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The purpose of this study was to determine whether toll-like receptor 9 (TLR9) gene polymorphisms were markers of susceptibility to or severity of systemic lupus erythematosus (SLE) in Taiwanese patients. The study included 211 healthy individuals and 167 Chinese patients with SLE. Polymorphisms of TLR9 [rs2066807 and rs187084 (−1486 T/C)] were typed from genomic DNA. The genotypes, allelic frequencies, and carriage rates were compared between patients with SLE and control subjects. The relationship between allelic frequencies and clinical manifestations of 167 patients with SLE was evaluated. There was no statistically significant difference in TLR9 (rs2066807) gene polymorphism, allelic frequency, and carriage rate between the SLE and control groups. However, for the genotype of TLR9 −1486 T/C (rs187084) polymorphism, there was a statistically significant difference between the SLE and the control groups ( P < 0.001, χ = 15.9). Moreover, there was a significant association between the two groups in allelic frequency and carriage rate of the T allele ( P < 0.001, χ = 18.5 and P < 0.01, χ = 8.06, respectively). We did not detect any association between the TLR9 genotype and the clinical or laboratory profiles in patients with SLE. The results suggest that the TLR9 −1486 T/C (rs187084), but not TLR9 (rs2066807), polymorphism is related to SLE in Taiwanese patients. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease and can lead to deformities and severe disabilities, due to irreversible damage of tendons, joints, and bones. Previous study indicated that DNA repair system was involved in the pathology of RA. In this study, we investigated the association of two 8-oxoguanine glycosylase 1 ( OGG1) gene polymorphisms (rs159153 and rs3219008) with the susceptibility to RA in 384 Taiwanese individuals (192 patients with RA and 192 controls). Our data showed that statistically significant difference in genotype frequency distributions was found at rs3219008 SNP between patients with RA and control groups ( P = 5.6E-0.5). Our data also indicated that individuals with the AG genotype at rs3219008 SNP may have a higher risk of developing RA. We did not observe any statistically significant association of OGG1 haplotype frequencies (rs159153 and rs3219008) with RA progression. The study suggested that OGG1 polymorphisms (rs159153 and rs3219008) are associated with RA progression and that these may be used as molecular markers of RA. [ABSTRACT FROM AUTHOR]

This study examines whether or not MBD4 polymorphism is a marker for rheumatoid arthritis (RA) susceptibility or severity for Chinese patients in Taiwan. This study included 193 patients with RA, while 190 unrelated healthy individuals living in Central Taiwan served as controls. The relationship between MBD4 polymorphism and clinical manifestations of RA was evaluated. For the genotype and allelic frequency of MBD4-1057 polymorphism, there were no statistically significant differences between patients with RA and controls. There were significant differences in the distribution of MBD4-8666 polymorphism frequencies between patients with RA and controls [ P = 0.013; P (Pc) = 0.039]. There were also significant relationships in the distribution of MBD4-9229 polymorphism genotype between patients with RA and controls ( P = 0.007; Pc = 0.021). However, we did not detect any associations for MBD4-1057, MBD4-8666 or MBD4-9229 with rheumatoid factor presence, extra-articular involvement or bone erosion in patients with RA. Results suggest that MBD4-8666 and MBD4-9229, but not MBD4-1057, gene polymorphisms are related to RA in Chinese patients in Taiwan. [ABSTRACT FROM AUTHOR]

Background: Idiopathic membranous nephropathy (IMN) is one of the most common forms of autoimmune nephritic syndrome in adults. The purpose of this study is to evaluate whether polymorphisms of PLA2R1 affect the development of IMN. Methods: Taiwanese-Chinese individuals (129 patients with IMN and 106 healthy controls) were enrolled in this study. The selected single nucleotide polymorphisms (SNPs) in PLA2R1 were genotyped by real-time polymerase chain reaction using TaqMan fluorescent probes, and were further confirmed by polymerase chain reaction-restriction fragment length polymorphism. The roles of the SNPs in disease progression were analyzed. Results: Genotype distribution was significantly different between patients with IMN and controls for PLA2R1 SNP rs35771982 (p = 0.015). The frequency of G allele at rs35771982 was significantly higher in patients with IMN as compared with controls (p = 0.005). In addition, haplotypes of PLA2R1 may be used to predict the risk of IMN (p = 0.004). Haplotype H1 plays a role in an increased risk of IMN while haplotype H3 plays a protective role against this disease. None of these polymorphisms showed a significant and independent influence on the progression of IMN and the risk of end-stage renal failure and death (ESRF/death). High disease progression in patients having C/T genotype at rs6757188 and C/G genotype at rs35771982 were associated with a low rate of remission. Conclusions: Our results provide new evidence that genetic polymorphisms of PLA2R1 may be the underlying cause of IMN, and the polymorphisms revealed by this study warrant further investigation. [ABSTRACT FROM AUTHOR]

Progesterone and progesterone receptors (PGR) are known to play important roles in the pathophysiology of pelvic organ prolapse (POP). We investigated whether the PGR gene polymorphisms were associated with POP by conducting a case-control association study in 87 women with POP and 150 women without POP. Genotypes of the PGR gene polymorphisms (rs500760 and rs484389) were determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. There was significant difference between women with and those without POP in the distribution of the PGR rs484389 genotypes evaluated. Using multivariable logistic regression, older age, increased body mass index, menopausal status, and PGR rs484389 genotype CT were significantly associated with POP. The present study shows that PGR genotype may be associated with POP. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether pelvic organ prolapse (POP) is associated with collagen 3 alpha 1 (COL3A1) polymorphisms and other factors.Methods: A case-control association study was conducted with 84 women affected with POP and 147 controls. The genotypes of nucleotides COL3A1 rs1800255 and COL3A1 rs1801184 polymorphisms were ascertained by polymerase chain reaction and restriction fragment length polymorphism analysis.Results: The distribution of the COL3A1 rs1800255 genotypes was significantly different among affected women and controls. Older age and incidence of COL3A1 rs1800255 genotype AA were significantly associated with risk of POP.Conclusion: There may be an association between COL3A1 genotype and risk of POP. [ABSTRACT FROM AUTHOR]

