Genetic Polymorphisms In Susceptibility Research Articles

Role of the ACE ID and PPARG P12A Polymorphisms in Genetic Susceptibility of Diabetic Nephropathy in a South Indian Population

BackgroundDiabetic nephropathy (DN) is one of the life-threatening disorders characterized by persistent albuminuria, raised arterial blood pressure, a lowered glomerular filtration rate, and high risk of cardiovascular morbidity and mortality. The vascular genes ACE (Angiotensin-converting enzyme), and PPARG (peroxisome proliferator activated receptor gamma) are involved in alterations in vascular endothelium, and are suggested to play a role in the susceptibility of diabetic nephropathy.ObjectivesThe aim of our study was to find out the role of ACE ID and PPARG P12A polymorphisms in genetic susceptibility of diabetic nephropathy in south Indian population.Patients and MethodsA total of 54 cases with diabetic nephropathy and 67 control subjects with diabetes were enrolled for our study. DNA was isolated from peripheral blood leucocytes, and genotyped using PCR-electrophoresis (ACE ID) or PCR-RFLP (PPARG P12A) methods.ResultsACE ID genotypes followed Hardy-Weinberg equilibrium in both cases and controls. But P12A genotypes deviated from Hardy-Weinberg equilibrium in diabetic controls. Chi2 test was applied for the analysis of genotypic distributions in genotypic and dominant models. Odds ratios were also calculated. No significant differences in genotype frequencies of ACE ID and PPARG P12A polymorphisms were found on comparing patients with diabetic nephropathy with diabetic controls. The synergistic role of ACE ID* PPARG P12A interaction, did not show any association in patients with diabetic nephropathy when compared to diabetic controls.ConclusionsIn conclusion, the ACE and PPARG genes do not have a key role in conferring risk for diabetic nephropathy.

The IL6 gene polymorphism − 634C>G and IL17F gene polymorphism 7488T>C influence bone mineral density in young and elderly Japanese women

Osteoporosis is an important public health problem because of the significant morbidity and mortality associated with its complications, particularly fractures. An important clinical risk factor in the pathogenesis of osteoporosis is the presence of genetic polymorphisms in susceptibility genes.However, few studies have investigated the relevance of these polymorphisms in premenopausal women. Recent studies have demonstrated interactions between bone and immune cells, and that cytokines produced by immune cells regulate bone turnover. In this study, we examined the associations between bone mineral density (BMD) and polymorphisms in genes encoding interleukin (IL)-6 (−634C>G; rs1800796), tumor necrosis factor (TNF)-α (−308G>A; rs1800629), IL-17F (7488T>C; rs763780), transforming growth factor (TGF)-β (869T>C; rs1800470), osteoprotegerin (OPG; 163A>G; rs3102735) and methylenetetrahydrofolate reductase (MTHFR; 677C>T; rs1801133) in young and elderly Japanese women. Whole-body, lumbar spine (L1 or L2–L4), and femoral neck BMD were measured in 100 young subjects (18–23years), and 100 elderly subjects (60–83years). Whole-body, lumbar spine, and femoral neck BMD were 1.13±0.06, 1.14±0.12, and 1.00±0.11g/cm2, respectively, in young subjects, and 0.92±0.09, 0.86±0.15, and 0.63±0.10g/cm2, respectively, in elderly subjects. The frequencies of the IL-6 CC, CG, and GG genotypes were 48%, 49%, and 3%, respectively. The frequencies of the IL17F TT, TC, and CC genotypes were 79%, 15%, and 6%, respectively, in young subjects. Polymorphisms of the IL-6 and IL17F genes were significantly associated with BMD. To our knowledge, this is the first report to examine these associations in a cohort of 200 Japanese women.

