At-risk Haplotype Research Articles

ASSOCATION BETWEEN PSORIASIS AND CELIAC DISEASE : A SYSTEMATIC REVIEW

Psoriasis is an inflammatory illness that affects the skin and is characterised by the formation of erythematous and scaly plaques. Psoriasis is a chronic condition. Psoriasis vulgaris, often known as plaque psoriasis, is the most common form of psoriasis; however, there are many other types of psoriasis as well. Psoriasis vulgaris is the most common form of psoriasis. The bulk of the research that was done to study whether or not celiac disease and psoriasis could have a connection was flawed or biased in some way, which resulted in conclusions that could not be considered definitive. These flaws or biases included a small sample size, a lack of controls, a low accuracy of serological methods used to screen for celiac disease (i.e. anti-gliadin antibodies, AGAs), and the setting, including the design as single-centre studies. All of these issues contributed to the conclusion that the study was flawed or biased. Despite the fact that there is a connection between the two disorders, the physiopathologic mechanisms that are at the root of the connection between psoriasis and CD have not been fully explored. The presence of shared genes (at-risk HLA haplotypes), which are frequently taken into consideration when attempting to explain the increased incidence of CD in a number of autoimmune illnesses, could be present in people who have psoriasis, according to our working hypothesis. Psoriasis is a chronic inflammatory skin condition that can affect any part of the body. Although the results of the link between psoriasis and celiac disease based on the research that was conducted in 2010 are inconsistent, newer studies and studies that were conducted before 2010 provide evidence that there is a connection between the two conditions. Celiac disease is an autoimmune disorder that affects the small intestine and can cause psoriasis.

Preimplantation genetic testing for a chr14q32 microdeletion in a family with Kagami-Ogata syndrome and Temple syndrome

IntroductionKagami-Ogata syndrome (KOS14) and Temple syndrome (TS14) are two disorders associated with reciprocal alterations within the chr14q32 imprinted domain. Here, we present a work-up strategy for preimplantation genetic testing (PGT)...

Human Leukocyte Antigen Gene Testing and Carbamazepine-Induced Toxic Epidermal Necrolysis: A Study of Pediatric Practice.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug-induced dermatologic conditions. SJS/TEN occurs in 1-10 per 10 000 patients taking carbamazepine (CBZ) (Pratt VM, McLeod HL, Rubinstein WS et al. Medical Genetics Summaries. National Center for Biotechnology Information US; 2018: 1-527). The development of SJS/TEN is associated with variable drug metabolism and presence of an at-risk HLA haplotype. HLA-B*15:02 and HLA-A*31:01 haplotypes can produce a hyperimmune response in the setting of CBZ use in patients of Asian and European descent, respectively (Schneider JA, Cohen PR. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther. 2017; 34:1235-1244). The US Food and Drug Administration (FDA) and the Canadian pharmacogenomics Network for Drug Safety (CPNDS) recommend that patients with high-risk ethnic backgrounds should be genetic tested before initiating CBZ (Sukasem C, Chaichan C, Nakkrut T et al. Association between HLA-B Alleles and Carbamazepine-induced maculopapular exanthema and severe cutaneous reactions in Thai patients. Journal of Immunology Research. 2018; 1-11).We sought out to assess the awareness of this in prescribing practitioners and their standard of practice. We created a 15-question survey and distributed to pediatric neurologists and pediatricians at the University of Alberta. We hypothesized that there was a discordance between the standard of practice and the recommendation by the FDA and CPNDS. The survey results indicated a lack of awareness of the at-risk ethnicities for CBZ-induced SJS/TEN. HLA gene testing was rarely done prior to initiation of CBZ in high-risk patients. In addition, there was a lack of awareness for standard of care for genetic testing in Canada and worldwide. Our results demonstrate an evident gap between current prescriber practices and existing FDA and CPNDS recommendations to screen for HLA genotypes. We hope that this study captures the realistic potential to improve patient outcomes.

Spinocerebellar ataxia type 10 (SCA10): Mutation analysis and common haplotype based inference suggest its rarity in Indian population.

The implications of the findings of this study are 1.) For the diagnostic work-up of SCAs in the Indian population and to decide upon inclusion of SCA10 in panel based genetic investigations even for Indians living abroad. 2.) The haplotype based inference of its presumptive prevalence through the estimation of at-risk haplotype using population genetics approach (South-Asians as the background) allowed us to estimate the possible absence of SCA10 in Indian population. SCA10 is a rare autosomal dominant cerebellar ataxia mostly reported among SCA patients from Latin America and recently described in East Asia population. The genetic study of SCA10 performed in the unrelated Indian spinocerebellar ataxia patients with heterogeneous ethnicity confirmed its absence from the Indian population and that conforms to population genetic based inference of its rarity or absence. 3.) This approach may be adopted for the screening of other subtypes of SCAs, i.e. other rare SCAs e.g. SCA31, SCA36, and SCA37.

