Genetic polymorphisms of MAFK,encoding a small Maf protein,are associated with susceptibility to ulcerative colitis in Japan

AIM To investigate whether single nucleotide polymorphisms in maf protein K(MAFK), which encodes the MAFK, lead to increased susceptibility to ulcerative colitis in the Japanese population. METHODS This case control study examined the associations between MAFK single nucleotide polymorphisms(rs4268033 GA, rs3735656 TC and rs10226620 CT) and ulcerative colitis susceptibility in 174 patients with ulcerative colitis(UC) cases, and 748 subjects without no lower abdominal symptoms, diarrhea or hematochezia(controls). In addition, as the second controls, we set 360 subjects, who have an irregular bowel movement without abnormal lower endoscopic findings(IBM controls).RESULTS The genotype frequency of rs4268033 AA and allelic frequency of the rs4268033 A allele were significantly higher in the UC cases than in both controls(P = 0.0005 and 0.0001, P = 0.015 and 0.0027 vs controls and IBM controls, respectively). Logistic regression analysis after adjustment for age and gender showed that the rs4268033 AA and rs3735656 CC genotypes were significantly associated with susceptibility to UC development(OR = 2.63, 95%CI: 1.61-4.30, P = 0.0001 and OR = 1.81; 95%CI: 1.12-2.94, P = 0.015, respectively). Similar findings were observed by the comparison with IBM controls. In addition, the rs4268033 AA genotype was significantly associated with all phenotypes of UC except early onset. There was no significant association between rs10226620 and ulcerative colitis. CONCLUSION Our results provide the first evidence that MAFK genetic polymorphisms are significantly associated with susceptibility to UC development. In particular, rs4268033 is closely associated with an increased risk for the development of UC.     

Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population

Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus (SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case–control association study was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val → Phe substitution was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in the susceptibility genes for SLE.     

Lack of an association between interleukin-12 receptor beta1 polymorphisms and tuberculosis in Koreans

BACKGROUND: The fact that only 10% of people infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) suggests the presence of genetic factors in the pathogenesis of TB. To date, a number of single nucleotide polymorphisms (SNPs) in several candidate genes have been proposed as genetic risk factors of TB; however, reports are conflicting. OBJECTIVES: We investigated whether SNPs in the interleukin (IL)-12 receptor beta1 gene are associated with TB in Koreans. METHODS: One hundred and fifteen patients with bacteriologically or pathologically confirmed TB and 151 healthy anonymous blood donors were enrolled. The genotypes of 5 SNPs on IL-12 receptor beta1 gene, +705A/G (Q214R), +1158T/C (M365T), +1196G/C (G378R), +1637G/A (A525T) and +1664 C/T (P534S), were determined by PCR-RFLP. RESULTS: No difference was observed between TB patients and controls in terms of the genotype frequencies of the 5 SNPs of the IL-12 receptor beta1 gene or of their haplotypes. CONCLUSIONS: In view of the finding that these SNPs have been reported to be associated with TB in the Japanese and Moroccan populations, our results may reflect racial differences in genetic susceptibility to TB.     

Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in infants. Only a proportion of children infected with RSV require hospitalization. Because known risk factors for severe disease, such as premature birth, cannot fully explain differences in disease severity, genetic factors have been implicated. METHODS: To study the complexity of RSV susceptibility and to identify the genes and biological pathways involved in its development, we performed a genetic association study involving 470 children hospitalized for RSV bronchiolitis, their parents, and 1008 random, population controls. We analyzed 384 single-nucleotide polymorphisms (SNPs) in 220 candidate genes involved in airway mucosal responses, innate immunity, chemotaxis, adaptive immunity, and allergic asthma. RESULTS: SNPs in the innate immune genes VDR (rs10735810; P=.0017), JUN (rs11688; P=.0093), IFNA5 (rs10757212; P=.0093), and NOS2 (rs1060826; P=.0031) demonstrated the strongest association with bronchiolitis. Apart from association at the allele level, these 4 SNPs also demonstrated association at the genotype level (P=.0056, P=.0285, P=.0372, and P=.0117 for the SNPs in VDR, JUN, IFNA5, and NOS2, respectively). The role of innate immunity as a process was reinforced by association of the whole group of innate immune SNPs when the global test for groups of genes was applied (P=.046). CONCLUSION: SNPs in innate immune genes are important in determining susceptibility to RSV bronchiolitis.     