P055 Relationship of impaired macrophage cytokine release to genetic susceptibility polymorphisms in Crohn's disease

P055 Relationship of impaired macrophage cytokine release to genetic susceptibility polymorphisms in Crohn's disease

Gene-Environment Interactions in 7610 Women With Breast Cancer: Prospective Evidence From the Million Women Study

Both genetic and environmental factors contribute to the risk of breast cancer but it is unclear whether specific gene-environment interactions increase risk. Genome-wide association studies identified a number of breast cancer low-penetrance genetic susceptibility polymorphisms. There are scant data on the combined effects of these polymorphisms and environmental factors on the incidence of breast cancer. Some studies suggested possible interactions between some genetic susceptibility polymorphisms and use of hormone replacement therapy (HRT) or breast cancer, but the data were inconsistent. The aim of this prospective cohort study was to determine whether environmental risk factors modified the relative risks of breast cancer associated with several single nucleotide polymorphisms (SNPs) previously associated with the disease. Routine screening for breast cancer was performed at 66 screening centers in the United Kingdom during 1996-2001 in 1.3 million women (mean age, 56 years). The study participants were 7610 women who developed breast cancer and 10,196 randomly selected women without breast cancer. The investigators tested the association between 10 established environmental risk factors for breast cancer (age at menarche, parity, age at first birth, breast-feeding, menopausal status, age at menopause, use of HRT, body-mass index, height, and alcohol consumption) and 12 SNPs (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs 13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8- rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB 1- rs 1982073, and ATM-rs 1800054). Logistic regression models were used to determine the main effect of each of the 12 SNPs on the relative risk for breast cancer by calculating the per-allele age-adjusted relative risks for the high-risk versus the low-risk allele. The data showed that none of 120 possible gene-environment interactions in 7610 women with breast cancer remained significant after allowance for the multiple tests. There was little evidence for interactions between genotype, use of HRT, and estrogen-receptor-positive breast cancer. After adjustment for multiple testing, no significant associations were found between 11 of the 12 polymorphisms and the 10 environmental risk factors. A significant association was found for only 1 of the 12 polymorphisms: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than noncarriers; the mean heights of carriers versus noncarriers were 162 ± 4 cm (95% confidence interval: 162.1-162.7) and 163 ± 1 cm (162.9-163.2), respectively, after adjustment for multiple testing (P = 0.01). These findings show no significant increased risk of breast cancer associated with low-penetrance susceptibility polymorphisms for 10 established environmental risk factors.

Immunogenetics of invasive aspergillosis

Invasive aspergillosis is one of the most important infections in hematopoietic stem cell transplant recipients, with an incidence rate of 5-15% and an associated mortality of 30-60%. It remains unclear why certain patients develop invasive aspergillosis while others, undergoing identical transplant regimen and similar post transplant immunosuppression, do not. Over the last decade, pattern recognition receptors such as Toll-like receptors (TLRs) and the C-type lectin receptors (CLRs) have emerged as critical components of the innate immune system. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, pattern recognition receptors are strategically located at the molecular interface of hosts and pathogens. Polymorphisms in pattern recognition receptors and downstream signaling molecules have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming years. Infectious risk stratification may be particularly relevant for patients with hematologic malignancies, because of the high prevalence and severity of infections in this population. This review summarizes the innate immune mechanisms involved in Aspergillus fumigatus detection and the role of host genetic polymorphisms in susceptibility to invasive aspergillosis.

Gene–environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study

SummaryBackgroundInformation is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene–environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study.MethodsWe tested gene–environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption).FindingsAfter allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene–environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162·4 cm [95% CI 162·1–162·7] vs 163·1 cm [162·9–163·2]; p=0·01 after allowance for multiple testing).InterpretationRisks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors.FundingCancer Research UK and the UK Medical Research Council.