Risk Assessment for Huntington's Disease for (Future) Offspring Requires Offering Preconceptional CAG Analysis to Both Partners.

Amongst the main reasons people at risk for Huntington's disease (HD) have for undergoing predictive genetic testing are planning a family and prevention of passing on an expanded CAG-repeat to future offspring. After having received an unfavourable test result, a couple may consider prenatal testing in the foetus or preimplantation genetic diagnostic testing (PGD) in embryos. Testing of the foetus or embryos is possible by means of direct testing of the expanded repeat. Optimal reliability in testing the foetus or embryos requires the establishment of the origin of the repeats of both parents in the foetus. For PGD the analysis is combined with or sometimes solely based on identification of the at-risk haplotype in the embryo. This policy implies that in the context of direct testing, the healthy partner's CAG repeat lengths in the HD gene are also tested, but with the expectation that the repeat lengths of the partner are within the normal range, with the proviso that the partner's pedigree is free of clinically confirmed HD. However, recent studies have shown that the expanded repeat has been observed more often in the general population than previously estimated. Moreover, we have unexpectedly observed an expanded repeat in the non-HD partner in four cases which had far-reaching consequences. Hence, we propose that in the context of reproductive genetic counselling, prior to a planned pregnancy, and irrespective of the outcome of the predictive test in the HD-partner, the non-HD partner should also be given the option of being tested on the expanded allele. International recommendations for predictive testing for HD should be adjusted.

Abstract 2261: Synergistic effect and VEGF/HSP70-hom haplotype analysis: Relationship to prostate cancer risk and clinical outcome

Abstract Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Our previous single-locus analysis showed that VEGF and HSP70-hom polymorphisms were significantly associated with PCa susceptibility and prognosis. Both genes encoding these proteins were located on chromosome 6p21, and combining the neighboring single nucleotide polymorphisms (SNPs) into haplotypes may increase the association with the disease. Three tagging polymorphisms, the HSP70-hom 2437 T/C, the VEGF-1154 G/A, and the VEGF-634 G/C SNPs were genotyped in 101 cases and 80 controls. For the combined analysis of VEGF and HSP70-hom, we found a positive gradient in the odds ratios (ORs) related to the number of high-risk genotypes with a 3.53-fold increase of prostate carcinoma risk (OR= 3.53; p= 0.015). Furthermore, the TAG and CAG haplotypes at positions HSP70-hom, VEGF-1154 and VEGF -634 exhibited a two-fold (OR= 0.46; p= 0.014) and a seven-fold (OR= 0.14; p= 0.00005) reduction in PCa risk, respectively. Regarding PCa prognosis, the TAG haplotype had a negative association with the aggressive phenotype as defined by the histopathological grade (OR= 0.28; p= 0.006). Our findings confirm the role of at-risk haplotype across the HSP70-hom/VEGF gene cluster in determining susceptibility to PCa. Note: This abstract was not presented at the meeting. Citation Format: Sana Sfar, Hamadi Saad, Faouzi Mosbah, Lotfi Chouchane. Synergistic effect and VEGF/HSP70-hom haplotype analysis: Relationship to prostate cancer risk and clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2261. doi:10.1158/1538-7445.AM2017-2261

Serum Levels of MicroRNA-206 and Novel Mini-STR Assays for Carrier Detection in Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a “liquid biopsy” for carrier detection and genetic counseling in DMD.

Towards a complete functional characterization of the disease-associated genetic variants found in the CFH gene

It is well established that common genetic variants in CFH, CD46 and the CFHRs are additional risk factors for the development of aHUS. To examine the hypothesis that common variants in other complement genes have a similar effect we genotyped 501 SNPs in 47 complement genes in 94 aHUS patients from Newcastle, 126 aHUS patients from Paris, 374 UK controls and 165 French controls. We replicated the associations in CFH, CD46 and the CFHRs but found no association with any other complement gene. The strongest associations replicated in both cohorts were found for four SNPs within CD46 (p-value < 10−3) and five SNPs within CFH (p-value <5 × 10−3). Significant replicable associations with single SNPs in CFHR2, CFHR4 and an intergenic SNP (CR1–CD46) were also found. Analysis of the Paris cohort showed that the association with CD46 SNPs was only present in those patients with complement mutations. Haplotype analysis showed at-risk and protective haplotypes in both CD46 and CFH. The CD46 haplotype was only disease-associated in those patients with mutations.