To investigate whether polymorphisms of IL-2 and IL-18 genes are associated with rheumatoid arthritis (RA), polymorphisms of IL-2 and IL-18 genes were detected by polymerase-chain-reaction-based restriction analysis in the patients with RA and normal controls. The results for the IL-18 gene revealed a significant difference between the patients and the normal controls ( p = 0.000003), but there was no significant difference for the IL-2 gene ( p = 0.876). The IL-18 gene 105A allele was associated with RA in Chinese patients. Individuals possessing the 105A allele had a higher incidence of RA. A lack of association of IL-2 gene polymorphism between RA patients and healthy individuals was noted. The results of this study provide genetic evidence that IL-18-105A/C polymorphism may play an effective role in RA. [ABSTRACT FROM AUTHOR]

The objective of the study is to examine whether interleukin-10 (IL-10) promoter polymorphism is a marker of susceptibility of systemic lupus erythematosus (SLE) in Chinese patients in Taiwan. The study included 119 Chinese patients with SLE. One hundred unrelated healthy individuals living in central Taiwan served as control subjects. Each polymorphism was detected as a result of a polymerase chain reaction (PCR)-based restriction analysis. The PCR product length was determined to be 412 bp (CC) whereas two fragments of 236 and 176 bp were determined to be excisable lengths (AA). The relationship between the IL-10 gene polymorphism and clinical manifestations of SLE was evaluated. For the genotype and allelic frequency, there were statistically significant differences between the SLE patients and the normal control subjects ( p=0.007 and 0.003, respectively). But we did not detect any association of carriage rate of the IL-10 polymorphism and the normal control subjects ( p=0.077). Furthermore, we did not detect any association of IL-10 genotype with antinuclear antibody, malar rash, photosensitivity, discoid lupus, mucosal ulcer, arthritis, serositis, hematology, immunology, involvement of central nervous system, and renal disease involvement in the SLE patients. The significant relation of −627 IL-10 genotype and allelic frequency with SLE implies that the IL-10 gene polymorphism can serve as a candidate gene marker for further study in patients with SLE in Taiwan. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine whether −627 interleukin-10 (IL-10) promoter polymorphism is a marker of susceptibility to or severity of rheumatoid arthritis (RA) in Chinese patients in Taiwan. The study included 198 Chinese patients with RA. One hundred unrelated healthy individuals living in central Taiwan served as the control subjects. The relationship between IL-10 gene polymorphism and clinical manifestations of RA was evaluated. For the genotype, allelic frequency, and carriage rate of IL-10 polymorphism, there were no statistically significant differences found between patients and controls. Furthermore, we did not detect any association of IL-10 genotype with rheumatoid factor (RF), extra-articular involvement, or bone erosion in the RA patients. The lack of association of −627 IL-10 gene polymorphism with RA and the clinical findings in our study implies that the IL-10 gene polymorphism cannot serve as a candidate gene marker for screening RA patients. [ABSTRACT FROM AUTHOR]

We investigated whether there is an association between polymorphism of the CYP17 gene and rheumatoid arthritis in Chinese patients in central Taiwan. Genomic DNA was extracted from the peripheral blood of 146 female and 47 male RA patients, as well as from 42 female and 59 male control subjects; restriction fragment length polymorphism (defined as the A1 and A2 alleles) was then determined. Clinical variables such as rheumatoid factor positivity, extra-articular manifestations, and joint erosion were also investigated for the RA patients. We found that more male RA patients had the A1 allele ( P=0.019) and fewer female RA patients the A2 allele than control subjects ( P=0.048). In male RA patients, A1 carriers showed more extra-articular manifestations ( P=0.048). In female patients, a significant decrease in A2 carriers mainly occurred in the later-onset age group ( P=0.024). This study suggests that the A2 allele may significantly decrease the overall risk of developing RA. In women, the protective effect of A2 mainly affects the older age group. In men, the clinical severity of RA may decrease in patients with the A2/A2 genotype. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine whether interleukin-1 beta (IL-1ß) promoter and exon 5 gene polymorphisms are markers of susceptibility or clinical manifestations in Taiwanese patients with gout. The study included 196 patients in addition to 103 unrelated healthy control subjects living in central Taiwan. From genomic DNA, polymorphisms of the gene for IL-1ß promoter and IL-1ß exon 5 were typed. Allelic frequencies were compared between the two groups, and the relationship between allelic frequencies and clinical manifestations of gout was evaluated. No significant differences were observed in the allelic frequencies of the IL-1ß promoter between patients with gout and healthy control subjects. Additionally, we did not detect any association of the IL-1ß promoter genotype with the clinical and laboratory profiles of gout patients. However, there was a significant difference between the two groups in terms of hypertriglyceridemia (P=0.0004, ?2=12.52, OR 7.14, 95%CI 0.012-0.22). There was also a significant difference in the genotype of IL-1ß exon 5 polymorphism between patients with and without hypertriglyceridemia. Results of the present study suggest that polymorphisms of the IL-1ß promoter and IL-1ß exon 5 are not related to gout patients in central Taiwan. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenic purpura (ITP) is an immune-mediated disorder. We investigated the polymorphisms of interleukin (IL)-4 intron 3, IL-6 (−572 G/C), and IL-10 (−627 C/A) in 50 children with acute ITP, 30 children with chronic TIP, and 100 healthy individuals. There were significant differences in the RP1/RP2 genotype proportion (P = 0·04) and the RP2 allelic frequency (P = 0·03) of IL-4 intron 3 and the A/C genotype proportion (P = 0·01) of IL-10 (−627) between children with chronic ITP and controls. This finding suggests that the IL-4 intron 3 and IL-10 (−627) polymorphisms contribute to the susceptibility of developing childhood chronic ITP. [ABSTRACT FROM AUTHOR]