A meta-analysis of interleukin-6 promoter polymorphisms on risk of hip and knee osteoarthritis

Interleukin-6 is a pro-inflammatory cytokine involved in the pathogenesis of osteoarthritis (OA). We investigated the role of two single nucleotide polymorphisms (SNPs) mapping to the promoter of the IL-6 gene on genetic susceptibility to hip and knee OA. The -174G/C (rs1800795) and -597G/A (rs1800797) SNPs, implicated in the literature in risk of hip and hand OA, were genotyped in 2511 controls, 1101 hip OA cases and 1904 knee OA cases from four cohorts from the UK and Estonia. Data were analysed in conjuntion with published data on rs1800797 from the Genetics of OA and Lifestyle study (UK) on 791 controls, 1034 knee and 997 hip OA cases and rs1800795 data on 75 hip OA cases and 96 controls from Italy. Cases included both radiographic OA only and radiographic and symptomatic OA. Fixed and random-effects meta-analysis models were tested. No significant association was found with hip OA or knee OA with either SNP nor with the haplotypes formed by them. For individual SNPs the smallest P-value for hip OA was observed using a random-effects model for rs1800795 OR(Gallele)=1.066 (95% CI 0.89-1.28) P<0.49, and significant heterogeneity between cohorts (I(2)=65%, P<0.034) was detected. For knee OA the smallest P-value was seen for rs1800797 OR(Aallele)=1.055 (95%CI 0.98-1.12) P<0.18, no significant heterogeneity was observed (I(2)=0%, P<0.68). Our data do not support a role for the -174 and -597 IL-6 promoter polymorphisms in genetic susceptibility to knee or hip OA in Caucasian populations.

Investigation of TNFA 308G &gt; A and TNFB 252G &gt; A polymorphisms in genetic susceptibility to migraine

We aimed to look for the association of tumor necrosis factor (TNF) gene polymorphisms (TNFA 308G > A, and TNFB 252G > A) in genetic susceptibility to migraine. The pathogenesis of migraine involves many immune-mediated mechanisms in the vascular endothelium. TNF, being a potent immunomodulator and pro-inflammatory cytokine, is suggested to be involved in inflammatory reactions leading to migraine attacks. A total of 216 normotensive migraine patients, 160 tension type headache (TTH) patients and 216 healthy controls (HC) were recruited in the study. The genetic polymorphisms were investigated through SNP association analysis using a matched case control migraine population. Genotyping of TNFA 308G > A polymorphism and TNFB 252G > A was done using ARMS PCR and PCR-RFLP, respectively. A borderline association was observed in TNFA 308GA genotype in migraine patients versus HC (p = 0.043; OR = 1.763; 95% CI = 1.019-3.051). After sub-grouping migraine into migraine with aura (MA) or without aura, significant difference at genotypic (p = 0.015; OR = 2.293; 95% CI = 1.172-4.487) as well as allelic (p = 0.035; OR = 1.955; 95% CI = 1.047-3.651) level was evident. The difference was even more significant in female MA at genotypic (p = 0.006; OR = 2.901; 95% CI = 1.361-6.181) and allelic level (p = 0.017; OR = 2.318; 95% CI = 1.159-4.635) as well as for A allele carriers in MA [p value = 0.020; OR = 2.205 (1.132-4.295)] and female MA (p value = 0.008; OR = 2.741; CI = 1.297-5.792). No association of TNFB252G > A was observed in migraine patients or any subgroups. We did not find any association of TNFA or TNFB gene polymorphisms with TTH. In conclusion, the TNFA 308G > A polymorphism was found to be associated with MA, particularly in females, whereas we could not find any association of TNFB 252G > A polymorphism in genetic susceptibility to migraine on comparing the migraine patients with HC or TTH patients.

Role of the oestrogen receptor (ESR1 PvuII and ESR1 325 C→G) and progesterone receptor (PROGINS) polymorphisms in genetic susceptibility to migraine in a North Indian population

