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ABSTRACT: The SNP R30Q (rs1248696) within the discs large homolog 5 (DLG5) gene has been associated with inflammatory bowel disease (IBD). In this study, we examined the genetic association of another DLG5 SNP P1371Q (rs2289310) with IBD and its interaction with R30Q in disease susceptibility.
A total of 213 IBD patients [106 familial; 59 Crohn's disease (CD) and 47 ulcerative colitis (UC)] and 107 sporadic [57 CD and 50 UC] were included in this study. Controls included 139 non-diseased family members of IBD patients and 170 unrelated healthy subjects. Genotypes for P1371Q and G1066G polymorphisms were determined by PCR-based RFLP. Epistasis between P1371Q and R30Q in disease susceptibility was analysed using a novel statistical model.
P1371Q was associated with IBD (OR = 2.335, 95% CI = 1.097-4.972, p = 0.0246), however, the synonymous variant G1066G (rs1648234) was not. Gender distribution analysis revealed the A allele of P1371Q was significantly associated with IBD in women (OR = 3.765, 95% CI = 1.307-10.85, p = 0.0095). Modeling interaction between P1371Q and R30Q showed a significant increase in disease association (OR = 2.265, 95% CI = 1.405-3.652, p = 0.0007) incidence for sporadic and familial IBD patients. Further epistatic analysis identified an increased significance in the association of gender with IBD (OR = 4.311, 95% CI = 2.101-8.846, p = 0.0001).
DLG5 P1371Q was associated with IBD and this association was female-specific. A significant epistatic interaction between P1371Q and R30Q was observed, suggesting that P1371Q is complementary to R30Q, with R30Q exhibiting a dominant effect in IBD susceptibility.
Schweizerische medizinische Wochenschrift 01/2011; 141:w13290. · 1.68 Impact Factor
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Z Lin,
L Poritz,
A Franke,
T Y Li,
A Ruether,
K A Byrnes,
Y Wang,
A W Gebhard,
C MacNeill,
N J Thomas,
R Wu,
S Schreiber,
W A Koltun
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ABSTRACT: The association of DLG5 R30Q with IBD has been replicated in several populations, but is not statistically significant in others. We studied the incidence of DLG5 alleles in a population of IBD patients from Pennsylvania.
DLG5 R30Q (rs1248696) and G1066G (rs1248634) were analyzed with PCR-based RFLP methods in a total of 521 subjects, that included 105 individuals with IBD and 139 without IBD from a familial IBD registry, 107 with sporadic IBD, and 170 unrelated healthy controls. R30Q was further analyzed with SNPlex Genotyping System in 473 samples.
RFLP genotyping data showed that, DLG5 R30Q was significantly associated with IBD overall (p=0.006), and separately with CD (p=0.009) and UC (p=0.024). The association of R30Q with IBD was entirely due to a male-associated effect (male vs female p=0.015 vs 0.241 (IBD), p=0.024 vs 0.190 (CD), and p=0.019 vs 0.575 (UC)). The frequency of the A allele carriage was elevated in both affected and unaffected members in the familial IBD cohort compared to healthy controls (p=0.037). In the family pedigrees, we observed differences in the expression of IBD in individuals carrying the A allele between families.
In the studied population, DLG5 R30Q was associated with all forms of IBD. An elevated presence of the R30Q variant was observed in all members of a familial IBD registry. This association of the R30Q variant with IBD was male-specific.