Conclusion Patients who carry the T/T homozygote of CYP17 C/T gene polymorphism may have a higher risk of developing oral cancer. Objective Cancer of the oral cavity is the most commonly seen malignancy in Taiwan, and its rising incidence poses a formidable challenge to oncologists. The CYP17 gene encodes P450c17alpha, an enzyme involved in the metabolism of steroid hormones. Tumor necrosis factor-α (TNF-α) is one of the cytokines produced by macrophages, and its function has been postulated to play a role in cancer formation. We investigated whether polymorphisms of CYP17 and TNF-α genes are associated with oral cancer. Material and methods Polymorphisms of CYP17 and TNF-α genes were detected by polymerase chain reaction-based restriction analysis in 137 patients with oral cancer and 102 normal controls. Results The results for the CYP17 gene revealed a significant difference between oral cancer patients and normal controls ( p =0.0063), but there was no significant difference for the TNF-α gene ( p =0.4753). [ABSTRACT FROM AUTHOR]

The role of genetics in Parkinson’s disease (PD), previously controversial, is now documented by several studies. A major breakthrough has been the discovery of two single-gene defects in familial PD. A single base pair change at position 209 from G to A (G209A) in the fourth exon of the α-synuclein gene has been identified in cases of autosomal dominant familial PD. Mutations in the Parkin gene can induce autosomal recessive juvenile parkinsonism. A polymorphism of R/W366 in the Parkin gene was found to be associated with a protective factor for sporadic PD. We surveyed the polymorphisms of the Parkin gene, including S/N167, R/W366 and V/L380, in 92 cases of sporadic PD and 98 nonaffected individuals in Taiwanese Chinese. The allele frequencies of these polymorphisms are not significantly different between PD and nonaffected controls. We conclude that polymorphisms of the Parkin gene, S/N167, R/W366, V/L380, are not genetic factors for sporadic PD among Chinese in Taiwan.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Various studies have shown that brain-derived neurotrophic factor (BDNF) increased neuronal excitability. We tested that BDNF might be involved in the etiology of febrile seizures (FSs). A total of 186 Taiwanese children were divided into two groups: (1) FSs (n = 104); (2) normal control subjects (n = 83). A single base pair polymorphism SNP6265 (Val66Met) at position 196 was analyzed. Our findings suggest that the BDNF polymorphisms were not candidate genetic markers. [Copyright &y& Elsevier]

A letter to the editor focusing on gene polymorphism is presented.

Objective: To investigate whether certain polymorphisms are correlated with leiomyoma susceptibility, i.e., interleukin (IL)-1, IL-2, IL-4, IL-8, IL-12, and IL-18, which are all immunomodulatory cytokines that play important roles in host immune responses against cancers. Setting: Departments of gynecology and genetics in a medical center. Patient(s): Women were divided into: [1] a leiomyoma group (n = 162) and [2] a nonleiomyoma group (n = 156). Intervention(s): Genotyping for the IL-1β-511 promoter, IL-1β exon 5, IL-1Ra, IL-2 114, IL-4 −590 intron 3, IL-8 3′-UTR 2767, IL-12Rβ1 codon 378, and IL-18 105 were evaluated by polymerase chain reaction-restriction fragment length polymorphism. Main Outcome Measurement(s): Genotypes and allelic frequencies in both groups were compared. Result(s): Proportions of IL-12Rβ1 codon 378 *CC/CG/GG in the leiomyoma and nonleiomyoma groups were: [1] 7.4%/43.8%/48.8% and [2] 11.5%/54.5%/34%, respectively. Distributions of other polymorphisms in both groups were not significantly different. Proportions of IL-1β-511 promoter *CC/CT/TT were: [1] 22.8%/50%/27.2% and [2] 21.8%/57.1%/21.1% in the leiomyoma and nonleiomyoma groups, respectively. The IL-1β exon 5 *E1 homozygote/heterozygote/E2 homozygote were: [1] 96.3%/3.7%/0% and [2] 96.9%/3.1%/0% in the leiomyoma and nonleiomyoma groups, respectively. Alleles I/II/III/IV/V for IL-1Ra were: [1] 92.6%/7.1%/0.3%/0/0% and [2] 93.9%/5.7%/0%/0.4/0% in the leiomyoma and nonleiomyoma groups, respectively. The IL-2 114 G homozygote/heterozygote/T homozygote were: [1] 27.8%/49.4%/22.8% and [2] 20.5%/53.2%/26.3% in the leiomyoma and nonleiomyoma groups, respectively. The IL-4 −590 intron 3 *RP1 homozygote/heterozygote/RP2 homozygote were: [1] 64.8%/32.7%/2.5% and [2] 69.2%/26.9%/3.9% in the leiomyoma and nonleiomyoma groups, respectively. The IL-8 3′-UTR 2767 A homozygote/heterozygote/G homozygote were: [1] 14.2%/43.8%/42% and [2] 20.5%/41.7%/37.8% in the leiomyoma and nonleiomyoma groups, respectively. The IL-18 *AA/AC/CC were: [1] 56.8%/40.7%/2.5% and [2] 59%/39.7%/1.3% in the leiomyoma and nonleiomyoma groups, respectively. Conclusion(s): The IL-12Rβ1 codon 378 *G homozygote and G allele are related to a higher susceptibility to leiomyoma. The IL-1β-511 promoter, IL-1β exon 5, and IL-1Ra, IL-2 114, IL-4 −590 intron 3, IL-8 3′-UTR 2767, and IL-18 105 gene polymorphisms are not correlated with the development of leiomyoma. [Copyright &y& Elsevier]

