A coding polymorphism of the kallikrein 1 gene is associated with essential hypertension: a tagging SNP-based association study in a Chinese Han population

OBJECTIVE: The aim of this study was to investigate the association between common variants in the human tissue kallikrein 1 (KLK1) gene and susceptibility to essential hypertension in Chinese Han. METHODS: A tagging single nucleotide polymorphism (tSNP) approach was used for a case-control study in 2411 patients with essential hypertension and 2348 controls. All DNA samples and clinical data were collected from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). RESULTS: Based on the HapMap data of Han Chinese in Beijing (CHB) population, two non-synonymous polymorphisms, namely rs5517 (Glu162Lys) and rs5516 (Gln121Glu), were selected as tSNPs which could efficiently tag eight SNPs of the KLK1 gene with R larger than 90% for both haplotypes and single locus. Significant differences were found between groups for frequencies of rs5517 A allele (42.48% in cases versus 39.32% in controls, P=0.0019) and AA genotype [adjusted odds ratio (OR)=1.25 for AA versus AG/GG, P=0.0067]. The haplotype composed of the rs5517 A and rs5516 G allele significantly increased the risk of hypertension, with adjusted OR of 1.12 [95% confidence interval (CI), 1.04-1.28, P=0.0377] when compared with the common haplotype G-C. Diplotype analysis also showed a significant association between the diplotype of AG-AC and essential hypertension (OR=1.34, 95% CI, 1.07-1.68, P=0.0096). CONCLUSIONS: The present study suggested that rs5517 in the KLK1 gene was significantly associated with essential hypertension in a Chinese Han population.     

Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170. METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses. RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45). CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.     

Association of prolactin and its receptor gene regions with familial breast cancer

CONTEXT: The contribution of prolactin (PRL) through its receptor (PRLR) to the pathogenesis and progression of human mammary tumors has received recent attention. OBJECTIVE: We investigated whether genetic variation in the PRL and PRLR genes is associated with the risk of breast cancer (BC). DESIGN: We conducted a case-control study with a total of seven single nucleotide polymorphisms (SNPs). SETTING: The study was conducted at an academic research laboratory and university clinics. PATIENTS AND OTHER PARTICIPANTS: A total of 441 German familial, unrelated BC cases and 552 controls matched by age, ethnicity, and geographical region participated in the study. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES(S): SNP genotype and haplotype distributions and haplotype interactions were correlated with the risk of BC. RESULTS: Two SNPs (rs1341239 and rs12210179) within the PRL promoter regions were significantly associated with increased risk in homozygotes for the variant alleles [odds ratio (OR), 1.67 and 95% confidence interval (CI), 1.11-2.50; and OR, 2.09 and 95% CI, 1.23-3.52, respectively]. The PRL haplotype containing the variant alleles of the promoter SNPs increased significantly the risk of BC (OR 1.42, 95%CI 1.07-1.90). A PRLR haplotype was associated with a significant decrease in BC risk (OR 0.69, 95% CI 0.54-0.89). An increasing number of PRL and PRLR risk haplotypes led to a significant trend of increasing risk for BC (chi(2) = 12.15; P = 0.007). CONCLUSIONS: Genetic variation in the PRL and PRLR genes was shown to influence BC risk. Additional studies are needed to further clarify the role of the PRL and PRLR genes in the risk of BC.     

Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients

Background

Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients.

Methods

Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction?Crestriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls.

Results

The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively.

Conclusions

CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.     

Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients

Background

To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes.

Methods

We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT-1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls.

Results

The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40–0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model (P = 0.032, OR 3.10, 95 % CI 1.05–9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model (P = 0.0002, OR 10.58, 95 % CI 2.36–47.54, and P = 0.006, OR 7.84, 95 % CI 1.39–44.36, respectively). Furthermore, the association of OCT-1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation.

Conclusions

The present study is the first report on the association of OCT-1 genetic polymorphisms with the overall development and jaundice-type progression of PBC.     

