A Systems Genetics Approach Provides a Bridge from Discovered Genetic Variants to Biological Pathways in Rheumatoid Arthritis

Genome-wide association studies (GWAS) have yielded novel genetic loci underlying common diseases. We propose a systems genetics approach to utilize these discoveries for better understanding of the genetic architecture of rheumatoid arthritis (RA). Current evidence of genetic associations with RA was sought through PubMed and the NHGRI GWAS catalog. The associations of 15 single nucleotide polymorphisms and HLA-DRB1 alleles were confirmed in 1,287 cases and 1,500 controls of Japanese subjects. Among these, HLA-DRB1 alleles and eight SNPs showed significant associations and all but one of the variants had the same direction of effect as identified in the previous studies, indicating that the genetic risk factors underlying RA are shared across populations. By receiver operating characteristic curve analysis, the area under the curve (AUC) for the genetic risk score based on the selected variants was 68.4%. For seropositive RA patients only, the AUC improved to 70.9%, indicating good but suboptimal predictive ability. A simulation study shows that more than 200 additional loci with similar effect size as recent GWAS findings or 20 rare variants with intermediate effects are needed to achieve AUC = 80.0%. We performed the random walk with restart (RWR) algorithm to prioritize genes for future mapping studies. The performance of the algorithm was confirmed by leave-one-out cross-validation. The RWR algorithm pointed to ZAP70 in the first rank, in which mutation causes RA-like autoimmune arthritis in mice. By applying the hierarchical clustering method to a subnetwork comprising RA-associated genes and top-ranked genes by the RWR, we found three functional modules relevant to RA etiology: “leukocyte activation and differentiation”, “pattern-recognition receptor signaling pathway”, and “chemokines and their receptors”

HLA-DPB1*04:01 allele is associated with non-obstructive azoospermia in Japanese patients

Azoospermia is defined by absence of sperm in the semen and can either be caused by obstruction of the seminal tract (obstructive azoospermia) or by defects in spermatogenesis (non-obstructive azoospermia, NOA). Previous studies reported that specific alleles and single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region were associated with NOA in East Asians. We attempt to expand upon previous findings by genotyping more HLA genes and to replicate SNP associations by focusing on Japanese NOA patients. HLA typing of six genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) was done on 355 NOA patients using SSO-Luminex assay while genotyping of two previously reported SNPs (rs498422 and rs3129878) was done on 443 patients and 544 fertile males using TaqMan assay. Association was assessed with Chi squared and logistic regression tests. We found that HLA-DPB1*04:01 [corrected p value, Pc 7.13 9 10-6 ; odds ratio (OR) 2.52], DRB1*13:02 (Pc 4.93 9 10-4 , OR 1.97), DQB1*06:04 (Pc 8.94 9 10-4 , OR 1.91) and rs3129878 (p value 3.98 9 10-4 ; OR 1.32) showed significant association with NOA, however, these loci are in linkage disequilibrium with each other. The conditional logistic regression tests showed that DPB1*04:01 is independently associated with NOA, confirming the involvement of the HLA region in the etiology of NOA in Japanese patients