Missense mutations in the γ2 subunit of γ-aminobutyric acid (GABA) receptor gene have recently been described in families with idiopathic generalized epilepsies. This study aimed to evaluate whether polymorphisms of the γ2 subunit of the GABA receptor gene are associated with idiopathic generalized epilepsies. A total of 77 children with idiopathic generalized epilepsies and 83 normal control subjects were included in the study. Polymerase chain reaction was used to identify the C/T and A/G polymorphisms of the γ2 subunit of the GABA receptor gene on chromosome 5q33. Genotypes and allelic frequencies in both groups were compared. The γ2 subunit of the GABA receptor (nucleotide position 3145 in intron G-> A) gene in both groups was not significantly different. In contrast, the γ2 subunit of GABA receptor (SNP211037)-C allele frequency in patients with idiopathic generalized epilepsies was significantly higher than that in healthy control subjects (P = 0.002). The odds ratio for developing idiopathic generalized epilepsies in individuals with the γ2 subunit of the GABA receptor (SNP211037)-C/C genotype was 3.61 compared with individuals with the γ2 subunit of the GABA receptor (SNP211037)-T/T genotype. These data suggest that the γ2 subunit of the GABA receptor gene might be one of the susceptibility factors for idiopathic generalized epilepsies. [Copyright &y& Elsevier]

Abstract: Gaucher disease, the most prevalent lysosomal storage disease characterized by a remarkable degree of clinical variability, results from deleterious mutations in the β-glucosidase gene. Although >200 mutations in the gene for human β-glucosidase have been described, most genotype/phenotype studies have focused on screening for a few common mutations. In the present study, whole gene sequencing analysis was performed. We sequenced eight patients with type 1, five patients with type 2, and six patients with type 3 Gaucher disease in Taiwan. A total of 37 Gaucher chromosome were identified. The detection rate is 97%. For types 1 and 3 Gaucher disease, 1448 T > C (L444P) account for 53.5% Gaucher chromosome and the recombinant allele [1448 T > C, 1483 T > G, 1497 G > C] (RecNciI) has 25% prevalence rate among those patients. For type 2 Gaucher disease, all five patients carry L444P mutation, and RecNciI is found in two of the six patients. Because L444P is also present in the RecNciI mutation, all the patients in this study have a L444P mutation in their Gaucher chromosomes. The third most common mutation of type 1 Gaucher disease is 475 C > T (R120W). L444P homozygote and R120W/RecNciI genotypes are associated with non-neuronopathic Gaucher disease. RecNciI is related to neuronopathic disease, while R120W is represented as a mild mutation in Taiwan. The mutation profile of Gaucher disease in Taiwan is limited. Only four different alleles were identified in types 1 and 3 as well as in type 2 Gaucher disease. [Copyright &y& Elsevier]

The pathophysiology of Tourette syndrome may involve the dopamine system. Dysfunction of the dopamine receptor D2 gene leads to many neuropsychiatric disorders. The objective of this study is to test the hypothesis that the dopamine receptor D2 gene may play a role in Tourette syndrome. A total of 151 children with Tourette syndrome and 183 normal control subjects were included in the study. Polymerase chain reaction was used to identify the Taq I DRD2 and DRD2 (H313H) polymorphisms of the dopamine receptor D2 gene. The genotype proportions of Taq I DRD2 and DRD2 (H313H) polymorphisms in the two groups were significantly different (P < 0.01 for both). The odds ratio for developing Tourette syndrome in individuals with the Taq I DRD2 A1 homozygote was 2.253 (95% confidence interval, 1.124-4.517) compared with individuals with the Taq I DRD2 A2 homozygote. The odds ratio for developing Tourette syndrome in individuals with the DRD2 (H313H) C homozygote was 2.96 (95% confidence interval, 1.398-6.269) compared with individuals with DRD2 (H313H) T homozygote. This study has demonstrated an association between the dopamine receptor D2 gene and Tourette syndrome. These data suggest that the dopamine receptor D2 gene or a closely linked gene might be one of the susceptibility factors for Tourette syndrome. [Copyright &y& Elsevier]

Abstract: Background: Membranous glomerulonephritis (MGN) is one of common causes of idiopathic nephrotic syndrome in adults, and 25% of MGN patients proceed to end-stage renal disease. STAT4 gene polymorphisms have been reported to be associated with many inflammatory diseases. The objective of this study was to clarify the relationship between STAT4 gene polymorphisms and the pathogenesis of MGN. Methods: We investigated the association of three STAT4 gene polymorphisms (rs3024912, rs3024908, and rs3024877) with the susceptibility to MGN in 403 Taiwanese populations (138 MGN patients and 265 controls). Results: The results indicated that the statistically significant difference in genotype frequency distribution was found at rs3024908 SNP in MGN patients and control groups (p =0.014). In addition, the individuals with the GG genotype at rs3024912 SNP may have a higher risk in kidney failure of MGN patients (adjusted odds ratio [OR]=3.255; 95% confidence interval [CI]=1.155–9.176, p =0.026). Conclusions: Our data provide a new information that the STAT4 (rs3024912 and rs3024908) polymorphisms may be the underlying cause of MGN, and these polymorphisms revealed by this study warrant further investigation. [Copyright &y& Elsevier]