Haplotypes of the beta-2 adrenergic receptor associate with high diastolic blood pressure in the Caerphilly prospective study

OBJECTIVES: Current evidence demonstrates that both genetic and environmental factors influence blood pressure. The sympathetic nervous system is a key player in blood pressure control and functional genetic variants of the beta-2 adrenergic receptor (B2AR) have been identified and implicated in the pathogenesis of hypertension. The present study aimed to determine the effects of common haplotypes of the B2AR gene upon blood pressure in the Caerphilly Prospective Study. DESIGN: Two thousand five hundred and twelve men (aged 45-59 years) participated in the study. We selected individuals in the upper (n = 347) and lower (n = 279) quintiles of the diastolic blood pressure distribution fixed at two time points [phase 2 (1984-88) or phase 3 (1989-93)] as cases and controls. METHODS: We analysed two functional polymorphisms (Arg16Gly and Gln27Glu) of B2AR and their haplotypes. RESULTS: We found a higher risk of hypertension in individuals homozygous for the Gln27 compared to those individuals homozygous for Glu27 [odds ratio (OR) = 1.94; 95% confidence interval (CI) = 1.34-2.81; P = 0.001]. Three haplotypes (Gly16Gln27, Gly16Glu27 and Arg16Gln27) were present in both quintile groups. Logistic regression analysis showed that haplotypes with a Gln27 allele (Gly16Gln27 and Arg16Gln27) conferred a significantly higher risk for hypertension than the Gly16Glu27 haplotype (OR = 1.55; 95% CI = 1.11-2.17, OR = 1.37; 95% CI = 1.04-1.81; P = 0.009 and P = 0.027, respectively). However, there was no evidence to support a statistically significant difference in odds ratios for the Gly16Gln27 and Arg16Gln27 haplotypes (P = 0.477), suggesting that it is the Gln27 allele alone, rather than any haplotype, which best explains the association. CONCLUSIONS: In a prospectively studied Caucasian male cohort, high diastolic blood pressure was associated with B2AR haplotypes containing the pro-downregulatory Gln27 variant.     

Association of prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism with type 2 diabetes in two German study populations

CONTEXT: On the basis of its chromosomal localization and its role in the synthesis of the antilipolytic compound prostaglandin E(2), the prostaglandin E synthase 2 (PTGES2) is a candidate gene for type 2 diabetes. OBJECTIVE: The aim of the present study was to investigate whether genetic variants in the PTGES2 gene are associated with type 2 diabetes. RESULTS: Sequencing of the PTGES2 gene revealed one nonsynonymous coding single-nucleotide polymorphism (SNP) (Arg298His, rs13283456) and a previously unknown promoter SNP g.-417G>T. Both SNPs and additional haplotype tagging SNPs (rs884115, rs10987883, rs4837240) were genotyped in a nested case-control study of 192 incident type 2 diabetes subjects and 384 controls (European Prospective Investigation into Cancer and Nutrition-Potsdam). Carriers of the minor allele of Arg298His had a lower risk to develop the disease [odds ratio (OR) 0.63, 95% confidence interval (CI) 0.41-0.97, P = 0.04], compared with homozygous individuals with the common allele. The PTGES2 Arg298His polymorphism was reinvestigated in a population-based cross-sectional study (Cooperative Health Research in the Augsburg Region) consisting of 239 individuals with impaired glucose tolerance, 226 with type 2 diabetes, and 863 normoglycemic controls. In this study population, the Arg298His polymorphism was significantly associated with impaired glucose tolerance (OR 0.68, 95% CI 0.50-0.93, P = 0.007) and type 2 diabetes (OR 0.61, 95% CI 0.43-0.86, P = 0.004). A pooled analysis of data from both study populations revealed reduced risk of type 2 diabetes (OR 0.62, 95% CI 0.47-0.81, P = 0.0005) in PTGES2 298His allele carriers. CONCLUSION: We obtained evidence from two Caucasian study populations that the His298-allele of PTGES2 Arg298His confers to reduced risk of type 2 diabetes.     

