Complete Linkage Disequilibrium Research Articles

Association of bovine leptin polymorphisms with energy output and energy storage traits in progeny tested Holstein-Friesian dairy cattle sires

BackgroundLeptin modulates appetite, energy expenditure and the reproductive axis by signalling via its receptor the status of body energy stores to the brain. The present study aimed to quantify the associations between 10 novel and known single nucleotide polymorphisms in genes coding for leptin and leptin receptor with performance traits in 848 Holstein-Friesian sires, estimated from performance of up to 43,117 daughter-parity records per sire.ResultsAll single nucleotide polymorphisms were segregating in this sample population and none deviated (P > 0.05) from Hardy-Weinberg equilibrium. Complete linkage disequilibrium existed between the novel polymorphism LEP-1609, and the previously identified polymorphisms LEP-1457 and LEP-580. LEP-2470 associated (P < 0.05) with milk protein concentration and calf perinatal mortality. It had a tendency to associate with milk yield (P < 0.1). The G allele of LEP-1238 was associated (P < 0.05) with reduced milk fat concentration, reduced milk protein concentration, longer gestation length and tended to associate (P < 0.1) with an increase in calving difficulty, calf perinatal mortality and somatic cells in the milk. LEP-963 exhibited an association (P < 0.05) with milk fat concentration, milk protein concentration, calving difficulty and gestation length. It also tended to associate with milk yield (P < 0.1). The R25C SNP associated (P < 0.05) with milk fat concentration, milk protein concentration, calving difficulty and length of gestation. The T allele of the Y7F SNP significantly associated with reduced angularity (P < 0.01) and reduced milk protein yield (P < 0.05). There was also a tendency (P < 0.1) for Y7F to associate with increased body condition score, reduced milk yield and shorter gestation (P < 0.1). A80V associated with reduced survival in the herd (P < 0.05).ConclusionsSeveral leptin polymorphisms (LEP-2470, LEP-1238, LEP-963, Y7F and R25C) associated with the energetically expensive process of lactogenesis. Only SNP Y7F associated with energy storage. Associations were also observed between leptin polymorphisms and calving difficulty, gestation length and calf perinatal mortality. The lack of an association between the leptin variants investigated with calving interval in this large data set would question the potential importance of these leptin variants, or indeed leptin, in selection for improved fertility in the Holstein-Friesian dairy cow.

Chlordecone Exposure and Risk of Prostate Cancer

Determining whether environmental estrogens are associated with the risk of prostate cancer may have important implications for our general understanding of this disease. The estrogenic insecticide chlordecone was used extensively in the French West Indies, contaminating the population for more than 30 years. We analyzed the relationship between exposure to chlordecone and the risk of prostate cancer. We investigated 623 men with prostate cancer and 671 controls. Exposure was analyzed according to case-control status, using either current plasma concentration or a cumulative exposure index based on years of exposure. We genotyped two single-nucleotide polymorphisms (rs3829125 and rs17134592) in the gene encoding chlordecone reductase. We found a significant increase in the risk of prostate cancer with increasing plasma chlordecone concentration (odds ratio [OR], 1.77; 95% CI, 1.21 to 2.58 for the highest tertile of values above the limit of detection [LD]; P trend = .002) and for cumulative exposure index (OR, 1.73; 95% CI, 1.04 to 2.88 for the highest quartile; P trend = .004). Stronger associations were observed among those with a positive family history of prostate cancer and among those who had lived in a Western country. The rs3829125 and rs17134592 allele variants were in complete linkage disequilibrium and were found at low frequency (0.04). Among subjects with plasma chlordecone concentrations above the LD, carriers of the allele variants had a higher risk of prostate cancer (OR, 5.23; 95% CI, 0.82 to 33.32). These findings support the hypothesis that exposure to environmental estrogens increases the risk of prostate cancer.