Abstract: Background: The national hepatitis B (HB) vaccination program in Taiwan that began in 1984 has resulted in a significant reduction in the carrier rate among children. However, a significant proportion of Taiwanese neonatal HB immunization recipients have exhibited low anti-HBs titers that fall to non-protective or undetectable levels. Methods: We recruited 1677 entering freshman and graduate student participants at a Taiwanese university health center, grouped them into three age groups representing three stages of Taiwan''s HB vaccination program, then conducted hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) serological surveillances for each individual. Univariate and multivariate regression analyses of clinical characteristics and Interleukin-10 (IL-10) genetic variations were also conducted. Results: A trend toward a decreasing HBsAg carrier rate was observed over the starting dates of the vaccination program (11.7%, 1.6% and 1.7% for age groups 1, 2 and 3, respectively), but we also observed an increasing rate of non-protective anti-HBs titers (15%, 26% and 50.3% for cohorts 1–3, respectively). The percentage of students with non-protective anti-HBs titers increased from 23.1% for students born in 1984, to 25.2% for those born in 1985, to 39.4% for birth-year 1986 students, to 45.7% for birth-year 1987 students, and to 56.5% for birth-year 1988 students. The risk for low anti-HBs titers increased concurrently with increases in systolic blood pressure (BP), the IL-10 ATA/ACC haplotype, and the IL-10 ATA present haplotype. Risk for low anti-HBs titers decreased with concurrent decreases in glucose ante cibum (AC, before meals) and the IL-10 ACC/ACC haplotype. Conclusions: These results suggest that the genetic determinants may also contribute to variations in anti-HBs titers in immune responses to HB vaccination. [Copyright &y& Elsevier]

Purpose: Diabetic retinopathy (DR) is a microvascular complication of diabetes with a complex multifactorial pathogenesis. The aim of this study was to identify the susceptibility genes that increase the risk of DR in type 2 diabetes (T2D) and to further elucidate the underlying mechanism of DR pathogenesis. Design: A case-control study. Participants: We included 749 unrelated individuals with T2D (174 with DR and 575 without DR) and 100 nondiabetic controls. Methods: We conducted a genome-wide association study using Illumina HumanHap550-Duo BeadChips. Main Outcome Measures: Compared with the genotypic distribution of single nucleotide polymorphisms (SNPs) between subjects with DR and without DR. Results: Using statistical models, we selected a total of 12 SNPs with P-values <1 × 10–6 that were associated with DR. After controlling for diabetes duration and hemoglobin A1C, 9 of the 12 SNPs located on 5 chromosomal regions were found to be associated with DR. Five loci not previously associated with DR susceptibility were identified in and around the following genes: MYSM1 (Myb-like, SWIRM, and MPN domains 1) located on chromosome 1p (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.03–2.20); PLXDC2 (plexin domain-containing 2) located on the chromosome 10p (OR, 1.67; 95% CI, 1.06–2.65); ARHGAP22 (Rho GTPase-activating protein 22) located on chromosome 10q (OR, 1.65; 95% CI, 1.05–2.60); and HS6ST3 (heparan sulfate 6-O-sulfotransferase 3) located on chromosome 13q (OR, 2.33; 95% CI, 1.13–4.77). The SNPs rs13163610 and rs17376456 located in the unknown gene on chromosome 5q were also associated with DR (OR, 3.63; 95% CI, 1.38–9.58). Conclusions: We identified a genetic association for susceptibility to DR in 5 novel chromosomal regions and PLXDC2 and ARHGAP22, the latter 2 of which are genes implicated in endothelial cell angiogenesis and increased capillary permeability. These findings suggest unsuspected pathways in the pathogenesis of DR. Financial Disclosures: The authors have no proprietary or commercial interest in any of the materials discussed in this article. [Copyright &y& Elsevier]

Tourette syndrome has a multifactorial etiology in which genetic, environmental, and immunologic factors interact to establish vulnerability. Various interleukin 1 genes are associated with several immunoinflammatory diseases. It is not known whether polymorphisms in those genes are involved in the pathogenesis of Tourette syndrome. In this association study, single nucleotide polymorphisms were used to investigate the distribution of genotypes of the interleukin 1 receptor antagonist gene (IL1RN; alias IL1RA) and of the interleukin 1β gene (IL1B) in patients with Tourette syndrome. A total of 159 children with Tourette syndrome and 175 healthy control subjects were included in the study. There was no significant difference between patients and control subjects in the distribution of genotype and allele frequencies for IL1B exon 5 and promoter region; however, the number of individuals homozygotic for IL1RN ∗1 was significantly greater (P < 0.0001), and the IL1RN ∗1 allele frequency was significantly higher (P < 0.0001), among patients than among control subjects. The odds ratio for developing Tourette syndrome in individuals with the IL1RN ∗1 allele, compared with IL1RN ∗2, was 7.65. Thus, the IL1RN gene may be a useful marker for prediction of the susceptibility to Tourette syndrome. [Copyright &y& Elsevier]

Abstract: Background: Membranous glomerulonephritis (MGN) is one of the most common causes of nephrotic syndrome in adults. NPHS1 encoding nephrin is a transmembrane protein of the immunoglobulin family. We clarified the relationship between NPHS1 gene polymorphisms and the susceptibility or progression of MGN. Methods: We recruited a cohort of 132 biopsy-diagnosed MGN patients and 257 healthy subjects. Genotyping of three SNPs (rs401824, rs437168 and rs3814995) at chromosome positions 41034749 (5′UTR), 41026259(exon17) and 41034052 (exon 3) was performed using a Taqman SNP genotyping assay. Results: There was a significant difference in genotype frequency distribution of rs437168 polymorphism between MGN patients and controls. The results also showed that the frequency of the G allele was significantly higher in the patient group. Among the polymorphisms rs437168, rs401824 and rs3814995, no significant haplotype was shown in MGN patients. A stratified analysis revealed that a high disease progression in the AA genotype of rs401824 and GG genotype of rs437168 patients were associated with a low rate of remission. Conclusions: The presence of the different genotypes of NPHS1 was associated with susceptibility of MGN and the remission of proteinuria during disease progression after the therapy. [Copyright &y& Elsevier]