We aimed to explore the single-locus, haplotype and epistasis patterns and the contribution of oestrogen receptor [ESR1 PvuII (rs2234693), ESR1 325 C→G (rs1801132)] and progesterone receptor [PROGINS (rs1042838)] polymorphisms in genetic susceptibility to migraine by analysing 613 subjects consisting of 217 migraine patients, 217 healthy controls (HC) and 179 patients with tension-type headache (TTH). Entire data were analysed by taking the Bonferroni corrected P-value into account. We found significant association of TT genotype [odds ratio (OR) 3.458, confidence interval (CI) 1.757, 6.806; P = 0.0003] and T allele (OR 1.729, CI 1.309, 2.284; P = 0.0001) of ESR1 PvuII single nucleotide polymorphism with migraine when compared with HC. Significant association was seen only in female migraine patients at both genotype (P = 0.002; OR 3.834, CI 1.625, 9.043) and allele level (P = 0.002; OR 1.721, CI 1.228, 2.413). Moreover, higher risk was limited to migraine with aura (MA) (in case of TT genotype, P = 0.002; OR 4.377, CI 1.703, 1.246; in case of T allele, P = 0.001; OR 1.888, CI 1.305, 2.735) rather than migraine without aura (MoA) (P-value of TT genotype = 0.003; OR 3.082, CI 1.465, 6.483; P-value T allele = 0.002; OR 1.630, CI 1.188, 2.236). In case of a recessive model, risk was seen with migraine patients (P = 0.0003; OR 2.514, CI 1.635, 3.867), MA (P = 0.0001; OR 3.583, CI 1.858, 6.909) and MoA patients (P = 0.002; OR 2.125, CI 1.304, 3.464) when compared with HC. No risk was observed when TTH patients were compared with HC. No significance of ESR 325 G→C polymorphism was seen in any of the models under study. Significant differences in genotypic (P = 0.0001) and allelic frequency (P = 0.0002) were seen in case of PROGINS polymorphism when migraine patients were compared with HC, showing a protective effect (for A1A2 genotype, OR 0.292, CI 0.155, 0.549; for A2 allele, OR 0.320, CI 0.174, 0.589). Moreover, significance was seen only in case of female migraine patients at genotype (P = 0.002; OR 0.344, CI 0.176, 0.684) as well as allele levels (P = 0.004; OR 0.379, CI 0.198, 0.727) in case of PROGINS polymorphism. ESR1 PvuII TT*ESR1 325 C→G CG genotype, PROGINS A1A2*ESR1 325 C→G CG genotype and ESR1 PvuII CT*PROGINS A1A2 interacted significantly, but significance was lost after Bonferroni correction. In conclusion, ESR1 PvuII polymorphism is a significant risk factor for migraine particularly in women and MA patients, but ESR 325 C→G polymorphism is not associated with migraine susceptibility. PROGINS polymorphism seems to play a protective role in genetic susceptibility to migraine in the North Indian population.

Genetic contribution of chemokine receptor 2 (CCR2) polymorphisms towards increased serum total IgE levels in Indian asthmatics

The chemokine (C–C motif) receptors (CCR) 2 and 5 are members of a large family of G protein-coupled receptors, playing important roles in asthma pathogenesis. Using standard sequencing techniques, a total of 15 single nucleotide and 8 insertion/deletion polymorphisms (DIPs) (5 novels) were identified in and around these two genes. None of the studied polymorphisms ( N = 7, selected on the basis on linkage disequilibrium) was associated with asthma in a case ( N = 315) – control ( N = 337) study and showed no evidence for non-random transmission to individuals with asthma/atopy in Indian pedigrees ( n = 235). However, multilocus haplotype analysis based on simulations yielded a P = 0.00005 in the case–control study and a P = 0.03 for the family-based association studies. Furthermore, rs3918356 and rs743660 polymorphisms in CCR2 were found to be associated with total serum IgE levels in both the study designs. Thus, our study supports a significant role for chemokine receptor polymorphisms in genetic susceptibility to asthma.