Replication of the association between the C8orf13–BLK region and systemic lupus erythematosus in a Japanese population

Objective

Recent genome‐wide association studies identified an association between single‐nucleotide polymorphisms (SNPs) in the C8orf13 region of BLK, the B lymphoid tyrosine kinase gene, with systemic lupus erythematosus (SLE) in Caucasians. The purpose of this study was to evaluate the significance of this region in the genetic background of Japanese patients with SLE.

Methods

Fourteen tag SNPs in the C8orf13–BLK region were genotyped in 327 Japanese patients with SLE and 322 healthy Japanese controls. The population‐attributable risk percentage (PAR%) of rs13277113 in Japanese was compared with that in Caucasians as well as with that of other SLE susceptibility genes in Japanese.

Results

As in Caucasians, rs13277113A demonstrated the strongest association in Japanese (P = 1.73 × 10^–6 for the genotype frequency, P = 4.75 × 10^–7 for the allele frequency, odds ratio [OR] 2.44 [95% confidence interval (95% CI) 1.43–4.16]). The association in Japanese was consistent with a recessive model (P = 2.74 × 10^–7, OR 2.27 [95% CI 1.66–3.11]). In contrast to the Caucasian population, this risk allele was the major allele in the Japanese population. Because both the risk allele frequency and the OR were higher in Japanese than in Caucasians, the PAR% of rs13277113 was estimated to be much higher in Japanese (35.4%) than in Caucasians (16.2%), and the second highest among the 6 confirmed SLE susceptibility genes in Japanese.

Conclusion

The association of the C8orf13–BLK region with SLE was replicated in a Japanese population. Contribution of this region to the genetic predisposition to SLE appeared to be greater in Japanese than in Caucasians.

     

FCRL3 promoter 169 CC homozygosity is associated with susceptibility to rheumatoid arthritis in Dutch Caucasians

BACKGROUND: Human leucocyte antigen is the only genetic risk factor for rheumatoid arthritis (RA) that has been consistently observed in different populations. A number of other genes such as PTPN22 and PADI4 showed population-specific association with RA susceptibility. Recently, Fc receptor-like 3 (FCRL3) gene was found to be associated with RA susceptibility in Japanese, but with conflicting results in other populations. OBJECTIVE: To investigate the association of FCRL3 polymorphism with RA susceptibility and severity in Dutch Caucasian patients with RA, as well as to perform a meta-analysis to reveal the contribution of this gene to RA susceptibility. METHODS: A total of 931 Dutch RA cases and 570 unrelated Dutch controls were genotyped for four FCRL3 single-nucleotide polymorphisms (SNPs). Genotyping was performed using the MassArray matrix-assisted laser desorption ionisation-time-of-flight mass spectrometry. Association of the FCRL3 SNPs with susceptibility to RA was examined by single-marker, carrier and haplotype analysis. RESULTS: Carrier analysis of the SNP (rs7528684) revealed the association of CC genotype with a higher risk of developing RA as compared with TT and TC carriers (p = 0.039 and OR = 1.31). There was no significant difference in the genotype and allele frequencies of all investigated SNPs between cases and controls. Meta-analysis of all studies comparing 9467 individuals showed that the OR for the CC genotype to develop RA was 1.2 and the p value <0.001. CONCLUSION: A promoter polymorphism of FCRL3 (rs7528684) is associated with an increased risk of developing RA in Dutch Caucasians, suggesting that this association is relevant for RA in both Japanese and Caucasian populations.     

Nucleotide excision repair pathway gene polymorphisms are associated with risk and prognosis of colorectal cancer

BACKGROUND Single nucleotide polymorphisms(SNPs)are universally present in nucleotide excision repair(NER)pathway genes,which could make impacts on colorectal carcinogenesis and prognosis.AIM To explore the association of all tagSNPs in NER pathway genes with colorectal cancer(CRC)risk and prognosis in a northern Chinese population by a two-stage case-control design composed of a discovery and validation stage.METHODS Genotyping for NER SNPs was performed using kompetitive allele specific PCR.In the discovery stage,39 tagSNPs in eight genes were genotyped in 368 subjects,including 184 CRC cases and 184 individual-matched controls.In the validation stage,13 SNPs in six genes were analyzed in a total of 1712 subjects,including 854 CRC cases and 858 CRC-free controls.RESULTS Two SNPs(XPA rs10817938 and XPC rs2607775)were associated with an increased CRC risk in overall and stratification analyses.Significant cumulative and interaction effects were also demonstrated in the studied SNPs on CRC risk.Another two SNPs(ERCC2 rs1052555 and ERCC5 rs2228959)were newly found to be associated with a poor overall survival of CRC patients.CONCLUSION Our findings suggest novel SNPs in NER pathway genes that can be predictive for CRC risk and prognosis in a large-scale Chinese population.The present study has referential values for the identification of all-round NER-based genetic biomarkers in predicting the susceptibility and clinical outcome of CRC.     

Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a multifactorial disease in which genetic factors rather than environmental factors may predominantly contribute to the pathogenesis. In order to identify the genetic determinants of the disease severity and progression of PBC, we examined an association of seven tag single-nucleotide polymorphisms (SNPs) in the multidrug resistance protein 3 (MDR3/ABCB4) gene in 148 Japanese PBC patients and 150 age- and sex-matched healthy control subjects. SNPs were detected via polymerase chain reaction (PCR) restriction fragment length polymorphism and PCR direct DNA sequencing methods. Subsequently, haplotypes were constructed from three tag SNPs (rs31658, rs31672, and rs1149222) that were significantly associated with progression of PBC. Logistic regression analyses revealed that a Hap 2 haplotype and its homozygous diplotype, Hap 2/Hap 2, in MDR3 were closely associated with the susceptibility to jaundice-type progression of PBC [P = 0.004, odds ratio (OR) 3.93, 95% confidence interval (CI) 1.56-9.90 and P = 0.0003, OR 17.73, 95% CI 3.77-83.42, respectively]. Conversely, another haplotype, Hap 1, and its homozygous diplotype, Hap 1/Hap 1, were associated with the insusceptibility to the progression to late-stage PBC (P = 0.021, OR 0.55, 95% CI 0.33-0.91 and P = 0.011, OR 0.24, 95% CI 0.08-0.71, respectively). CONCLUSION: The present study is the first report of an association of MDR3 haplotypes and diplotypes with progression of PBC. The Hap 2/Hap 2 diplotype in MDR3 could therefore be potentially applied to DNA-based diagnosis in Japanese patients with PBC as a strong genetic biomarker for predicting the progression and prognosis of PBC.     

Association between CYP24A1 polymorphisms and the risk of colonic polyps and colon cancer in a Chinese population

AIM To determine the pathogenesis and potential single nucleotide polymorphisms(SNPs) as screening sites for colonic polyps,colon cancer and ulcerative colitis,and to analyze the possible association between these genetic polymorphisms and the three diseases. METHODS We evaluated genetic polymorphisms in 144 newly diagnosed colonic polyp patients,96 colon cancer patients and 44 ulcerative colitis patients. The four SNPs genotyped were rs4809957,rs6068816,rs6091822 and rs8124792. The control group consisted of 504 East Asians enrolled in the 1000 Genomes Project. Correlations between CYP24A1 SNPs and the diseases were analyzed by Fisher's exact probability test.RESULTS CYP24A1 polymorphisms rs4809957 A/G and rs6068816 C/T showed a statistically significant association with risk of the three diseases,when both the genotypes and allele frequencies were considered. With regard to rs6091822 G/T,all three diseases were related to risk allele carriers(GT + TT) vs wild-type(GG),but the associations between the allele frequencies and the diseases were not significant. The risk of colonic polyps and colon cancer was related to the allele frequencies of rs8124792 G/A,and this association remained for genotype frequencies of this SNP. CONCLUSION Four SNPs are related to the risk of colonic polyps and colon cancer. G allele in rs6091822 G/T may play an anti-cancer role only if it is homozygous. The A allele,which is a minor component of rs8124792,may be indicated in the diagnosis of colonic polyps or colon cancer rather than ulcerative colitis.     

Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy

BACKGROUND/AIMS: We hypothesized that common genetic variation at ABCC2 influences ICP susceptibility. Hence we studied the association of single nucleotide polymorphisms (SNPs) of promoter, coding and non-coding regions of ABCC2 and intrahepatic cholestasis of pregnancy (ICP). METHODS: 70 ICP patients and 112 healthy pregnant women in the third trimester of their pregnancies were included in a cross sectional study. Four tag SNPs (rs717620 A/G; rs2756105 C/T; rs2002042 C/T; rs3740066 A/G) encompassing 70 kb in chr.10 and representing 46 polymorphic sites (r(2) > 0.8) were genotyped. Besides, 2 additional SNPs (rs17222723 A/T and rs8187710 G/A) were included. RESULTS: In univariate analysis, rs2002042 and rs3740066 were significantly associated with ICP (p < 0.04 and 0.01, respectively) but after multiple testing correction, only rs3740066 remained significantly associated with disease status (p < 0.03). We also observed a positive association between the rs3740066 and ALT, AST, alkaline phosphatase and total and conjugated bilirubin concentrations. Consistent with the analysis of individual markers, we observed that haplotype frequency of the ABCC2 gene in ICP patients significantly differed from controls (p < 0.03). CONCLUSIONS: We found an association between the rs3740066 in exon 28 of ABCC2 gene and ICP. The risk of disease for homozygous AA carriers is 4-fold higher (OR 4.44 CI 95% 1.83-10.78, p < 0.001) in comparison with GG carriers.     

NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population

Background. Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most prevalent and serious adverse drug reactions in the course of anti-tuberculosis (TB) treatment. Some researchers suggested that determination of N-acetyltransferase 2 (NAT2) genotype may be clinically useful to identify patients at high risk of developing ATDH. Aim. To evaluate whether the NAT2 genotype could be as a predictor for ATDH in Chinese community TB population. Material and methods. A total of 4304 community-based TB patients were followed up six to nine months prospectively. A nested case-control study was designed. Each ATDH case was 1:4 matched with controls by age (within 5 years old), gender, treatment history, disease severity and drug dosage. The polymorphisms of NAT2 were determined using polymerase chain reaction with restriction fragment length polymorphism. Conditional Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. Results. A total of 89 ATDH cases and 356 controls were included in this study. Allele frequency of NAT2*5, NAT2*6 and NAT2*7 in cases and controls were 4.5 and 3.2%, 25.3 and 26.5%, and 13.5 and 13.5%, respectively. Frequencies of genotypes and alleles of NAT2*5, NAT2*6 and NAT2*7 did not differ significantly between cases and controls. The OR of intermediate acetylator and slow acetylator compared with rapid acetylator was 1.040 (95%CI 0.616-1.758) and 0.990 (95%CI 0.509-1.925), respectively. The NAT2 haplotype distribution in cases was similar to controls. Conclusions. In conclusion, we did not find significant association between NAT2 genotype and ATDH in community-based Chinese population. It may be deficient to take NAT2 genotype as a predictor for ATDH in Chinese community TB patients.     

A polymorphism in the integrin ��V subunit gene affects the progression of primary biliary cirrhosis in Japanese patients

Background

Accumulating evidence indicates that multiple genetic factors are involved in the pathogenesis of primary biliary cirrhosis (PBC). The aim of this study was to investigate whether polymorphisms of the integrin ??V subunit gene (ITGAV), a component of integrin ??V??6, which plays an important role in the process of fibrosis, are associated with susceptibility to the onset and/or progression of PBC.

Methods

In the primary study, eight tag single nucleotide polymorphisms (SNPs) in ITGAV were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, direct DNA sequencing, or high-resolution melting curve analysis in 309 Japanese patients with PBC who were registered in the National Hospital Organization Study Group for Liver Disease in Japan (PBC cohort I) and 293 gender-matched healthy Japanese volunteers (control subjects). For the replication study, 35 PBC patients who progressed to end-stage hepatic failure and underwent liver transplantation (PBC cohort II) were also analyzed.

Results

Three tag SNPs (rs3911238, rs10174098, and rs1448427) in ITGAV were significantly associated with the severe progression of PBC, but not with susceptibility to the onset of PBC, in the primary study (PBC cohort I). Among these SNPs, rs1448427 was also significantly associated with the severe progression to end-stage hepatic failure in the replication study of PBC patients who underwent liver transplantation (PBC cohort II).

Conclusions

ITGAV is a genetic determinant for the severe progression of PBC in Japanese patients. Genetic polymorphisms of ITGAV may be useful for identifying high-risk Japanese PBC patients, including those who will require liver transplantation, at the time of initial diagnosis.     