Objective: To investigate whether the gene polymorphisms for p21, X-ray repair cross-complementing group 1 (XRCC1), human 8-oxoguanine glycosylase 1 (hOGG1), and dopamine D1 and D2 receptors (DRD1, -2) are associated with leiomyoma susceptibility. Design: Prospective study. Setting: Departments of gynecology and genetics in a medical center. Patient(s): Women were divided into two groups: leiomyoma (n = 120) and nonleiomyoma (n = 112). Intervention(s): The p21 codon 31, XRCC1 codon 399, hOGG1 codon 326, DRD1-48, and DRD2 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions (Blp I, MspI, Fnu4HI, Dde I, and NcoI, respectively). Main Outcome Measure(s): Genotypes and allelic frequencies. Result(s): The p21 codon 31∗C- and DRD2 codon 313∗T-related genotypes/alleles were associated with the presence of leiomyomas. The proportions of p21∗CC/CA/AA and DRD2∗CC/CT/TT in both groups were 27.5/68.3/4.2% and 12.5/51.7/35.8% (leiomyoma); and 14.3/51.8/33.9% and 33.9/40.2/25.9% (nonleiomyoma). XRCC1, hOGG1, and DRD1 were not correlated with the presence of leiomyomas. XRCC1∗GG/GA/AA, hOGG1∗TT/TA/AA, and DRD1∗GG/GA/AA were 54.2/37.5/8.3%, 36.7/44.2/19.1%, and 3.3/25.8/70.8% (leiomyoma); and 48.2/47.3/4.5%, 43.6/41/15.4%, and 3.6/25/71.4% (nonleiomyoma). Conclusion(s): The p21 codon 31∗C- and DRD2 codon 313∗T-related genotypes/alleles were associated with the presence of leiomyoma. XRCC1, hOGG1, and DRD1 were not correlated with leiomyoma development. [Copyright &y& Elsevier]

Abstract: Interleukin-2 (IL-2), one of the crucial immunoregulatory cytokines required for T lymphocyte activation, plays an important role in autoimmune diseases. An IL-2 genetic G/T polymorphism (rs2069763) has been linked with multiple sclerosis and rheumatoid arthritis. We tested a hypothesis that this polymorphism confers systemic lupus erythematosus (SLE) susceptibility. Study participants were Han Chinese SLE patients and a healthy control group in Taiwan. Our results indicate (a) a significantly higher G allele frequency in SLE patients (P =1.91×10−14; OR=3.94; 95% CI=2.74–5.66), (b) a significantly higher G allele frequency in SLE patients with antinuclear antibodies (ANA) (P =0.033; OR=4.21; 95% CI=1.01–17.51) and (c) a significantly lower G allele frequency in SLE patients with discoid rash (P =0.019; OR=0.41; 95% CI=0.19–0.88). Our results suggest that this polymorphism may be involved in the genetic background of Taiwanese SLE. [Copyright &y& Elsevier]

Purpose: To investigate vascular endothelial growth factor (VEGF) gene polymorphisms in unrelated Taiwan Chinese patients with late age-related macular degeneration (AMD) and controls.Design: Retrospective case-control study.Methods: We enrolled 190 late AMD patients and 180 age-matched and gender-matched controls. Late AMD was classified as either dry (atrophic; grade 4) or wet (neovascular; grade 5) according to the International Age-Related Maculopathy Epidemiologic Study. Genomic deoxyribonucleic acid was prepared from peripheral blood obtained from all subjects. Polymerase chain reactions were used to analyze five candidate single-nucleotide polymorphisms (SNPs) in VEGF gene: +405C/G (rs2010963), -460 T/C (rs833061), +674 C/T (rs1413711), +936C/T (rs3025039), and -2578C/A (rs699947).Results: Of the 190 late AMD patients, dry AMD was diagnosed in 104 and wet AMD in 86. Among the five candidate SNPs studied, only the +936 C/T was significantly associated with wet AMD (T allele: 30% in wet AMD vs 14% in controls; P = 1.45 x 10(-5); odds ratio, 2.61; 95% confidence interval, 1.68 to 4.07). No single haplotype was significantly associated with either late AMD or controls. Based on genotypes at both VEGF +936 C/T and the complement factor H (CFH) Y402H (rs1061170), the association of VEGF +936 C/T to AMD was significant when analyzed conditional on the presence of the CFH C risk allele and vice versa (P < .0001). The VEGF +936 C/T was in strong linkage disequilibrium with CFH Y402H (D' = 0.99).Conclusions: Both VEGF +936 C/T and CFH Y402H polymorphisms are dependently associated with wet AMD in the Taiwan Chinese population. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Estrogen and estrogen receptors are known to play important roles in the pathophysiology of pelvic organ prolapse (POP). We investigated whether estrogen receptor β (ERβ) gene polymorphisms were associated with POP by conducting a case-control association study in 69 women with POP and 141 women without POP. Study design: Genotypes of the ERβ gene polymorphisms (rs2987983, rs1271572, rs944459, rs1256049, and rs1255998) were determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. Haplotyping analysis was used to determine the relationship among five polymorphisms in the ERβ gene and POP. Results: There was no significant difference between women with and those without POP in the distribution of any of the genotypes evaluated. In haplotype frequency estimation analysis, haplotype CGCGC was more prevalent in women with POP (16.7%) than in women without POP (8.9%) (p =0.011). Using multivariable logistic regression, age, parity and haplotype CGCGC were significantly associated with POP. Conclusion: Although the sample size of women with POP studied is small, the present study shows that ERβ gene haplotype may be associated with POP. [Copyright &y& Elsevier]