Associations of polymorphisms in the promoter I of bovine acetyl‐CoA carboxylase‐α gene with beef fatty acid composition

The objectives of this study were to identify single nucleotide polymorphisms (SNPs) in the promoter I (PI) region of the bovine acetyl-CoA carboxylase-alpha (ACACA) gene and to evaluate the extent to which they were associated with lipid-related traits. Eight novel SNPs were identified, which were AJ276223:g.2064T>A (SNP1), g.2155C>T (SNP2), g.2203G>T (SNP3), g.2268T>C (SNP4), g.2274G>A (SNP5), g.2340A>G (SNP6), g.2350T>C (SNP7) and g.2370A>G (SNP8). Complete linkage disequilibrium was observed among SNP1, 2, 4, 5, 6 and 8. Phenotypic data were collected from 573 cross-bred steers with six sire breeds, including Hereford, Angus, Brangus, Beefmaster, Bonsmara and Romosinuano. The genotypes of SNP1/2/4/5/6/8 were significantly associated with adjusted backfat thickness. The genotypes of SNP3 were significantly associated with triacylglycerol (TAG) content and fatty acid composition of longissimus dorsi muscle (LM) in Brangus-, Romosinuano- and Bonsmara-sired cattle. Cattle with g.2203GG genotype had greater concentrations of TAG, total lipid, total saturated fatty acid and total monounsaturated fatty acid than did cattle with g.2203GT genotype. The genotypes of SNP7 were significantly associated with fatty acid composition of LM. Cattle with genotype g.2350TC had greater amounts of several fatty acids in LM than did cattle with genotype g.2350CC. Our results suggested that the SNPs in the PI region of ACACA gene are associated with variations in the fatty acid contents in LM.

The porcine tribbles homolog 3 (TRIB3) gene: Identification of a missense mutation and association analysis with meat quality and production traits in Italian heavy pigs

TRIB3 plays an important role in energy metabolism. This work aimed to study the porcine tribbles homolog 3 (TRIB3) gene and to evaluate its association with meat quality and carcass traits in pigs. By sequencing a portion of the porcine TRIB3 gene two single nucleotide polymorphisms (SNPs) in the first coding exon (one synonymous SNP: c.132 T>C; and one missense mutation: c.146C>T, p.P49L) were identified. The two polymorphisms were in complete linkage disequilibrium. In silico analysis of the p.P49L mutation suggested that it could have functional effects. Association studies in four groups of pigs (651 animals in total) indicated that this gene marker was associated with back fat thickness in Italian Large White and Italian Duroc pigs in two different experimental designs (P<0.1 and P<0.05). This polymorphism tended to be associated with lactate content of the semimembranosus muscle (P<0.1). Among several other tissues, TRIB3 is expressed in fat and skeletal muscle.

A functional promoter polymorphism −607G>C of WNT10B is associated with abdominal fat in Korean female subjects

WNT10B has been implicated as a potential regulator of adipogenesis in cellular and animal models of obesity. In this study, we attempted to characterize the associations between common genetic polymorphisms of WNT10B and fat accumulation in a sample of 1029 Korean female subjects. Direct sequencing of genomic DNAs of 45 subjects identified six common single-nucleotide polymorphisms (SNPs) of WNT10B, which were in almost complete linkage disequilibrium. Among the six SNPs, −607G>C (rs833840) showed differential nuclear factor binding in an electrophoretic mobility shift assay and differential promoter activity in a reporter assay, implicating it as a functional regulatory SNP. When body compositions of the subjects determined using bio-impedance analysis were compared according to their −607G>C genotype, only body fat mass showed a significant association. Body masses of protein, mineral and water showed no association. For more accurate evaluation of the effects of −607G>C genotype on body fat, cross-sectional fat areas of the subjects measured by abdominal computed tomography were compared. Genotype of −607G>C was significantly associated with abdominal total fat and abdominal subcutaneous fat areas ( P=.009 and P=.007 in recessive model, respectively). Of the 1029 subjects, 576 were treated with a 1 month very low calorie diet and changes of body weight and composition were compared with −607G>C genotype. No significant associations were evident. This study is the first report of the association of common genetic polymorphism of WNT10B with human fat accumulation.

Polymorphisms in CFH, HTRA1 and CX3CR1 confer risk to exudative age-related macular degeneration in Han Chinese

Background/AimsSingle nucleotide polymorphisms (SNPs) in Complement Factor H (CFH), HTRA1 and CX3CR1 are associated with age-related macular degeneration (AMD) in Caucasian population. We aimed to determine whether, and of what...

