METHODS AND RESULTS: A total of 343 MS patients and 284 controls were genotyped using PCR-RFLP methods. Both in MS and control groups, we confirmed the already known association of -1131C, IVS3+473A and 1259C minor alleles with elevated triglyceride levels. The prevalence of the APOA5*2 haplotype (the combination of T-1131C, IVS3+G476A and T1259C SNPs) was 13.1% in MS patients, and 4.9% in controls (p<0.001); multiple logistic regression analysis revealed that this haplotype confers risk for the development of MS (OR=2.880; 95% CI: 1.567-5.292; p=0.001). We also observed a gender effect: in males a more prominent degree of susceptibility was found. Contrary to the APOA5*2 haplotype, the prevalence rate of APOA5*4 (determined by the T-1131C SNP alone) did not differ between MS patients and controls. We identified a novel haplotype, designated here as APOA5*5 (1259C allele alone); which appears to be protective against MS. CONCLUSION: Our results refined the role of SNP T-1131C in the development of MS. The susceptibility nature of this SNP is limited to the APOA5*2 haplotype, while in APOA5*4 haplotype it did not confer a risk for the disease. In addition, as our current data suggest, the novel APOA5*5 haplotype can confer protection against MS.

Functional variants of interleukin-23 receptor gene confer risk for rheumatoid arthritis but not for systemic sclerosis.

OBJECTIVES: Recently, an association was found between Crohn's disease and the interleukin-23 receptor (IL-23R) gene. Since the IL-23/IL-17 pathway is known to associate with other autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc), we hypothesised that IL-23R could be a shared susceptibility gene. METHODS: Groups of patients with rheumatoid arthritis (n = 412), systemic sclerosis (n = 224), Crohn's disease (n = 190) and healthy controls (n = 220) were genotyped for rs10889677 (exon-3'UTR C2370A), rs2201841, and rs1884444 variants; the first two have been shown to confer risk for Crohn's disease. RESULTS: We observed an increased prevalence of the homozygous rs10889677 AA and homozygous rs2201841 CC genotypes both in the Crohn's disease and in the RA groups as compared to the controls (12.1%, 11.9% vs 5.91%, p<0.05; and 13.2%, 13.1% vs 5.91%, p<0.05), but not in the SSc patients. Logistic regression analysis revealed that bearing these alleles represent risk for the development of rheumatoid arthritis (chi(2) = 5.58, p = 0.018, OR = 2.15, 95% CI 1.14-4.06 for rs10889677; and chi(2) = 7.45, p = 0.006, OR = 2.40, 95% CI 1.28-4.51 for rs2201841). The rs1884444 allele, which has been previously reported as neutral for development of Crohn's disease, was also found neutral for all studied groups in the present study. CONCLUSIONS: The data reported here provide direct evidence that some allelic variants or haplogroups of IL-23R represent independent risk factors for rheumatoid arthritis as well as Crohn's disease, but not for scleroderma.

Prevalence of functional haplotypes of the peptidylarginine deiminase citrullinating enzyme gene in patients with rheumatoid arthritis: no influence of the presence of anti-citrullinated peptide antibodies.

OBJECTIVE: Citrullinated peptides produced by enzymatic deimination of arginine residues in proteins by peptidylarginine deiminases are of particular interest in the pathogenesis of rheumatoid arthritis (RA). One type of citrullinated protein - the cyclic citrullinated peptide - is the target of the anti-cyclic citrullinated peptide antibody, the most sensitive and specific autoantibody in RA. The peptidylarginine deiminase type 4 (PADI4) gene, which codes one of the PADI enzyme isotypes, has genetic variants that confer susceptibility to RA in Asian, but not in European populations. METHODS: Genetic associations were examined in 214 Hungarian RA patients characterized for the presence of anti-CCP and rheumatoid factor. The patients were characterized for the existing haplotypes of the PADI4 gene (defined by the combinations of 4 exonic padi4_89: 163G/A, padi4_90: 245T/C, padi4_92: 335C/G, padi4_104: 349T/C and 2 intronic padi4_94: 17535226C/T and padi4_102: 17546809C/T variants) by the PCR-RFLP method. RESULTS: None of the PADI4 haplotypes was accumulated in RA patients. One new finding was that we also did not detect the accumulation of any haplotypes either in the anti-CCP or in the RF-positive subgroups of patients. CONCLUSION: The data presented here show that none of the naturally occurring haplotypes of the PADI4 gene conferred susceptibility to RA in an average group of Hungarian patients; this is in agreement with findings for other European populations. In addition, none of the functional PADI4 haplotypes were associated with the pathologic immune response, which was evidenced by the absence of accumulation of anti-CCP-positive subjects in the specific PADI4 haplotypes.

Functional glucokinase regulator gene variants have inverse effects on triglyceride and glucose levels, and decrease the risk of obesity in children.

OBJECTIVE: Recently, the association of the natural variants rs1260326 and rs780094 of the glucokinase regulatory protein (GCKR) gene with increased fasting triglycerides and decreased fasting plasma glucose in diabetic adults was reported; the minor alleles were also found to reduce the risk of type 2 diabetes. The present study examined the possible associations of these variants with triglycerides and glucose levels, their allele distribution and their possible effects on childhood obesity. METHODS AND RESULTS: A total of 221 obese children and 115 healthy normal-weight children as controls were genotyped using PCR-RFLP methods. Both functional GCKR variants were found in association with elevated serum triglycerides and lower fasting plasma glucose levels. Results of logistic regression revealed that, despite higher triglyceride levels, the carriers of the GCKR variants were more protected against the development of obesity; the adjusted models confirmed the lower risk of obesity for both variants (rs1260326: OR, 0.46; 95% CI, 0.25-0.83; rs780094: OR, 0.41; 95% CI, 0.23-0.74). CONCLUSION: Our findings confirm the inverse modulating effect of functional GCKR variants on triglycerides and glucose levels in obese paediatric patients and healthy normal-weight controls. The results of our study strongly suggest that the minor alleles confer protection against the development of obesity in children. The findings also suggest that the minor alleles of functional GCKR may protect against diabetes and the metabolic syndrome in adults.