A Novel Risk Haplotype of ALOX5AP Gene is Associated with Ischemic Stroke in Chinese Han Population

Previous studies have implicated that two at-risk haplotypes (HapA and HapB) of gene-encoding 5-lipoxygenase-activating protein (ALOX5AP) were significantly associated with stroke. The aim of this study was to explore the association between haplotypes of ALOX5AP gene and risk for ischemic stroke (IS) in Chinese Han population. A total of 492 patients with IS and 490 matched control subjects were recruited. Six ALOX5AP SNPs (SG13S377, SG13S114, SG13S41, SG13S89, SG13S32 and SG13S35) were genotyped by SNaPshot minisequence technique. A common genetic variant SG13S114/AA in the ALOX5AP gene was associated with IS in this Chinese cohort (OR = 2.514, 95% CI = 1.667 ~ 3.790). HapA (TGA) and HapB (AAAG) had no significant difference in the patients (36.3 and 18.5%, respectively) and controls (37.6 and 16.3%, respectively) (P = 0.631 and P = 0.375, respectively). But, the frequency of Hap (GAAG) was significantly higher in the patients than that in the controls after Bonferroni's adjustment (P = 0.006). To conclude, SG13S114/AA of the ALOX5AP gene was associated with an increased risk for IS. A novel risk haplotype, Hap (GAAG) was a genetic risk factor for IS in this Chinese population.

Parental mosaicism is a pitfall in preimplantation genetic diagnosis of dominant disorders.

PCR amplification on single cells is prone to allele drop-out (PCR failure of one allele), a cause of misdiagnosis in preimplantation genetic diagnosis (PGD). Owing to this error risk, PGD usually relies on both direct and indirect genetic analyses. When the affected partner is the sporadic case of a dominant disorder, building haplotypes require spermatozoon or polar body testing prior to PGD, but these procedures are cost and time-consuming. A couple requested PGD because the male partner suffered from a dominant Cowden syndrome (CS). He was a sporadic case, but the couple had a first unaffected child and the non-mutated paternal haplotype was tentatively deduced. The couple had a second spontaneous pregnancy and the fetus was found to carry the at-risk haplotype but not the PTEN mutation. The mutation was present in blood from the affected father, but at low level, confirming the somatic mosaicism. Ignoring the possibility of mosaicism in the CS patient would have potentially led to selection of affected embryos. This observation emphasizes the risk of PGD in families at risk to transmit autosomal-dominant disorder when the affected partner is a sporadic case.

Molecular diagnosis of dystrophinopathies using a multi‐technique analysis algorithm

Dystrophinopathies are X-linked recessive neuromuscular diseases caused by mutations in the dystrophin gene. In this study we aimed to detect mutations within the dystrophin gene in DMD patients, to determine the carrier status of women, and to perform a prenatal diagnosis. We analyzed 17 individuals from 2 unrelated families with a history of DMD. We used multiplex PCR, multiplex ligation-dependent probe amplification (MLPA), and short tandem-repeat (STR) segregation analysis to accurately detect and characterize the mutations and to identify the at-risk haplotype. The selected methodology allowed for characterization of 2 single-exon out-of-frame deletions in affected patients. Nine of 13 women and a fetus were excluded from being carriers. Three recombination events were found and suggested that germline mosaicism had occurred in both families. This methodology proved to be efficient for characterizing the disease-causing mutation in affected individuals and for assessing the carrier status in healthy relatives. These findings helped inform precise genetic counseling and contributed to characterization of the disease in the Argentine population.

Genomic Structure and Variation of Nuclear Factor (Erythroid-Derived 2)-Like 2

High-density mapping of mammalian genomes has enabled a wide range of genetic investigations including the mapping of polygenic traits, determination of quantitative trait loci, and phylogenetic comparison. Genome sequencing analysis of inbred mouse strains has identified high-density single nucleotide polymorphisms (SNPs) for investigation of complex traits, which has become a useful tool for biomedical research of human disease to alleviate ethical and practical problems of experimentation in humans. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) encodes a key host defense transcription factor. This review describes genetic characteristics of human NRF2 and its homologs in other vertebrate species. NRF2 is evolutionally conserved and shares sequence homology among species. Compilation of publically available SNPs and other genetic mutations shows that human NRF2 is highly polymorphic with a mutagenic frequency of 1 per every 72 bp. Functional at-risk alleles and haplotypes have been demonstrated in various human disorders. In addition, other pathogenic alterations including somatic mutations and misregulated epigenetic processes in NRF2 have led to oncogenic cell survival. Comprehensive information from the current review addresses association of NRF2 variation and disease phenotypes and supports the new insights into therapeutic strategies.