Impact of BRCA1 gene alterations on tumor characteristics and clinical outcome in ovarian cancer (OC) patients.

5019 Background: Patients (pts) with BRCA1-associated OC appear to have a survival advantage over those with sporadic OC. It is unclear if this is due to a greater platinum sensitivity or due to a better surgical outcome. In order to examine this issue, we investigated a cohort of OC pts for BRCA1 mutations and correlated the data on the BRCA1-mutation status with the classical clinical prognostic factors and also analysed the impact of BRCA1 mutations on disease-free (DFS) and overall survival (OS). Methods: 298 pts with primary OC, who were treated at Charité University Hospital, Berlin between 09/2000 and 10/2008 were included. Blood samples from each patient were obtained intraoperatively according to a standard operating procedure within the systematic Tumor bank Ovarian Cancer (www.toc-network.de). Direct sequencing of Exon 11 of the BRCA1 gene was used as method for mutation detection. Staging, treatment and follow-up information was obtained by record review. Impact on time to progression/death was determined by Kaplan-Meier analysis and a Cox proportional-hazards model. Results: Thirty one mutations: 20 with previously reported clinical importance and 11 with unknown clinical importance were found. The majority of the pts were heterozygous or homozygous carriers of 6 polymorphisms in Exon11 (D693N, 2201C/T, 2430T/C, P871L, E1038G, K183R), which are in complete or pairwise linkage disequilibrium. Our study showed a significant association between BRCA1 positive status and grading (p = 0.021) and histology type (p = 0.008). BRCA1-positive tumours were more likely to be serous and low differentiated. Pts, who were carriers of polymorphisms, had significantly worse overall survival in comparison to the non- carriers. On multivariate analyse OS independently correlated with presence of polymorphisms, advanced FIGO stage, ascites amount greater 500 mL, tumor residue and platinum response. The presence of a mutation in Exon 11 was not a prognostic factor for DFS and OS. Conclusions: In this cohort, we demonstrated that in addition to the highly penetrant BRCA1 mutations some alterations in BRCA1 gene such as different polymorphisms may contribute to the ovarian cancer risk and predict disease outcome. No significant financial relationships to disclose.

Sequence variants in the bovine gonadotrophin releasing hormone receptor gene and their associations with fertility

Seven sequence variants (SVs) have been identified in exon 1 and in the promoter region upstream of the bovine gonadotrophin releasing hormone (GnRH) receptor gene, at nucleotides g.-331A>G, g.-108T>C, g.+206G>A, g.+260C>T, g.+341C>T, g.+383C>T and g.+410C>T relative to the translation start site. The SVs at nucleotides g.-108, g.260, g.341 and g.410 and those at g.206 and g.383 formed two groups with complete linkage disequilibrium within groups, but incomplete linkage disequilibrium between groups, and none of the SVs altered receptor amino acid sequence. The g.-108T>C allelic variants were associated with an approximately 0.4 day reduction in predicted transmitting ability for days to first service. None of the allelic variants affected the pattern of circulating LH following administration of GnRH. The g.260C>T alteration introduced a new transcription factor binding site in a region of DNA with relatively low nucleosome formation potential. The data suggest that selection for animals carrying the g.-108T>C group of alterations will improve fertility in the dairy cow.