Purpose: To investigate the Met72Thr (T/C) polymorphism (rs1136287) of pigment epithelium-derived factor (PEDF) gene exon 3 in unrelated Taiwan Chinese patients with late age-related macular degeneration (AMD) and control subjects without AMD. Design: Retrospective case-control study. Methods: We enrolled 190 unrelated Taiwan Chinese patients with late AMD and 90 age- and gender-matched control subjects. Grading of late AMD was classified based on a standardized set of diagnostic criteria established by the International Age-Related Maculopathy Epidemiologic Study. Late AMD was classified as either atrophic (dry, grade 4) or neovascular (wet, grade 5). Atrophic AMD refers to dry late-stage AMD without neovascularization, and wet AMD refers to neovascular AMD. Genomic deoxyribonucleic acid was prepared from peripheral blood obtained from all AMD patients and control subjects. Polymerase chain reaction analysis was used to analyze this polymorphism. Results: Of the 190 participants with late AMD, atrophic AMD was diagnosed in 104 patients and wet AMD was diagnosed in 86 patients. The genotype distribution of the Met72Thr (T/C) variant of PEDF was TT (homozygous T), TC (heterozygous), and CC (homozygous C). The T allele was found significantly more frequently in wet AMD patients than in controls (50% vs 31%; P =.0005). The allele frequencies in atrophic AMD (30%) and controls (31%) did not differ significantly (all P = .87). The homozygous T genotype was more prevalent in wet AMD than in controls (26/86 [30%] vs nine/90 [10%]; odds ratio, 3.9; all P = .0015). The homozygous T genotype in atrophic AMD patients (8%) and controls (10%) did not differ significantly (all P = .75). Conclusions: Our data suggest that the PEDF Met72Thr T allele may be a risk factor for wet AMD in the Taiwan Chinese population. PEDF may play a role in the pathogenesis of wet AMD. [Copyright &y& Elsevier]

Objective: Osteoporosis is a common disorder with a strong genetic component. We investigated the correlations between bone mineral density (BMD) and four gene polymorphisms (-308G>A tumor necrosis factor alpha (TNF-alpha), -34T>C CYP 17, *141T>C urokinase, and -627C>A interleukin 10 (IL-10) promoter), and their relationship to osteoporosis in postmenopausal women.Study Design: These polymorphisms were determined using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. BMD of the lumbar spine and proximal femur were measured using dual-energy X-ray absorptiometry.Results: The prevalence of each genotype was as follows: (1) 79.3% A/A, 16.6% A/G, and 4.1% G/G in -308G>A TNF-alpha; (2) 18.9% T/T, 52.1% T/C, and 29% C/C in -34T>C CYP 17; (3) 86.4% C/C and 13.6% C/T in *141T>C urokinase; (4) 46.2% A/A, 45% A/C, and 8.8% C/C in -627C>A IL-10 promoter. Subjects with genotype C/C in -627C>A IL-10 promoter had lower BMD values and a significantly greater risk for osteoporosis (OR 8.1, 95% CI 1.5-42.8) at the lumbar spine compared with subjects with genotype A/C in -627C>A IL-10 promoter, after adjustment for potential confounders.Conclusion: The RsaI IL-10 promoter gene polymorphism is associated with reduced BMD and predisposes women to osteoporosis at the lumbar spine. [ABSTRACT FROM AUTHOR]

Summary: Oral cancer is one of the most common malignant diseases in Taiwan. The incidence of male oral cancer is 9.01 times than that of female. The formation or progression of oral cancer may be associated with a polymorphism of the vascular endothelial growth factor (VEGF) gene. The most frequently seen polymorphism is BstUI (C to T) located at the −460th nucleotide upstream of the VEGF gene. We investigated whether this polymorphism could be a genetic marker of oral cancer. A normal control group of 230 healthy people and 137 patients with oral cancer were examined. The polymorphism was detected by polymerase chain reaction-based restriction analysis. The analysis revealed significant differences between normal individuals and patients with cancer (P &#60;0.001). The distribution of the “TT” homozygote in the patient group was greater than that in the control group. The odds ratio per copy of the “T/C” ratio was 9.62 (95% confidence interval 5.81–15.87), which means that for a group of people with a higher T/C ratio have higher risk in getting oral cancer. There is no gender difference in this VEGF gene polymorphism. Therefore, the BstUI polymorphism of the VEGF gene is a suitable genetic marker of oral cancer. [Copyright &y& Elsevier]

Objective: To investigate the association of endometriosis with estrogen receptor alpha (ERα) and cytochrome P450c17α (CYP17) gene polymorphisms in light of the fact that estrogen plays a role in the pathogenesis of endometriosis and the CYP17 enzyme is involved with estrogen biosynthesis. Design: Prospective study. Setting: Genetics and gynecology units. Patient(s): All patients were divided into two groups: group 1, women with endometriosis (n = 119); group 2, normal controls (n = 108). Intervention(s): A dinucleotide (thymine-adenine [TA]) repeat polymorphism lying upstream of the ERα gene and A1/A2 polymorphism of the CYP17 gene were amplified by polymerase chain reaction, enzyme restriction, and electrophoresis. Main outcome measure(s): The ER genotypes were classified into A through T (TA repeats, 10–29). The CYP17 genotypes included indigestible (A1 homozygote), heterozygote, and digestible (A2 homozygote). We compared these polymorphism distributions in both groups. Result(s): The percentage of genotypes D–G (TA, 13–16) in both groups were 10.5%, 29.4%, 13.0%, and 11.3% in group 1 and 7.9%, 16.7%, 19.9%, and 17.6% in group 2. The genotype E (14 TA repeats) is associated with a higher risk of endometriosis. Proportions of A1 homozygote/heterozygote/A2 homozygote for CYP17 were 26.1%/46.2%/27.7% for group 1 and 14.8%/44.5%/40.7% for group 2, respectively. The A1 homozygote and allele were associated with a higher susceptibility of endometriosis. Conclusion(s): ERα* 14 TA repeats and the CYP17* A1 allele are associated with an increased risk of endometriosis. Both polymorphisms are useful markers for predicting endometriosis susceptibility. [Copyright &y& Elsevier]