Association of inflammatory response gene polymorphism with atherothrombotic stroke in Northern Han Chinese

Atherosclerosis is an important pathophysiological basis of atherothrombotic stroke (ATS), and inflammation plays a significant role in atherosclerosis formation. In this study, single-nucleotide polymorphisms (SNPs) in three key inflammation-related genes, 5-lipoxygenase activating protein (ALOX5AP), phosphodiesterase 4D (PDE4D), and interleukin-1α (IL-1α), were investigated to determine their association with ATS in Northern Han Chinese. Six-hundred and eighty-two ATS patients and 598 unrelated controls were recruited. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and matrix-assisted laser desorption ionization time-of-flight mass spectrometry primer extension. The genotype and allele frequencies of each SNP were statistically analyzed. Risk of ATS was found for the ALOX5AP SG13S114A/T AA genotype (P = 0.040) and A allele (P = 0.033), PDE4D SNP83C/T TT genotype (P = 0.010) and T allele (P = 0.008) and SNP219A/G GG genotype (P = 0.025) and G allele (P = 0.022), and the IL-1α-889C/T T allele (P = 0.035). The differences still remained significant after adjustment. The ALOX5AP HapA haplotype was not correlated with ATS (P = 0.834), but GCGA represented an at-risk haplotype (P = 0.008). Furthermore, the PDE4D AA haplotype at SNP219-220 might be an at-risk haplotype (P = 0.013), while GA might be a protective haplotype (P = 0.005). The ALOX5AP (SG13S114A/T), PDE4D (SNP83C/T, 219A/G), and IL-1α (-889C/T) SNPs were associated with an increased risk of ATS in Northern Han Chinese.

Genetic polymorphisms in centrobin and Nek2 are associated with breast cancer susceptibility in a Chinese Han population

Centrosome aberrations have been suggested to cause chromosomal instability and aneuploidy, and eventually promote cancerdevelopment. The Centrobin and Nek2 proteins interact with each other and both are involved in centrosome duplication and chromosome segregation. This study aimed to investigate whether genetic polymorphisms in these two genes may affect breast cancer susceptibility in Chinese Han population using a haplotype-based analysis. Five single nucleotide polymorphisms (SNPs) in centrobin and four SNPs in Nek2 were genotyped in 1,215 cases of infiltrating ductal breast cancer and 1,215 age-matched cancer-free controls from Chinese Han population. The results showed that CATCG haplotype of centrobin was strongly associated with decreased breast cancer risk (adjusted OR=0.14, 95% CI=0.09-0.22), which was mainly driven by the C allele of SNP rs11650083 (A>C, located in exon 12, resulting in Pro578Gln). None of the individual SNPs in Nek2 was associated with breast cancer risk. However, haplotype GTAT of Nek2 was associated with increased risk of breast cancer (adjusted OR=1.56, 95% CI=1.18-2.06) and its risk was significantly elevated among women with both family history of cancer and a longer menarche-first full-term pregnancy (FFTP) interval (>11years) (adjusted OR=5.31, 95% CI=1.97-14.32). Furthermore, women harboring both at-risk haplotype GTAT of Nek2 and protective haplotype CATCG of centrobin were linked with decreased breast cancer risk, suggesting that the association between genetic variants of Nek2 and increased breast cancer risk was modified by genetic variants of centrobin. Our results indicate that genetic polymorphisms of centrobin and Nek2 are related to breast cancer susceptibility in Chinese Han women.

A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function

AbstractAtypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with pro-inflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event.

Atypical Hemolytic Uremic Syndrome, Genetic Basis, and Clinical Manifestations

Atypical hemolytic uremic syndrome (aHUS) is now well recognized to be a disease characterized by excessive complement activation in the microvasculature. In both the familial and sporadic forms, inherited and acquired abnormalities affecting components of the alternative complement pathway are found in ~ 60% of patients. These include mutations in the genes encoding both complement regulators (factor H, factor I, membrane cofactor protein, and thrombomodulin) and activators (factors B and C3) and autoantibodies against factor H. Multiple hits are necessary for the disease to manifest, including a trigger, mutations, and at-risk haplotypes in complement genes. The prognosis for aHUS is poor, with most patients developing end-stage renal failure. Renal transplantation in most patients also has a poor prognosis, with frequent loss of the allograft to recurrent disease. However, improving results with combined liver-kidney transplantation and the advent of complement inhibitors such as eculizumab offer hope that the prognosis for aHUS will improve in future years.