33 The GTPase RAC1 is Associated With Inflammatory Bowel Disease

Background: Several reports have shown an association between Crohn's disease (CD) and SNPs at 10q21. Since reported associations have been with non-coding intergenic SNPs, “causal” variants remain to be identified. Aim: Fine-map the 10q21 region. Methods: We genotyped 86 SNPs across the region of reported association (Chr. 10, position 63,798,139 to 64,219,617) in 1,683 CD cases and 1,049 non-IBD controls. Single marker and conditional analyses were performed using logistic regression (PLINK). ZNF365 isoform D expression was assessed using RT-PCR. Results: Peak association with CD was observed within ZNF365 at rs7076156 and rs7071642, two SNPs in complete linkage disequilibrium (LD) (Table 1). Conditioning on nonsynonymous SNP rs7076156 (Ala62Thr) nullified all other significant associations and the threonine allele protected against CD (p=1.05x10-7; OR 0.71; 23.6% in patients with CD and 30.1% in controls). Four isoforms of ZNF365 (A-D) have previously been identified and rs7076156 is located in an exon unique to ZNF365 isoform D. We further detected expression of this isoform in a terminal ileum resection specimen from a patient with CD. Conclusion: We have demonstrated significant associations between CD and the ZNF365 locus. Conditional analyses suggested that a coding variant (rs7076156; Ala62Thr) confers protection against CD. Furthermore, mRNA for ZNF365 isoform D is expressed in small intestine. Taken together these data suggest that this variant explains the CD association observed at 10q21. ZNF365* SNPs Associated with CD

31 Putative Genetic Loci and Confirmation of Association in IBD

Background: Several reports have shown an association between Crohn's disease (CD) and SNPs at 10q21. Since reported associations have been with non-coding intergenic SNPs, “causal” variants remain to be identified. Aim: Fine-map the 10q21 region. Methods: We genotyped 86 SNPs across the region of reported association (Chr. 10, position 63,798,139 to 64,219,617) in 1,683 CD cases and 1,049 non-IBD controls. Single marker and conditional analyses were performed using logistic regression (PLINK). ZNF365 isoform D expression was assessed using RT-PCR. Results: Peak association with CD was observed within ZNF365 at rs7076156 and rs7071642, two SNPs in complete linkage disequilibrium (LD) (Table 1). Conditioning on nonsynonymous SNP rs7076156 (Ala62Thr) nullified all other significant associations and the threonine allele protected against CD (p=1.05x10-7; OR 0.71; 23.6% in patients with CD and 30.1% in controls). Four isoforms of ZNF365 (A-D) have previously been identified and rs7076156 is located in an exon unique to ZNF365 isoform D. We further detected expression of this isoform in a terminal ileum resection specimen from a patient with CD. Conclusion: We have demonstrated significant associations between CD and the ZNF365 locus. Conditional analyses suggested that a coding variant (rs7076156; Ala62Thr) confers protection against CD. Furthermore, mRNA for ZNF365 isoform D is expressed in small intestine. Taken together these data suggest that this variant explains the CD association observed at 10q21. ZNF365* SNPs Associated with CD

30 Variants in Znf365 on 10q21 are Associated With Crohn's Disease

Background: Several reports have shown an association between Crohn's disease (CD) and SNPs at 10q21. Since reported associations have been with non-coding intergenic SNPs, “causal” variants remain to be identified. Aim: Fine-map the 10q21 region. Methods: We genotyped 86 SNPs across the region of reported association (Chr. 10, position 63,798,139 to 64,219,617) in 1,683 CD cases and 1,049 non-IBD controls. Single marker and conditional analyses were performed using logistic regression (PLINK). ZNF365 isoform D expression was assessed using RT-PCR. Results: Peak association with CD was observed within ZNF365 at rs7076156 and rs7071642, two SNPs in complete linkage disequilibrium (LD) (Table 1). Conditioning on nonsynonymous SNP rs7076156 (Ala62Thr) nullified all other significant associations and the threonine allele protected against CD (p=1.05x10-7; OR 0.71; 23.6% in patients with CD and 30.1% in controls). Four isoforms of ZNF365 (A-D) have previously been identified and rs7076156 is located in an exon unique to ZNF365 isoform D. We further detected expression of this isoform in a terminal ileum resection specimen from a patient with CD. Conclusion: We have demonstrated significant associations between CD and the ZNF365 locus. Conditional analyses suggested that a coding variant (rs7076156; Ala62Thr) confers protection against CD. Furthermore, mRNA for ZNF365 isoform D is expressed in small intestine. Taken together these data suggest that this variant explains the CD association observed at 10q21. ZNF365* SNPs Associated with CD

Abstract 932: Molecular characterization of transcription factors binding to the cancer-related interleukin-1 B gene polymorphisms