Genetic polymorphisms in the surfactant proteins in systemic sclerosis in Japanese: T/T genotype at 1580 C/T (Thr131Ile) in the SP-B gene reduces the risk of interstitial lung disease

OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs) in the pulmonary surfactant protein (SP) genes and the presence or absence of interstitial lung disease (ILD) in SSc patients. METHODS: We studied 127 Japanese patients with SSc and 206 normal subjects. Investigated SNPs were C/T within amino acid (aa) 219, Arg219Trp in the SP-A1 gene (rs4253527), C/T within aa 131 (at nucleotide 1580) and Thr131Ile of the SP-B gene (rs1130866). Genotypes were determined by the TaqMan method. RESULTS: Genotype frequencies were not different between the SSc patients and normal controls for both loci. The patients were subsequently divided into two groups based on presence or absence of ILD. In the SNP in the SP-B gene, the frequency of the T/T genotype was significantly lower in the patients with ILD than in those without ILD. Limited in the patients who were positive for anti-Scl-70 antibody, the difference in the frequency of the T/T genotype between the ILD-positive and ILD-negative groups became more apparent. On the other hand, in the SNP in the SP-A1 gene, there was no significant skewing for a certain genotype. CONCLUSION: In SSc, where massive fibrosis occurs, possession of the T/T genotype in the SP-B gene would reduce the risk of ILD in Japanese.     

Interleukin-18 promoter polymorphisms in Japanese patients with rheumatoid arthritis: protective effect of the T allele and T/T genotype at rs360722

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a strong genetic contribution to its pathogenesis. Among numerous candidate genes, cytokine gene polymorphisms have been implicated. Interleukin-18 (IL-18) induces production of tumor necrosis factor-α and promotes T helper (Th)1-type immune responses. This study investigates the association between IL-18 promoter polymorphisms and RA susceptibility. A total of 2471 Japanese case–control samples (1493 RA patients and 978 healthy controls) were examined. Three haplotype tag single-nucleotide polymorphisms, rs1946518A/C, rs360718T/G, and rs360722T/C, spanning from the 5′UTR to intron 1 were genotyped using allelic discrimination with the use of specific TaqMan probes, and three haplotypes (A–T–T, C–T–C, and A–G–C) were determined. Among these polymorphisms, the frequency of the T allele at rs360722, which tags the A–T–T haplotype, was significantly lower in the RA patient group compared with the normal subjects [0.46 versus 0.49, P = 0.0061, Fisher’s exact probability test, odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75–0.95]. Having the T/T genotype further increased the significance (0.20 versus 0.27, P = 0.0006, OR = 0.72, 95% CI = 0.58–0.86). Therefore, presence of the T allele and T/T genotype at rs360722 reduces the susceptibility of Japanese people to RA.     

MicroRNA gene polymorphisms in pancreatic cancer

MicroRNAs (miRNAs) act as regulators of gene expression via translational repression. Single nucleotide polymorphisms (SNPs) in miRNAs have been shown to affect the regulatory capacity of miRNAs by influencing miRNA processing and/or miRNA-mRNA interactions. The purpose of this study was to investigate the association between 2 SNPs commonly found in precursor miRNA and the susceptibility and clinicopathological characteristics of pancreatic cancer. The rs11614913/miR-196a2, rs2910164/miR-146a SNPs were genotyped in 93 patients with pancreatic cancer and in 122 healthy controls. No significant differences in genotype distributions between controls and PC patients were observed. However, rs2910164 GG and rs11614913 CC genotypes and the rs2910164C/rs11614913C and rs2910164G/rs11614913C haplotypes were significantly overrepresented in PC patients with T1 and T2 tumor status than in those with T3 and T4. Our findings suggested that the rs2910164 and rs11614913 SNPs might play a role in pancreatic tumorigenesis, but the molecular mechanism underlying the particular sequence variations in miRNA that can cause aberrant expression remains to be determined.     