Disease markers 01/2009; 27(5):193-201. · 1.64 Impact Factor
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ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation. It is most likely the result of complex interactions of environmental and genetic factors. Because pulmonary surfactant components play important roles in normal lung function, innate host defence, and inflammation in the lung, this study investigated the hypothesis that the surfactant protein genes are involved in certain cases of COPD. Genotype analysis of surfactant protein (SP)-A, SP-B, SP-B-linked microsatellite, and SP-D marker alleles was performed in patients with COPD (n=97) and smoker (n=82) or nonsmoker (n=99) controls. Univariate and multiple logistic regression analyses were performed. The regression analysis results between COPD and smokers revealed several COPD susceptibility alleles (AA62_A, B1580_C, D2S388_5), based on an odds ratio (OR >2.5). The predictive ability of this model for developing COPD is good (c=0.926). Allele-allele (B1580_C and D2S388_5) and allele-environment (i.e. smoking) interactions were detected. When smoker controls were compared to nonsmoker controls, marker D2S388 5 appeared to be smoking-independent (p=0.874), whereas marker alleles AA62_A (p=0.045) and B1580_5 (p=0.007) were smoking-dependent. Males were at higher risk (OR=6.05, p=0.001), and smoking (>50 packs x yr(-1)) increased risk (OR=5.38, p=0.007). Males and alleles of loci flanking SP-B were associated with more severe cases (forced expiratory volume in one second/forced vital capacity < or = 40%). The present results indicate that the surfactant protein alleles may be useful in chronic obstructive pulmonary disease by either predicting the disease in a subgroup and/or by identifying disease subgroups that may be used for therapeutic intervention. These observations should now be confirmed in a larger study, designed according to strict epidemiological criteria.
European Respiratory Journal 09/2001; 18(3):482-90. · 5.89 Impact Factor
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BioTechniques 10/2000; 29(3):460-2, 464, 466. · 2.67 Impact Factor
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ABSTRACT: An allele association study of 19 polymorphisms in surfactant proteins SP-A1, SP-A2, SP-B, and SP-D genes in acute respiratory distress syndrome (ARDS) was carried out. Trend-test analysis revealed differences (p < 0.05) in the frequency of alleles for some of the microsatellite markers flanking SP-B, and for one polymorphism (C/T) at nucleotide 1580 [C/T (1580)], within codon 131 (Thr131Ile) of the SP-B gene. The latter determines the presence or absence of a potential N-linked glycosylation site. Multivariate analysis revealed significant differences only for the C/T (1580) polymorphism. When the ARDS population was divided into subgroups, idiopathic (i.e., pneumonia, etc.) or exogenic (i.e., trauma, etc.), significant differences were observed for the C/T (1580), for the idiopathic ARDS group, and the frequency of the C/C genotype was increased in this group. Based on the odds ratio, the C allele may be viewed as a susceptibility factor for ARDS. Although the expression of both C and T alleles occurs in heterozygous individuals, it is currently not known whether these alleles correspond to similar levels of SP-B protein. These data suggest that SP-B or a linked gene contributes to susceptibility to ARDS.
Clinical Genetics 09/2000; 58(3):181-91. · 3.13 Impact Factor
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Chest 06/2000; 117(5 Suppl 1):249S-50S. · 5.25 Impact Factor
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ABSTRACT: Mutations in the surfactant protein (SP)-B gene are responsible for SP-B deficiency in congenital alveolar proteinosis (CAP) (Nogee et al. J Clin Invest 1994: 93: 1860-1883; Lin et al. Mol Genet Metab 1998: 64: 25-35; Klein et al. Pediatrics 1998: 132: 244-248; Ballard et al. Pediatrics 1995: 96: 1046-1052). The multigenerational consanguineous pedigree under study does not carry any of the known mutations, although this pedigree had 14 infant deaths following respiratory distress at birth. Immunostaining of the lungs from three such infants revealed decreased or absent SP-B. By sequencing of SP-B exons, exon-intron junctions, and the 5' and 3' flanking regions, nine polymorphisms were found in this pedigree, but none of them could explain the observed SP-B deficiency. Further analysis of SP-B mRNA by reverse transcription-polymerase chain reaction from paraffin-embedded lung tissue of CAP patients showed that SP-B mRNA is not intact. Although the sequence of mRNA from exon 1-exon 7 and from exon 8-exon 10 could be amplified, the region between exons 7 and 8 could not. From fluorescence in situ hybridization of the short arm of chromosome 2p, only 2 signals were identified, eliminating the possibility of translocation as the cause of the SP-B mRNA aberrance. Although the nature of the genetic basis of SP-B deficiency in this family is currently unknown, the existence of aberrant SP-B mRNA may, at least in part, be responsible for the SP-B deficiency in this pedigree.