Abstract Pulmonary inflammation together with chemical exposure may potentiate the carcinogenic process, underlining the importance of inflammation in cancer development. Interleukin-1beta (IL-1β) encoded by the IL1B gene, has been associated with chronic inflammation and plays an important role in lung inflammatory diseases, including COPD and lung cancer. Elevated levels of IL-1β will greatly enhance the intensity of the inflammatory response. There are large inter-individual differences in IL1B gene expression, which may be explained genetically by presence of single-nucleotide polymorphisms (SNPs) scattered throughout the regulatory region (rSNPs) of the gene. These rSNPs may affect IL1B expression by changing the binding affinity of transcription factors or creating novel transcription binding sites. Our studies have shown that several polymorphisms located in the promoter and the enhancer regions of the IL1B gene may affect risk of non-small cell lung cancer. Notably, rSNPs at −3893 G, −1464 G, −511 C and −31 T position formed a specific haplotype (GGCT) with near complete linkage disequilibrium in lung cancer patients, but not in controls where the risk haplotype (GGCT) was present in 65% of cases compared with 36% of controls. The risk haplotype was correlated with significantly higher IL1B mRNA levels in the lung of lung cancer patients. Particularly, we found that the T to C SNP at the −31 position which is located close to the transcription start site of the gene resulted in binding of different transcription factors to the C and T variants. We have further characterized the specific transcription factors binding to the −31 SNP. In DNA-protein interaction studies using Electrophoretic Mobility Shift Assay (EMSA) and human lung epithelial cells we found evidence that the transcription factor Ying Yang 1 (YY1) bound preferentially to the C SNP. The binding of YY1 to the C SNP was further confirmed using Chromatin Immunoprecipitation (ChIP) assay in human lung epithelial cells. In summary, we have characterized transcription factors that may interact differentially with base changes in the SNPs and thereby may explain the biological effects of the SNPs in modifying the risk to cancer (supported by the Norwegian Cancer Society). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 932.

Abstract 2848: The DEC1 promoter polymorphism −249 T&amp;gt;C reduces the risk of squamous cell carcinoma of the head and neck

Abstract The human DEC1 (deleted in esophageal cancer 1) gene is located on chromosome 9q, a region frequently deleted in various types of human cancers, including squamous cell carcinomas of the head and neck (SCCHN). Previous studies have shown that DEC1 expression was greatly reduced or absent in esophageal cancer, and its tumor suppressive ability was observed in both in vitro and in vivo assays. Therefore, we hypothesized that DEC1 might also play roles in the etiology of SCCHN. To assess the association between DEC1 polymorphisms and SCCHN risk, two independent promoter SNPs, −1628 G&amp;gt;C (rs1591420) and −606 T&amp;gt;C (rs4978620), the latter being in complete linkage disequilibrium with both −249 T&amp;gt;C (rs2012775) and −122 (rs2012566), were genotyped in 1,111 non-Hispanic whites SCCHN patients and 1,130 age-and sex-matched cancer-free controls recruited at The University of Texas M. D. Anderson Cancer Center. The joint effect of DEC1 SNPs and the TP53 tumor suppressor gene codon 72 (Arg72Pro, rs1042522) polymorphism, which has been suggested to be associated with susceptibility to tobacco-related cancers, was also assessed. After adjustment for age, sex, and smoking and drinking status, a significantly protective effect on SCCHN risk was observed for the −606 T&amp;gt;C (rs4978620) CC homozygotes (adjusted OR = 0.72, 95% CI= 0.52-0.98), compared with those carrying the −606 TT genotype. Stratification analyses showed that a decrease risk associated with the −606 CC genotype remained significant in the subgroups of never smokers, never drinkers, younger subjects (≤55 yr), patients with oropharyngeal cancer, and in the presence of the TP53Arg/Arg (rs1042522) genotype. By an in silico analysis, we identified that the −249 T&amp;gt;C SNP would gain a transcription factor binding site. Indeed, further functional analysis showed that the T to C allelic change at the −249 site significantly enhanced transcriptional activity of the DEC1 promoter and the DNA-protein binding activity, supporting a tumor suppressor role of DEC1 in SCCHN. We conclude that the DEC1 promoter −249 T&amp;gt;C (rs2012775) polymorphism is functional, modulating susceptibility to SCCHN among non-Hispanic whites. The association with oropharyngeal cancer among never smokers and never drinkers and with TP53 Arg/Arg genotype suggests that this polymorphism could modulate the human papillomavirus-induced carcinogenic process. (Supported by NIH grants R01CA131274 and R01ES011740) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2848.