新疆维吾尔族人心肌梗死与前列环素合酶基因单体型的相关性

目的 探讨前列环素合酶基因(CYP8A1)单体型与新疆维吾尔族人心肌梗死(MI)的相关性.方法 采用聚合酶链反应-限制性片段长度多态性方法 ,对210例MI患者和206例健康体检者CYP8A1基因的3个单核苷酸多态性(SNP)(rs5602,rs5629和rs45498106)进行基因分型和单体型构建,应用病例对照单体型分析的方法 进行相关性分析.结果 MI组CPY8A1基因rs5629的CC基因型频率为71.42%,明显高于对照组(61.65%,P=0.035),而rs5602和rs45498106基因型在两组间分布差异无统计学意义;MI组A-C-T单体型频率为0.60%,明显低于对照组(4.02%,P=0.001),但MI组C-T-T单体型频率为7.40%,明显高于对照组(3.31%,P=0.011).logistic回归分析结果 显示,调整吸烟、高血压和高胆固醇血症等因素后发现,rs5629CC基因型(P=0.021,OR=1.665,95%C/ :1.024～2.156)和C-T-T单体型仍是MI的独立危险因素(P=0.011,OR=1.876,95%CI:1.410-3.171).结论 CYPSA1基因rs5629位点CC基因型可能与新疆维吾尔族人MI的发生相关;C-T.T单体型可能为新疆维吾尔族人MI的易感标志;A-c-T单体型可能为新疆维吾尔族人群MI的保护因子.     

Relationship between interleukin-6 polymorphism and susceptibility to chronic hepatitis B virus infection

AIM:To identify the relationship between tag single nucleotide polymorphisms(tag SNPs) of interleukin-6(IL-6) gene and susceptibility to chronic hepatitis B virus(HBV) infection in a Han Chinese population.METHODS:We performed a case-control study of501 Chinese patients with chronic HBV infection and301 self-limiting HBV-infected individuals as controls.Genomic DNA was isolated from the whole blood of all subjects using phenol/chloroform with MaXtract highdensity tubes. Tag SNPs were identified using genotype data from the panel(Han Chinese in Beijing) of the phase II HapMap Project. Four tag SNPs in IL-6(rs17147230A/T,rs2066992G/T,rs2069837A/G and rs2069852A/G) were genotyped by the Multiplex Snapshot technique. The genotype and allele frequencies were calculated and analyzed.RESULTS:Five haplotypes were involved in the analysis,with frequencies higher than 0.03. One of the haplotypes,TTAA,was significantly different between the two groups. Overall haplotype P values were:ATAA,P = 0.605,OR(95%CI) = 1.056(0.860-1.297); TGAG,P = 0.385,OR(95%CI) = 1.179(0.813-1.709); TGGG,P = 0.549,OR(95%CI) = 1.087(0.827-1.429); TTAA,P = 0.004,OR(95%CI) = 0.655(0.491-0.873); TTAG,P = 0.266,OR(95%CI) = 1.272(0.832-1.944). However,the four SNPs showed no significant genotype/allele associations with susceptibility to chronic HBV infection. Overall allele P values were:rs17147230,P = 0.696,OR(95%CI) = 1.041(0.850-1.276); rs2066992,P = 0.460,OR(95%CI)= 1.090(0.868-1.369); rs2069837,P = 0.898,OR(95%CI) = 0.983(0.759-1.274); rs2069852,P = 0.165,OR(95%CI) = 0.859(0.693-1.064). Overall genotype P values were:rs17147230,P = 0.625; rs2066992,P= 0.500; rs2069837,P = 0.853; and rs2069852,P =0.380.CONCLUSION:The four tag SNPs of IL-6 gene may be associated with susceptibility to chronic HBV infection in the Han Chinese population.     

Study of functional variants of the BANK1 gene in rheumatoid arthritis

Objective

To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA).

Methods

Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single‐nucleotide polymorphisms (SNPs) using a TaqMan 5′‐allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi‐square test.

Results

We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03–1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00–1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04–1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07–1.29]) with RA in the pooled analysis. In a 3‐SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04–1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74–0.92]).

Conclusion

These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk.