Purpose: Glaucomatous neuropathy is a type of cell death by apoptosis. Apoptosis is a genetically controlled form of cell death, and one of its primary regulatory steps is the activation of the tumour suppressor protein p53, of which p21 is an effector protein. The association between p21 codon 31 polymorphism and primary open-angle glaucoma (POAG) patients was evaluated in this study. Methods: The study included 58 POAG patients and a control group of 59 healthy volunteers. Polymerase chain reaction-based analysis was used to resolve the p21 codon 31 polymorphism. Results: The genotype frequencies of p21 codon 31 polymorphism were statistically different (p <0.05) between the two groups. The Arg allele of the p21 codon 31 polymorphism was more frequently found in POAG patients than in healthy individuals (odds ratio: 2.389, 95% confidence interval: 1.14-5.01). Conclusion: This study suggests that an association exists between the Arg allele of the p21 codon 31 polymorphism and POAG in the Chinese population. [ABSTRACT FROM AUTHOR]

Objective: To investigate the correlation of the androgen receptor gene microsatellite polymorphism (CAG trinucleotide repeat polymorphism on exon 1) with bone mineral density and their relationship to osteoporosis in postmenopausal women. Study design: A number of 168 of 477 postmenopausal women were randomly recruited. The androgen receptor gene microsatellite polymorphism was determined using polymerase chain reaction-based microsatellite analysis. Bone mineral density of the lumbar spine and proximal femur was measured using dual-energy X-ray absorptiometry. Results: The AR genotype was classified from “9” to “32” according to the number of CAG trinucleotide repeats they contained to represent “signposts”. After adjustment for potential confounding factors such as age, height, weight, years since menopause, and daily calcium intake, subjects with genotype 20+ (n=64) had lower bone mineral density values and a significantly greater risk for osteoporosis (OR 4.2, 95% CI 1.0–17.2) when compared with subjects with genotype 20− (n=104) at the femoral neck. Conclusion: The present study suggests that the androgen receptor gene microsatellite polymorphism may be a candidate genetic marker for risk of osteoporosis in postmenopausal women. [Copyright &y& Elsevier]

: ObjectiveTo evaluate the association between leiomyomas and estrogen receptor gene polymorphism.: DesignProspective study.: SettingDepartment of gynecology and genetics.: Patient(s)Women with (n = 159) or without leiomyomas (n = 131).: Main outcome measure(s)Polymerase chain reaction was used to detect dinucleotide (thymine–adenine [TA]) repeat polymorphisms upstream of the estrogen receptor gene. Genotypes were classified as A through P according to the number of the TA repeats from 12 to 27. Distributions of TA repeat for estrogen receptor in both groups were compared.: Result(s)Genotypes A to E were detected in 10.7%, 18.9%, 15.7%, 16.4%, and 4.4%, respectively, of women with leiomyomas and 4.2%, 9.5%, 20.6%, 19.1%, and 10.3% of women without leiomyomas. Women with genotypes A and B (12 or 13 TA repeats) have a higher risk for leiomyomas, and those with genotype E (16 TA repeats) have a lower risk.: Conclusion(s)Estrogen receptor gene polymorphism probably contributes to the pathogenesis of leiomyoma and may predict the susceptibility to leiomyoma. The 12 and 13 TA repeats are associated with a higher risk of leiomyoma. [Copyright &y& Elsevier]

Interleukin-4 (IL-4) is a cytokine with anti-inflammatory properties. This study was undertaken to investigate whether IL-4 intron 3 gene polymorphism could be used as markers of susceptibility to febrile seizures and epilepsy of children. Children were divided into three groups: group 1, febrile seizures (n = 51); group 2, epilepsy (n = 43); and group 3, normal control group (n = 83). Polymorphisms for IL-4 intron 3 were detected by polymerase chain reaction. Genotypes and allelic frequencies for IL-4 intron 3 gene polymorphism in three groups were compared. We found that proportions of different IL-4 intron 3 polymorphisms in three groups were nonsignificantly different. Proportions of RP1 homozygote/heterozygote/RP2 homozygote for IL-4 intron 3 in three groups were as follows: group 1, 56.9/41.2/1.9%; group 2, 62.8/32.6/4.6%; and group 3, 62.7/33.7/3.6%. The proportion of RP1/RP2 for IL-4 intron 3 in three groups were as follows: group 1, 77.5/22.5%, group 2, 79.1/20.9%, and group 3, 79.5/20.5%. We concluded that the association of IL-4 polymorphisms with febrile seizures and epilepsy of children does not exist. IL-4 intron 3 polymorphism is not a useful marker for prediction of the susceptibility of febrile seizure and epilepsy of children. [Copyright &y& Elsevier]

Abstract: Objective: Matrix metalloproteinase-9 is known to play an important role in the pathophysiology of pelvic organ prolapse. We investigated whether the matrix metalloproteinase-9 gene polymorphisms were associated with pelvic organ prolapse by conducting a case–control association study in 92 women with pelvic organ prolapse and 152 women without pelvic organ prolapse. Study design: Genotypes of the matrix metalloproteinase-9 gene polymorphisms (rs3918242, rs17576, and rs2250889) were determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. Results: There was significant difference between women with and without pelvic organ prolapse in the distribution of the matrix metalloproteinase-9 rs17576 genotypes evaluated. Using multivariable logistic regression, menopausal status, matrix metalloproteinase-9 rs17576 genotype AG, and matrix metalloproteinase-9 rs17576 genotype GG were significantly associated with pelvic organ prolapse. Conclusion: The present study shows that the polymorphism of matrix metalloproteinase-9 rs17576 may be associated with pelvic organ prolapse. [Copyright &y& Elsevier]

Interleukin (IL)-2 R-627*C homozygote and C allele are related to higher susceptibility to endometriosis. Interleukin-12R?1 codon 378 and IL-18 105 gene polymorphisms are not correlated with endometriosis development. [Copyright &y& Elsevier]