Effects of genetic variability of the dairy goat growth hormone releasing hormone receptor (GHRHR) gene on growth traits

Growth hormone-releasing hormone receptor (GHRHR) plays a critical role in growth hormone (GH) synthesis, release and regulation of pituitary somatotroph expansion in vertebrates. The objective of this study was to investigate variations in goat GHRHR gene and their associations with growth traits in 668 dairy goats. The results showed four novel single nucleotide polymorphisms (SNPs): NC_007302:g.5203C>T, 7307C>G, 9583G>A and 9668A>C. In detail, the novel SNP C>T in the 5203rd nucleotide identified a missense mutation: CCC (Pro)>TCC (Phe) at position 116aa of the goat GHRHR (423aa). Besides, 9583G>A and 9668A>C polymorphism were in complete linkage disequilibrium. The genetic diversity analysis revealed that the Guanzhong dairy goat possessed intermediate genetic diversity in P3 and P7 loci, and the Xinong Sannen dairy goat belonged to poor genetic diversity in P4 locus. Significant associations between the genotypes of P3 locus and body length, body height and chest circumference was observed in Guanzhong goat (P<0.05). However, in Xinong saanen population, significant statistical difference was only found in body height and body length (P<0.05). In P4 and P7 loci, no significant associations were detected between any variant sites and body length, body height and chest circumference, as well as for the milk traits (P>0.05). These results strongly suggested that the goat GHRHR gene is a candidate gene that influences growth traits in dairy goat.

A at Single Nucleotide Polymorphism-358 Is Required for G at -420 to Confer the Highest Plasma Resistin in the General Japanese Population

Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at −420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P<10−13 in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r2 = 0.98), and were tightly correlated with SNP-420 (r2 = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r2 = 0.5224, P = 4.94×10−324; G at SNP-420, r2 = 0.2616, P = 1.71×10−133). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at −358, generally had G at −420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P<0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at −420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at −358 may not exist, suggesting that SNP-358 could explain this ethnic difference.

Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease induced by the combinations of environmental and genetic factors. Recently, mice in which the early growth response 2 (EGR2) gene, a zinc-finger transcription factor, is conditionally knocked out in CD2(+) T cells have been shown to develop a lupus-like autoimmune disease. Here, we evaluated if polymorphisms in the EGR2 gene influence SLE susceptibility in humans. We first analyzed the effect of SNPs in the EGR2 region on EGR2 expression, and a significant positive correlation with expression was identified in an SNP located at the 5' flanking region of EGR2 (rs10761670, R=0.23, P=0.00072). We then performed a case-control association study using three sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region. A peak of association with SLE susceptibility was observed for rs10761670 [Pooled: OR = 1.23 (95% CI 1.10-1.37), P=0.00023). This SNP was also associated with susceptibility to rheumatoid arthritis (RA) [OR = 1.15 (95% CI 1.05-1.26), P = 0.0019), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670 (r(2) = 1.0), two SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.

Family‐based studies indicate association of Engrailed 2 gene with autism in an Indian population