Phosphodiesterase 4D (PDE4D) Gene Variants and Risk of Ischemic Stroke in the Taiwanese Population

Objectives: It has been suggested that genetic variants in the phosphodiesterase 4D (PDE4D) gene confer risk of ischemic stroke. However, the cerebral infarction/cerebral hemorrhage ratio is lower in Asian populations compared with those in Caucasian and black populations. Thus, the association between variations in the PDE4D gene and ischemic stroke in Taiwan needs to be replicated. In the present study, we evaluated whether the PDE4D gene polymorphism confers a risk of ischemic stoke in Taiwanese patients. Methods: Two single-nucleotide polymorphisms (SNPs) covering the PDE4D gene were genotyped using genomic DNA sequencing and a high-throughput TaqMan PCR assay in 100 patients who had suffered an ischemic stroke and 270 healthy individuals. Results: No significant associations with ischemic stroke were observed with the SNP87 (rs2910829) or SNP41 (rs152312) SNPs from PDE4D, which were a part of the Icelandic at-risk haplotypes. Conclusions: The present data does not support a significant role for PDE4D polymorphisms in genetic susceptibility to ischemic stroke in the Taiwanese population.

Analysis of ERCC2/XPD functional polymorphisms in systemic lupus erythematosus

Sunlight/ultraviolet (UV) irradiation has been recognized as an important risk factor for developing systemic lupus erythematosus (SLE). However, the interpretation of genetic variations involved in UV-light sensitivity is largely unknown. Recent studies indicated that two genetic variations of ERCC2/XPD gene (rs1799793 in exon 10 and rs13181 in exon 23) have been found to exert negative influences on nucleotide excision repair system. To analyse the possible contribution of the ERCC2/XPD functional single nucleotide polymorphisms in genetic susceptibility to SLE, the rs13181 and rs1799793 SNPs in ERCC2/XPD were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Association was studied by case-control analyses using samples from 172 SLE patients and 160 healthy controls. Haplotype analysis was performed to detect the association with genetic predisposition to SLE and the clinical features. Although these two functional genetic variations are linked to several immune dysfunction-induced diseases, no statistically significant differences in allele or genotype frequencies were observed between SLE patients and controls. Haplotype analysis showed that none of ERCC2/XPD haplotypes was associated with the incidence of SLE disease, nor the preference of clinical features. In conclusion, the ERCC2/XPD functional polymorphisms analysed in this study showed no association in genetic susceptibility to SLE.

Role of the ACE ID and MTHFR C677T polymorphisms in genetic susceptibility of migraine in a north Indian population

Migraine is a common debilitating neurovascular disorder. The vascular genes ACE and MTHFR are involved in alterations in vascular endothelium and are suggested to play a role in migraine susceptibility. The aim of our study was to find out the role of ACE ID (rs no. 4646994) and MTHFR C677T (rs no.1801133) polymorphisms in genetic susceptibility of migraine in north Indian population. A total of 150 migraine patients, 220 non-migraine headache patients (Disease controls) and 150 age–sex matched normotensive healthy controls were enrolled for our study. DNA was isolated from peripheral blood leucocytes, and subjected to amplification using specific primers and genotyped using PCR (in case of ACE ID) or PCR-RFLP (in case of MTHFR C677T) methods. χ2 test was applied for the analysis of genotypic and allelic distributions. Logistic regression analysis was used to find out contribution of genetic polymorphisms to the risk of disease. ACE DD genotype showed significant association in migraine patients with aura (MA) but a marginal significance in female MA patients in comparison with healthy controls. No significant differences in genotype and allelic frequencies of MTHFR C677T polymorphism were found on comparing migraine patients with either disease controls or healthy controls. In contrast, we found synergistic role of ACE (DD)⁎MTHFR (CT) interaction, showing a positive association in total migraine with aura patients as well as female migraine patients with aura when compared with healthy controls.

Cytokine Gene Polymorphisms in Heavy Drinkers With and Without Decompensated Liver Disease: A Case-Control Study

