The ITGAV rs3738919 variant and susceptibility to rheumatoid arthritis in four Caucasian sample sets

INTRODUCTION: Angiogenesis is an important process in the development of destructive synovial pannus in rheumatoid arthritis (RA). The ITGAV +gene encodes a cell cycle-associated antigen, integrin alphanubeta 3, which plays a role in RA angiogenesis. Previously, two independent studies identified an association between the major allele of the ITGAV single-nucleotide polymorphism (SNP) rs3738919 and RA. We therefore tested this association in an independent study using New Zealand (NZ) and Oxford (UK) RA case control samples. METHODS: We compared genotype frequencies in 740 NZ Caucasian RA patients and 553 controls genotyped for rs3738919, using a polymerase chain reaction-restriction fragment length polymorphism assay. A TaqMan genotyping SNP assay was used to type 713 Caucasian RA patients and 515 control samples from Oxford for the rs3738919 variant. Association of rs3738919 with RA was tested in these two sample sets using the chi-square goodness-of-fit test. The Mantel-Haenszel test was used to perform a meta-analysis, combining the genetic results from four independent Caucasian case control cohorts, consisting of 3,527 cases and 4,126 controls. Haplotype analysis was also performed using SNPs rs3911238, rs10174098 and rs3738919 in the Wellcome Trust Case Control Consortium, NZ and Oxford case control samples. RESULTS: We found no evidence for association between ITGAV and RA in either the NZ or Oxford sample set (odds ratio [OR] = 0.88, P(allelic) = 0.11 and OR = 1.18, P(allelic) = 0.07, respectively). Inclusion of these data in a meta-analysis (random effects) of four independent cohorts (3,527 cases and 4,126 controls) weakens support for the hypothesis that rs3738919 plays a role in the development of RA (OR(combined) = 0.92, 95% confidence interval 0.80 to 1.07; P = 0.29). No consistent haplotype associations were evident. CONCLUSIONS: Association of ITGAV SNP rs7378919 with RA was not replicated in NZ or Oxford case control sample sets. Meta-analysis of these and previously published data lends limited support for a role for the ITGAV in RA in Caucasians of European ancestry

The PTPN22 Locus and Rheumatoid Arthritis: No Evidence for an Effect on Risk Independent of Arg620Trp

The Trp(620) allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype '5', haplotype group '6-10' and susceptibility haplotype '4', suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility.A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used.The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR = 0.85, P = 1.4×10(-5)). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85).We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant

The Oxytocin Receptor Gene (OXTR) Variant rs53576 Is Not Related to Emotional Traits or States in Young Adults

Background: To understand the genetic underpinnings of emotion, researchers have studied genetic variants in the oxytocin system, a hormone and neurotransmitter important to socio-emotional functioning. The oxytocin receptor gene (OXTR) variant rs53576 has been associated with emotional traits such as positive affect and related constructs such as optimism and self-esteem. Individuals carrying the A allele (AG and AA genotypes) of rs53576 have been found to score lower in these traits when compared to GG homozygotes, although not always. Given recent mixed evidence regarding this polymorphism, replication of these associations is critical.Methods: Using a cross-sectional design, the present study tested the association between rs53576 and a wide variety of emotional traits and states in a sample of 611 young adults ages 18 – 25 of various ethnicities (European, Asian, Māori/Pacific Islander, other). Participants completed standard trait measures of positive and negative affect, depressive symptoms, life engagement, psychological well-being, optimism, and self-esteem. They also completed state measures of positive and negative affect and life engagement for 13-days using Internet daily diaries.Results: Controlling for ethnicity and gender, variation at the OXTR variant rs53576 obtained from blood samples was not related to any of the emotional traits or states. This null finding occurred despite measuring emotions in “near to real time” using daily diaries and having sufficient power to detect a medium effect size difference between homozygous genotype groups.Conclusion: These findings suggest that variation at the rs53576 locus may not be as involved in emotional differences as initial studies suggested

A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation

A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation

Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips

The Brassica napus 60K Illumina Infinium™ SNP array has had huge international uptake in the rapeseed community due to the revolutionary speed of acquisition and ease of analysis of this high-throughput genotyping data, particularly when coupled with the newly available reference genome sequence. However, further utilization of this valuable resource can be optimized by better understanding the promises and pitfalls of SNP arrays. We outline how best to analyze Brassica SNP marker array data for diverse applications, including linkage and association mapping, genetic diversity and genomic introgression studies. We present data on which SNPs are locus-specific in winter, semi-winter and spring B. napus germplasm pools, rather than amplifying both an A-genome and a C-genome locus or multiple loci. Common issues that arise when analyzing array data will be discussed, particularly those unique to SNP markers and how to deal with these for practical applications in Brassica breeding applications

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Investigation of linkage of chromosome 8 to type 1 diabetes: multipoint analysis and exclusion mapping of human chromosome 8 in 593 affected sib- pair families from the UK and US

Type 1 diabetes is a common multifactorial disease that is strongly clustered in families: the sibling risk-to-population prevalence ratio (λs) is 15 (6%/0.4%). Two loci, IDDM1 in the major histocompatibility complex (MHC) on chromosome 6p21 and IDDM2 in the insulin gene (INS) region of chromosome 11p15.5 can account for similar to 50% of the observed familial clustering(1). Locus-specific λs values (1) in 356 U.K. affected sib-pair families (2) for IDDM1 and IDDM2 are 3.0 and 1.3, respectively, or 41 and 8%, assuming a multiplicative model (J.A.T., unpublished observations). The rapid reduction in risk from first- to second- to third-degree relatives of type 1 diabetic patients (3) and whole genome scanning of a spontaneous mouse model of autoimmune type 1 diabetes (4,5) suggest that other genes may account for the rest of the familial clustering (1,4,5). In humans, two genome-wide scans, both based on the analysis of affected sib pairs, have been published so far (6,7), with the larger scan evaluating 290 markers in 96 U.K. families (data were analyzed in 93 of these families, so henceforth, this scan will be referred to as the 93 U.K. family scan) (6). The main conclusions of these studies were that the presence elsewhere in the genome of a second gene with an effect similar to IDDM1 (λs) = 3) is unlikely, and that other genes with λs < 3 are involved. Subsequently, additional evidence for linkage to some of these and other regions has been reported (8-10)