     

Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33

We performed a three-phase genome-wide association study (GWAS) using cases and controls from a genetically isolated population, Ashkenazi Jews (AJ), to identify loci associated with breast cancer risk. In the first phase, we compared allele frequencies of 150,080 SNPs in 249 high-risk, BRCA1/2 mutation-negative AJ familial cases and 299 cancer-free AJ controls using chi(2) and the Cochran-Armitage trend tests. In the second phase, we genotyped 343 SNPs from 123 regions most significantly associated from stage 1, including 4 SNPs from the FGFR2 region, in 950 consecutive AJ breast cancer cases and 979 age-matched AJ controls. We replicated major associations in a third independent set of 243 AJ cases and 187 controls. We obtained a significant allele P value of association with AJ breast cancer in the FGFR2 region (P = 1.5 x 10(-5), odds ratio (OR) 1.26, 95% confidence interval (CI) 1.13-1.40 at rs1078806 for all phases combined). In addition, we found a risk locus in a region of chromosome 6q22.33 (P = 2.9 x 10(-8), OR 1.41, 95% CI 1.25-1.59 at rs2180341). Using several SNPs at each implicated locus, we were able to verify associations and impute haplotypes. The major haplotype at the 6q22.33 locus conferred protection from disease, whereas the minor haplotype conferred risk. Candidate genes in the 6q22.33 region include ECHDC1, which encodes a protein involved in mitochondrial fatty acid oxidation, and also RNF146, which encodes a ubiquitin protein ligase, both known pathways in breast cancer pathogenesis.     

Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan

BACKGROUND: In Europeans and populations of European origin, several groups have recently identified novel type 2 diabetes susceptibility genes, including FTO, SLC30A8, HHEX, CDKAL1, CDKN2B, and IGF2BP2, none of which were in the list of functional candidates. OBJECTIVE AND DESIGN: The aim of this study was to replicate in a Japanese population previously identified associations of single nucleotide polymorphisms (SNPs) within 10 candidate loci with type 2 diabetes using a relatively large sample size: 1921 subjects with type 2 diabetes and 1622 normal controls. RESULTS: A total of 15 SNPs were genotyped. Eight SNPs in five loci were found to be associated with type 2 diabetes: rs3802177 [odds ratio (OR) = 1.16 (95% confidence interval (CI) 1.05-1.27); P = 4.5 x 10(-3)] in SLC30A8; rs1111875 [OR = 1.27 (95% CI 1.14-1.40); P = 1.4 x 10(-5)] and rs7923837 [OR = 1.27 (95% CI 1.13-1.43); P = 1.0 x 10(-4)] in HHEX; rs10811661 [OR = 1.27 (95% CI 1.15-1.40); P = 1.9 x 10(-6)] in CDKN2B; rs4402960 [OR = 1.23 (95% CI 1.11-1.36); P = 8.1 x 10(-5)] and rs1470579 [OR = 1.18 (95% CI 1.07-1.31); P = 8.3 x 10(-4)] in IGF2BP2; and rs7754840 [OR = 1.28 (95% CI 1.17-1.41); P = 4.5 x 10(-7)] and rs7756992 [OR = 1.27 (95% CI 1.15-1.40); P = 9.8 x 10(-7)] in CDKAL1. The first and second strongest associations were found at variants in CDKAL1 and CDKN2B, both of which are involved in the regenerative capacity of pancreatic beta-cells. CONCLUSION: Some of these variants represent common type 2 diabetes-susceptibility genes in both Japanese and Europeans.     

Genetic variants and susceptibility to neurological complications following West Nile virus infection

To determine genetic factors predisposing to neurological complications following West Nile virus infection, we analyzed a cohort of 560 neuroinvasive case patients and 950 control patients for 13 371 mostly nonsynonymous single-nucleotide polymorphisms (SNPs). The top 3 SNPs on the basis of statistical significance were also in genes of biological plausibility: rs2066786 in RFC1 (replication factor C1) (P = 1.88 × 10(-5); odds ratio [OR], 0.68 [95% confidence interval {CI}, .56-.81]); rs2298771 in SCN1A (sodium channel, neuronal type I α subunit) (P = 5.87 × 10(-5); OR, 1.47 [95% CI, 1.21-1.77]); and rs25651 in ANPEP (ananyl aminopeptidase) (P = 1.44 × 10(-4); OR, 0.69 [95% CI, .56-.83]). Additional genotyping of these SNPs in a separate sample of 264 case patients and 296 control patients resulted in a lack of significance in the replication cohort; joint significance was as follows: rs2066786, P = .0022; rs2298771, P = .005; rs25651, P = .042. Using mostly nonsynonymous variants, we therefore did not identify genetic variants associated with neuroinvasive disease.     