Twin studies have suggested some genetic predisposition to alcoholic liver disease (ALD). Cytokines may be involved in ALD pathogenesis. Several cytokine genes contain functionally significant polymorphisms. Associations between ALD and polymorphisms on the interleukin-1 (IL-1), IL-10, and tumor necrosis factor-alpha (TNF-alpha) genes have been reported but not confirmed. Comparison of allelic frequencies of cytokine gene polymorphisms between 223 patients with decompensated ALD (a more severe phenotype than in previous studies) and 162 controls with similar lifetime alcohol consumption but without serious liver disease. Genotyping of polymorphisms of the genes for IL-1A (+4,845), IL-1B (+3,954 and -511), IL-1 receptor antagonist (+2,018), IL-6 (-174), IL-10 (-574 and -1,117), and TNF-alpha (-238 and -308). There were increases with respect to IL-6 -174 (2 x 3 chi(2)P < 0.1, OR for G allele carriage 1.61[1.05-2.48]) and Il-10 -592 (2 x 3 chi(2) 7.90, P < 0.01, OR for AA genotype carriage 4.85[1.40-16.8]) polymorphisms in patients compared with heavy-drinking controls. Differences were greater with analysis confined to Child's C patients. Genotype distribution for the other seven polymorphisms did not differ significantly between patients and heavy-drinking controls. These data are consistent with a modest role for IL-6 -174, and IL-10 -592 polymorphisms in genetic susceptibility to ALD.

Systemic Functional Expression of N-Acetyltransferase Polymorphism in the F344 Nat2 Congenic Rat

Rat lines congenic for the rat N-acetyltransferase 2 [(RAT)Nat2] gene were constructed and characterized. F344 (homozygous Nat2 rapid) males were mated to Wistar Kyoto (homozygous Nat2 slow) females to produce heterozygous F1. F1 females were then backcrossed to F344 males. Heterozygous acetylator female progeny from this and each successive backcross were identified by rat Nat2 genotyping and mated with F344 rapid acetylator males. After 10 generations of backcross mating, heterozygous acetylator brother/sister progeny were mated to produce the homozygous rapid and slow acetylator Nat2 congenic rat lines. p-Aminobenzoic acid (selective for rat NAT2) and 4-aminobiphenyl N-acetyltransferase activities were expressed in all tissues examined (liver, lung, esophagus, stomach, small intestine, colon, pancreas, kidney, skin, leukocytes, and urinary bladder in male and female rats and in breast of female and prostate of male rats). NAT2 expression in rat extrahepatic tissues was much higher than that in liver. In each tissue, activities were Nat2-genotype-dependent, with the highest levels in homozygous rapid acetylators, intermediate levels in heterozygous acetylators, and lowest in homozygous slow acetylators. Sulfamethazine (selective for rat NAT1) N-acetyltransferase activities were observed in all tissues examined in both male and female rats except for breast (females), bladder, and leukocytes. In each tissue, the activity was Nat2 genotype-independent, with similar levels in homozygous rapid, heterozygous, and homozygous slow acetylators. These congenic rat lines are useful for investigating the role of NAT2 genetic polymorphisms in susceptibility to cancers related to arylamine carcinogen exposures.

Polymorphisms of interferon-γ, interleukin-10, and interleukin-12 genes in myasthenia gravis

To assess the involvement of polymorphisms in genetic susceptibility to myasthenia gravis (MG), this study analyzed four polymorphisms of interferon (IFN)-gamma, interleukin (IL)-10, and IL-12 genes in 115 patients and 204 healthy controls (HC). IFNG +874T carriers were less frequent in MG, in patients with anti-acetylcholine receptor (AChR) (63%) and anti-titin (56.2%) antibodies compared with HC (p = 0.01 for all, OR: 0.5, 0.5, and 0.4, respectively). The presence of thymoma was also associated with lower frequency of IFNG +874T allele (p = 0.018, OR = 0.34). At IL10, -2763A allele was found to be slightly more frequent in MG and in patients with anti-AChR than in HC group (p = 0.05, OR = 1.7, p = 0.036, OR = 1.83). However, these associations did not remain significant after correction for multiple comparisons. IL12B allele distribution was not different among groups. These data suggest that some cytokine gene polymorphisms may contribute to susceptibility to or antibody production in MG. These findings need to be replicated in further studies.

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Promoter polymorphism in the 5-lipoxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population.