Engrailed 2 (EN2) is a homeobox transcription factor involved in the patterning of cerebellum during brain development. Linkage analysis and studies on knockout mice support EN2, located on chromosome 7q36.3, as a potential risk locus for autism. Candidate gene approach also suggested association of EN2 with autism spectrum disorder (ASD) in various populations. Here, we have investigated the association of five markers [rs3735653 (C/T) in exon 1; rs34808376 (GC/-) and rs6150410 (CGCATCCCC/-) in promoter region; rs1861972 (A/G) and rs1861973 (C/T) in the intron] of the gene with autism and ASD in Indian population using family-based approach. Probands have been recruited using Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) diagnostic criteria. Genotypic distributions conform to Hardy-Weinberg equilibrium. Genotyping analysis showed that the intronic single nucleotide polymorphisms (SNPs) are in complete linkage disequilibrium showing A-C and corresponding G-T allelic association. We observed significant preferential transmission of C allele of rs1861973 from the parents to affected offspring [transmission disequilibrium test (TDT): narrow diagnosis likelihood ratio statistics (LRS) = 6.63, P = 0.006; broad diagnosis LRS = 4.47, P = 0.05]. Interestingly, gender-based investigations showed significant transmission of C allele to the affected females [TDT: LRS = 7.36, P = 0.0025; haplotype-based haplotype relative risk (HHRR): LRS = 7.16, P = 0.02]. A maternal overtransmission for these alleles was also noted (TDT: LRS = 3.65, P = 0.036; HHRR: LRS = 2.81, P = 0.036). Bioinformatic analysis using TFSearch showed generation of Sp1 binding site in the presence of C allele. While Del-T haplotype formed from rs34808376-rs1861973 markers showed increased non-transmission, the Ins-C showed significant transmission suggesting protective effect and risk, respectively, conferred by these haplotypes in autism etiology. These results suggest positive genetic correlation of EN2 with autism in the Indian population.

Association of matrix metalloproteinase 9 genotypes and cardiovascular disease risk factors with serum matrix metalloproteinase 9 concentrations in Taiwanese individuals

Circulating concentrations of matrix metalloproteinase 9 (MMP-9) are associated with cardiovascular disease mortality in patients with coronary artery disease. We investigated the determinants of MMP-9 concentrations by analyzing MMP-9 genotypes and risk factors for cardiovascular disease. A total of 596 individuals were recruited for this study. Six single nucleotide polymorphisms (SNP) with coverage of the MMP-9 gene region were analyzed; and two genotypes, rs3918242-TT and rs2274756-AA, which were in nearly complete linkage disequilibrium, were associated with higher MMP-9 values (p=0.007 and p=0.008, respectively). In age- and gender-adjusted regression models, MMP-9 concentrations were positively associated with the homeostasis model assessment of insulin resistance (HOMA-IR) index and triglyceride concentrations, fasting serum insulin, fasting plasma glucose, C-reactive protein, fibrinogen, and serum amyloid A. By multivariate analysis, rs2274756 genotypes, age, smoking status, fibrinogen and fasting plasma glucose concentrations were all independently associated with MMP-9 (p=0.007, p=0.033, p=0.003, p=0.013, and p=0.012, respectively). The rs2274756-AA and rs3918242-TT genotypes, younger age, current smoking status and increased fasting plasma glucose, and fibrinogen concentrations were independently associated with high serum MMP-9 concentrations in Taiwanese individuals.

Genetic association of physically unlinked islands of genomic divergence in incipient species of Anopheles gambiae

Previous efforts to uncover the genetic underpinnings of ongoing ecological speciation of the M and S forms of the African malaria vector Anopheles gambiae revealed two centromere-proximal islands of genetic divergence on X and chromosome 2. Under the assumption of considerable ongoing gene flow between M and S, these persistently divergent genomic islands were widely considered to be 'speciation islands'. In the course of microarray-based divergence mapping, we discovered a third centromere-associated island of divergence on chromosome 3, which was validated by targeted re-sequencing. To test for genetic association between the divergence islands on all three chromosomes, SNP-based assays were applied in four natural populations of M and S spanning West, Central and East Africa. Genotyping of 517 female M and S mosquitoes revealed nearly complete linkage disequilibrium between the centromeres of the three independently assorting chromosomes. These results suggest that despite the potential for inter-form gene flow through hybridization, actual (realized) gene flow between M and S may be substantially less than commonly assumed and may not explain most shared variation. Moreover, the possibility of very low gene flow calls into question whether diverged pericentromeric regions-characterized by reduced levels of variation and recombination-are in fact instrumental rather than merely incidental to the speciation process.

Is rs34861192 or rs1862513 a more promising variant for determining plasma resistin in an aged Japanese population?

Is rs34861192 or rs1862513 a more promising variant for determining plasma resistin in an aged Japanese population?