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.     

The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes

Aim:  The goal of this study was to develop and implement methodology that would aid in the analysis of extended high-density single nucleotide polymorphism (SNP) major histocompatibility complex (MHC) haplotypes combined with human leucocyte antigen (HLA) alleles in relation to type 1 diabetes risk.
Methods:  High-density SNP genotype data (2918 SNPs) across the MHC from the Type 1 Diabetes Genetics Consortium (1240 families), in addition to HLA data, were processed into haplotypes using P ed C heck and M erlin , and extended DR3 haplotypes were analysed.
Results:  With this large dense set of SNPs, the conservation of DR3-B8-A1 (8.1) haplotypes spanned the MHC (≥99% SNP identity). Forty-seven individuals homozygous for the 8.1 haplotype also shared the same homozygous genotype at four 'sentinel' SNPs (rs2157678 'T', rs3130380 'A', rs3094628 'C' and rs3130352 'T'). Conservation extended from HLA-DQB1 to the telomeric end of the SNP panels (3.4 Mb total). In addition, we found that the 8.1 haplotype is associated with lower risk than other DR3 haplotypes by both haplotypic and genotypic analyses [haplotype: p = 0.009, odds ratio (OR) = 0.65; genotype: p = 6.3 × 10⁻⁵, OR = 0.27]. The 8.1 haplotype (from genotypic analyses) is associated with lower risk than the high-risk DR3-B18-A30 haplotype (p = 0.01, OR = 0.23), but the DR3-B18-A30 haplotype did not differ from other non-8.1 DR3 haplotypes relative to diabetes association.
Conclusion:  The 8.1 haplotype demonstrates extreme conservation (>3.4 Mb) and is associated with significantly lower risk for type 1 diabetes than other DR3 haplotypes.     

Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis

Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA) DRB1*08:03 allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the DRB1*08:03-DQB1*06:01 (13% versus 6%; P = 0.000025; odds ratio [OR] = 2.22) and DRB1*04:05-DQB1*04:01 haplotypes (17% versus 13%; P = 0.044; OR = 1.38). Conversely, there were significant protective associations with the DRB1*13:02-DQB1*06:04 (2% versus 5%; P = 0.00093; OR = 0.27) and DRB1*11:01-DQB1*03:01 haplotypes (1% versus 4%; P = 0.03; OR = 0.37). The frequency of the DRB1*09:01-DQB1*03:03 haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%; P = 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (P = 0.0000015; OR = 1.83) of the DRβchain differed the most in patients with PBC, compared with healthy subjects. CONCLUSION: This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC.     

Association of CD24 gene polymorphisms with susceptibility to biopsy-proven giant cell arteritis

OBJECTIVE: To investigate the possible implication of CD24 gene in the genetic predisposition to giant cell arteritis (GCA). METHODS: A total of 120 patients diagnosed with biopsy-proven GCA and 195 ethnically matched controls from the same region were studied. Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646) were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. RESULTS: The 2 genetic variants showed statistically significant differences between patients with GCA and controls. The strongest association was observed for the rs3838646 TG/del polymorphism, conferring on the "del" allele an increased risk of GCA genetic susceptibility (odds ratio 1.94, 95% confidence interval 1.15-3.27, p = 0.01). In addition, genotypes carrying the rs3838646 "del" allele showed an increased frequency among GCA patients compared to controls (OR 2.31, 95% CI 1.30-4.1, p = 0.003). For the rs8743, an increased frequency of Val/Val homozygous individuals in patients with GCA compared to controls (OR 6.08, 95% CI 1.50-24.63, p = 0.001) was observed. A high degree of linkage disequilibrium was estimated between the 2 polymorphisms (D' = 0.7) and the C/del haplotype was associated with an increased risk of GCA susceptibility (OR 2.10, 95% CI 1.23-3.60, p = 0.005), whereas the C/TG haplotype showed a protective effect (OR 0.63, 95% CI 0.45-0.87, p = 0.005). CONCLUSION: Our results suggest a potential role for the CD24 gene in the susceptibility to GCA in our population.