5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are essential for cysteinyl-leukotriene (cys-LT) production, critical mediators in asthma. We sought to identify novel promoter polymorphisms within the FLAP (ALOX5AP) gene promoter and test the role of these and the previously identified 5-LO (ALOX5) Sp1 promoter polymorphism in asthma susceptibility. To assess genetic association with asthma phenotypes, we genotyped 341 Caucasian families (containing two asthmatic siblings) and non-asthmatic control subjects (n=184). Genetic association was determined by case-control and transmission disequilibrium test (TDT) analyses. To determine the functional role of polymorphisms on basal transcription, we generated ALOX5AP-promoter-luciferase constructs and transiently transfected human HeLa cells. A novel G/A substitution at -336 bp and a poly(A) repeat (n=19 or 23) at position -169 to -146 bp were identified in the ALOX5AP promoter. Genotyping found the -336 A and poly(A19) alleles at frequencies of q=0.06 and 0.12, respectively. No ALOX5AP allele was associated with asthma or asthma-related phenotypes in case-control or TDT analyses. ALOX5AP-promoter-luciferase analyses did not support a functional role of the -336 or poly(A) polymorphism in determining basal transcription. The ALOX5 Sp1 polymorphism was predominantly homozygous wild-type 5/5 (frequency q=0.70) and heterozygous 4/5 (q=0.23) genotypes and no allele was associated with asthma or asthma-related phenotypes. Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.

HLA-DRB1 allele polymorphisms in genetic susceptibility to esophageal carcinoma.

To probe into the genetic susceptibility of HLA-DRB1 alleles to esophageal carcinoma in Han Chinese in Hubei Province. HLA-DRB1 allele polymorphisms were typed by polymerase chain reaction with sequence-specific primers(PCR-SSP) in 42 unrelated patients with esophageal cancer and 136 unrelated normal control subjects and the associated HLA-DRB1 allele was measured by nucleotide sequence analysis with PCR.SAS software was used in statistics. Allele frequency (AF) of HLA-DRB1*0901 was significantly higher in esophageal carcinoma patients than that in the normal controls (0.2500 vs 0.1397, P=0.028, the odds ratio 2.053, etiologic fraction 0.1282). After analyzed the allele nucleotide sequence of HLA-DRB1*0901 which approachs to the corresponded exon 2 sequence of the allele in genebank. There was no association between patients and controls in the rested HLA-DRB1 alleles. HLA-DRB1*0901 allele is more common in the patients with esophageal carcinoma than in the healthy controls, which is positively associated with the patients of Hubei Han Chinese. Individuals carrying HLA-DRB1*0901 may be susceptible to esophageal carcinoma.

HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and CTLA-4 polymorphisms in Tunisian patients with rheumatoid arthritis and Sjögren's syndrome.

To evaluate the contribution of HLA class II region and the CTLA-4 gene in genetic susceptibility to rheumatoid arthritis (RA) and Sjögren's syndrome (SS) in the Tunisian population. The polymorphisms of a (CA)n microsatellite of HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and an (AT)n microsatellite in the 3'-untranslated region of exon 3 of the CTLA-4 gene were analysed after specific polymerase chain reaction (PCR) amplification. Typing of CTLA-4 A/G exon 1 polymorphism was achieved by the PCR-restriction fragment length polymorphism method. Genomic DNA from 60 patients with RA, 58 patients with SS and 150 healthy individuals was genotyped. The distribution of HLA-DQ CAR1/CAR2 allele frequencies differed between patients and controls in both diseases (RA, P<10(-15); SS, P=7.6x10(-15); RA+SS, P<10(-15)). The analysis of TNFa IR2/IR4 and CTLA-4 A/G polymorphisms did not show any differences in allele or genotype frequencies between patients and control subjects in either disease. The distribution of CTLA-4 (AT)n allele frequencies differed between patients with RA and controls (P=10(-3)), whereas no significant difference was detected between patients with SS and controls. These data suggest the involvement of HLA-DQ CAR1/CAR2 polymorphisms in genetic susceptibility to RA and SS and the participation of the CTLA-4 gene, or a gene closely associated with it, in the development of RA.