Common genetic variants in complement genes other than CFH, CD46 and the CFHRs are not associated with aHUS

It is well established that common genetic variants in CFH, CD46 and the CFHRs are additional risk factors for the development of aHUS. To examine the hypothesis that common variants in other complement genes have a similar effect we genotyped 501 SNPs in 47 complement genes in 94 aHUS patients from Newcastle, 126 aHUS patients from Paris, 374 UK controls and 165 French controls. We replicated the associations in CFH, CD46 and the CFHRs but found no association with any other complement gene. The strongest associations replicated in both cohorts were found for four SNPs within CD46 (p-value<10−3) and five SNPs within CFH (p-value<5×10−3). Significant replicable associations with single SNPs in CFHR2, CFHR4 and an intergenic SNP (CR1–CD46) were also found. Analysis of the Paris cohort showed that the association with CD46 SNPs was only present in those patients with complement mutations. Haplotype analysis showed at-risk and protective haplotypes in both CD46 and CFH. The CD46 haplotype was only disease-associated in those patients with mutations.

Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population

Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD. Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population. Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10-15%) susceptibility haplotype covering the entire coding region and 3' untranslated region (UTR) of NR3C1. This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.

A tagging SNP in ALOX5AP and risk of stroke: a haplotype-based analysis among eastern Chinese Han population

A genome-wide approach found significant association of two at-risk haplotypes (HapA, HapB) in the ALOX5AP gene with myocardial infarction and stroke. To date, it is still controversial whether ALOX5AP gene polymorphisms are risk factors for stroke. The aim of the present study is to investigate the association between the ALOX5AP gene polymorphism and the risk for stroke in Eastern Chinese Han population with a haplotype-based analysis. We conducted a comprehensive association study of 507 stroke patients and 510 healthy controls to assess the association between the ALOX5AP tagging single-nucleotide polymorphisms (tSNPs) and stroke risk. Genotyping was performed using the PCR-RFLP assay. In the single-locus analysis, we found that the rs9579646 AG genotype was associated with a marginally decreased risk for stroke (adjusted odds ratio, 0.65; 95% confidence interval, 0.45-0.96), compared with the AA genotype. Haplotype-based association analysis of block 2 involving rs10507391 and rs12429692 revealed that the decreased risk of stroke was significantly associated with haplotype AA (OR, 0.66; 95% CI, 0.46-0.95). These results suggested that the genetic variants in ALOX5AP might modulate the risk of stroke in Eastern Chinese Han population. The frequencies of single-marker alleles and haplotypes showed remarkable differences from those in other populations.

Joint effect of peroxisome proliferator-activated receptor γ genetic polymorphisms and estrogen-related risk factors on breast cancer risk: results from a case–control study in Taiwan

Peroxisome proliferator-activated receptor γ (PPARγ) has been linked with possible antineoplastic effects in colorectal carcinogenesis. However, data for the possible link between PPARγ and breast cancer risk are sparse. We assessed the association of three polymorphisms in PPARγ (rs10865710 [C-681T], rs1805192 [Pro12Ala], and rs3856806 [C1431T]) with the risk of breast cancer in an ethnic Chinese female population in Taiwan. In addition, interactions with estrogen exposures were also explored. Genotypes for the PPARγ polymorphisms were determined on 291 incident breast cancer cases and 589 matched controls by fluorogenic 5'-nuclease assay. The at-risk haplotypes were defined according to the three polymorphisms in the following order: C-681T, Pro12Ala, and C1431T, which include CCT, GGT, and GGC. In addition, a critical period of estrogen exposure was estimated by the interval between age at menarche and age at first full-term pregnancy. Overall, there was no evidence of a significant impact of individual polymorphisms of PPARγ on breast cancer risk. However, the haplotype analysis revealed that women harboring at-risk haplotypes showed a significant 67% increase in breast cancer risk [adjusted odds ratio (OR) 1.67; 95% confidence interval (CI) 1.11-2.52]. Furthermore, there was a significant joint effect of estrogen exposure-related factors and at-risk haplotypes of PPARγ on breast cancer risk (adjusted OR 4.04; 95% CI 1.89-8.65), particularly in premenopausal women. The present study implicates a role for PPARγ in breast cancer risk. Mechanistic studies to fully elucidate the mechanisms underlying PPARγ's effects should be pursued in future investigations.