Angiotensinogen gene haplotype is associated with the prevalence of Japanese non-alcoholic steatohepatitis

Aim: Non-alcoholic steatohepatitis (NASH) patients frequently have hypertension, which is considered to be an important predictive factor for the subsequent development of hepatic fibrosis. The renin-angiotensin system is also known to contribute to the progression of NASH. Various types of functional single-nucleotide polymorphisms (SNPs) involved in the development of NASH have been proposed. Angiotensinogen (AGT) gene SNPs related to cardiovascular diseases have been reported. We aimed to evaluate the involvement of the AGT gene haplotype in Japanese NASH patients. Methods: Previously described genotypes of SNPs of the AGT gene, rs4762 C/T polymorphism (T207M), rs699 C/T polymorphism (T268M), and rs7079 C/A polymorphism (C11537A), were determined in 124 Japanese biopsy-proven NASH patients and 150 healthy volunteers (controls). Results: The allele and genotype frequencies in rs4762 and rs699 SNPs in NASH patients were similar to those in controls, while the frequency of the A allele and A/- genotype in rs7079 SNPs were much higher in NASH patients than in controls. In addition, the 3-SNP haplotype CTA was significantly over-represented in NASH patients compared with controls. Regarding clinical features of NASH patients, diastolic blood pressures in patients with the CTA/- genotype were much higher than in patients with other genotypes. Conclusions: We found a 3-SNP haplotype of the AGT gene that is involved in the development of NASH and influences hypertension in NASH patients. These results provide new insight into the therapy of NASH patients with the CTA haplotype using ACE inhibitors or angiotensin II type 1 receptor blockers.     

Association between fatty acid binding protein 3 gene variants and essential hypertension in humans

BACKGROUND: We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans. METHODS: We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data. RESULTS: The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences. CONCLUSION: We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.     

Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults

We investigated the association of 14 polymorphisms in the endothelial nitric oxide synthase gene (NOS3) with ankle brachial index (ABI) in non-Hispanic white hypertensives belonging to hypertensive sibships. Subjects (n=659, mean age 61+/-9 years, 54% women) underwent measurement of ABI using a standard protocol, and the lowest of 4 ABI values was used in the analyses. Non-synonymous SNPs with a minor allele frequency >0.02 and tag SNPs selected based on a measure of linkage disequilibrium (r(2)) were genotyped. We reduced the chance of false positives by testing for replication, randomly selecting 1 hypertensive sib from each sibship to create Subset 1 (n=330) and Subset 2 (n=329). Multivariable linear regression models were used to assess the associations of single NOS3 polymorphisms and haplotypes with ABI after adjustment for covariates (age, sex, body mass index, smoking, total cholesterol, HDL cholesterol, and diabetes). Two specific SNPs in significant LD with each other (rs891512 and rs1808593) were significantly associated with ABI in both subsets. Based on a sliding window approach with a window size of 2, estimated haplotypes from 2 SNP pairs (rs2070744-rs3918226 and rs1808593-rs7830) were also significantly associated with ABI in both subsets. In conclusion, specific NOS3 SNPs and haplotypes were associated with inter-individual variation in ABI, a non-invasive marker of peripheral arterial disease, in replicate subsets of hypertensive subjects. These findings motivate further investigation of the role of NOS3 variants in determining susceptibility to peripheral arterial disease.     

Association of PTPN22 haplotypes with Graves' disease

CONTEXT: A recent study reported associations of a series of single nucleotide polymorphisms (SNPs) within PTPN22, including rs2476601, with rheumatoid arthritis. OBJECTIVE: Having previously reported significant association of the T allele of rs2476601 in a Graves' disease (GD) cohort, we sought to determine whether novel rheumatoid arthritis-associated SNPs were also contributing to susceptibility to GD. DESIGN: Case control and family-based studies of five PTPN22 tag SNPs were performed. SETTING: An United Kingdom academic department of medicine was the setting for the study. PATIENTS OR OTHER PARTICIPANTS: A total of 768 GD patients, 768 control subjects, and 313 families with autoimmune thyroid disease participated. MAIN OUTCOME MEASURE: Tests for association with disease were the main outcome measure. RESULTS: No association with disease of any of the individual SNPs and no correlation between genotype and clinical phenotype were seen. However, haplotype analysis of the SNP markers with addition of rs2476601 did reveal a strong association of a haplotype containing the T allele, in both the case control (chi2 = 29.13; P = 6.77 x 10(-8)) and family data sets (chi2 = 5.24; P = 0.02). Furthermore, a novel protective effect of a haplotype containing all six SNPs was observed (chi2 = 17.02; P = 3.7 x 10(-5)). CONCLUSIONS: These data suggest that the association of SNPs within the PTPN22 region differs between autoimmune diseases, occurring individually and/or as part of a haplotype, indicating that the mechanisms by which PTPN22 confers susceptibility to GD may, in part, be disease specific.