Clinical Genetics 06/2000; 57(5):359-69. · 3.13 Impact Factor
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ABSTRACT: We have previously identified an allele of the human SP-A2 gene that occurs with greater frequency in an RDS population [12]. Because of the importance of SP-A in normal lung function and its newly emerging role in innate host defense and regulation of inflammatory processes, we wish to better characterize genotypes of both SP-A1 and SP-A2 genes. It has been determined that SP-D shares similar roles in immune response. Therefore, in this report we 1) describe a novel, non radioactive PCR based-cRFLP method for genotyping both SP-A and SP-D; 2) describe two previously unpublished biallelic polymorphisms within the SP-D gene; 3) present the partial sequence of one new SP-A1 allele (6A14) and describe other new SP-A1 and SP-A2 alleles; and 4) describe additional methodologies for SP-A genotype assessment. The ability to more accurately and efficiently genotype samples from individuals with various pulmonary diseases will facilitate population and family based association studies. Genetic polymorphisms may be identified that partially explain individual disease susceptibility and/or treatment effectiveness.
Disease markers 01/2000; 15(4):269-81. · 1.64 Impact Factor
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ABSTRACT: We identified an alternatively-spliced surfactant protein B (SP-B) mRNA from normal human lung with a 12 nt deletion at the beginning of exon 8. This deletion causes a loss of four amino acids in the SP-B precursor protein. Sequence comparison of the 3' splice sites reveals only one difference in the frequency of U/C in the 11 predominantly-pyrimidine nucleotide tract, 73% for the normal and 45% for the alternatively-spliced SP-B mRNA (77-99% for the consensus sequence). Analysis of SP-B mRNA in lung indicates that the abundance of the alternatively-spliced form is very low and varies among individuals. Although the relative abundance of the deletion form of SP-B mRNA remains constant among normal lungs, it is found with relatively higher abundance in the lungs of some individuals with diseases such as congenital alveolar proteinosis, respiratory distress syndrome, bronchopulmonary dysplasia, alveolar capillary dysplasia and hypophosphatasia. This observation points to the possibility that the alternative splicing is a potential regulatory mechanism of SP-B and may play a role in the pathogenesis of disease under certain circumstances.
Biochemical Journal 11/1999; 343 Pt 1:145-9. · 4.90 Impact Factor
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BioTechniques 07/1998; 24(6):937-40. · 2.67 Impact Factor
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ABSTRACT: We have previously identified a SP-B length polymorphism that appears with higher frequency in the RDS population (Biochem. J., 305, 1995, p583). This polymorphism encompasses a fairly large region, thus it is difficult to distinguish between variants with small size differences. Because of the importance of SP-B in normal lung function and the association of this SP-B polymorphism with RDS, we wished to identify and characterize polymorphic markers linked to the SP-B locus that would allow better resolution of SP-B alleles. In this report we a) characterized a novel (AAGG)n linked SP-B microsatellite marker; b) determined linkage of published markers with the SP-B locus and also determined the distance of each marker from the SP-B locus using medium and high resolution radiation hybrid panels; c) determined heterozygosity index and PIC values of the novel and known markers in various populations; and d) determined haplotypes using CEPH families. The availability of these SP-B linked markers/haplotypes will facilitate population and family based association studies. We are hopeful that the information gained will help to unravel the genetic complexity of RDS and respiratory diseases with regards to the SP-B locus.
Disease markers 12/1997; 13(3):153-67. · 1.64 Impact Factor
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ABSTRACT: The human SP-A locus consists of two functional genes and one pseudogene, and SP-A is shown to play a role in local host defense and the regulation of inflammation in lung. Because the intestine, like the lung, is constantly exposed to foreign and potentially harmful substances, we investigated the hypothesis that both human SP-A genes are expressed in intestine. We demonstrate that both SP-A genes are expressed in human small and large intestine. The presence of SP-A mRNA in human intestine was detected by reverse transcription polymerase chain reaction (RT-PCR), Northern blot analysis, and immunohistochemistry. The size of intestinal SP-A mRNA is the same as that in human lung, but the level of expression, compared with that in the lung, is very low in both the small and large intestine. Immunohistochemical analysis revealed positive reactivity for SP-A in a subgroup of epithelial cells in the intestine. Expression of both SP-A1 and SP-A2 genes was established by gene-specific PCR amplification, PCR-based converted RFLP discrimination, and direct sequencing of RT-PCR products. We speculate that SP-A in the intestine plays a role in local host defense and inflammation.
Pediatric Pathology and Molecular Medicine 20(5):367-86.