口臭と胃内ヘリコバクタピロリ感染との関連

口臭の原因は,ほとんどが口腔内の舌苔や歯周病に起因し,その主な原因ガスは揮発性硫黄化合物(VSCs)だと言われている.胃内ヘリコバクタピロリ感染も口臭の一因であるとする報告がなされたが,VSCsを定性・定量的に測定した研究はない.この研究の目的は,胃内ヘリコバクタピロリ感染の陽性者群と陰性者群の口臭と舌苔臭を官能試験およびガスクロマトグラフィによるVSCsの測定を用いて比較することである.また,両群の背景因子として,年齢,性別,口臭に関連すると考えられる口腔内パラメーター(歯垢指数,歯肉炎指数,4mm以上の歯周ポケット数,出血歯周ポケット数,視診による舌苔スコア,舌苔重量)を検討した.80名の患者のうち,胃内ヘリコバクタピロリ感染の陽性者は31名(平均44.7歳)で,陰性者は49名(平均33.8歳)であった.年齢は陽性者の方が有意に高かったが,性別比や口腔内パラメーターなどの背景因子には差を認めなかった.口臭の官能試験では,息をとめた状態の口臭に有意差を認め(オッズ比:2.76,95%信頼区間:1.78～3.74),胃内ヘリコバクタピロリ感染の陽性者の方が陰性者に比較して口臭は臭いことが確認された.しかし,息を吐いた状態の口臭および舌苔臭には両群間に差を認めなかった.ガスクロマトグラフイによるVSCsの測定では,メチルメルカプタンに差を認めなかったが,硫化水素とジメチルサルファイドに有意差(p<0.05)を認めた.今後,胃内ヘリコバクタピロリ感染と口臭との関連について,さらに検討が必要である.The aim of the present study was to assess whether oral odour and tongue coating odour in the gastric Helicobacter pylori (H. pylori) positive patients are more severe organoleptically than those of the negative patients. Moreover, this is the first study of halitosis on H. pylori in which qualitative-quantitative measurements were made by gas chromatography (GC). In addition, the backgrounds (age, gender, oral periodontal parameters and tongue coating) were compared between the 31 H. pylori positive and 49 negative patients. The H. pylori positive group was significantly older than the H. pylori negative group. There were no significant differences in gender, periodontal parameters or visual tongue coating assessment between the two groups. The oral odour assessed with patient holding breath by organoleptic measurement, the gastric H. pylori positive patients was more severe than that of the negative patients (Odds ratio: 2.76, 95% CI: 1.78 to 3.74). There were no significant differences in oral odour assessed with patient exhaling breath and tongue coating odour. The levels of H_2S and (CH_3)_2S but not CH_3SH, in oral air measured by GC were significantly higher in the H. pylori positive patients than in the negative patients (p<0.05). Further research confirming the relation between gastric H. pylori infection and halitosis is needed

口臭と胃内ヘリコバクタピロリ感染との関連

口臭の原因は,ほとんどが口腔内の舌苔や歯周病に起因し,その主な原因ガスは揮発性硫黄化合物(VSCs)だと言われている.胃内ヘリコバクタピロリ感染も口臭の一因であるとする報告がなされたが,VSCsを定性・定量的に測定した研究はない.この研究の目的は,胃内ヘリコバクタピロリ感染の陽性者群と陰性者群の口臭と舌苔臭を官能試験およびガスクロマトグラフィによるVSCsの測定を用いて比較することである.また,両群の背景因子として,年齢,性別,口臭に関連すると考えられる口腔内パラメーター(歯垢指数,歯肉炎指数,4mm以上の歯周ポケット数,出血歯周ポケット数,視診による舌苔スコア,舌苔重量)を検討した.80名の患者のうち,胃内ヘリコバクタピロリ感染の陽性者は31名(平均44.7歳)で,陰性者は49名(平均33.8歳)であった.年齢は陽性者の方が有意に高かったが,性別比や口腔内パラメーターなどの背景因子には差を認めなかった.口臭の官能試験では,息をとめた状態の口臭に有意差を認め(オッズ比:2.76,95%信頼区間:1.78～3.74),胃内ヘリコバクタピロリ感染の陽性者の方が陰性者に比較して口臭は臭いことが確認された.しかし,息を吐いた状態の口臭および舌苔臭には両群間に差を認めなかった.ガスクロマトグラフイによるVSCsの測定では,メチルメルカプタンに差を認めなかったが,硫化水素とジメチルサルファイドに有意差(p<0.05)を認めた.今後,胃内ヘリコバクタピロリ感染と口臭との関連について,さらに検討が必要である.The aim of the present study was to assess whether oral odour and tongue coating odour in the gastric Helicobacter pylori (H. pylori) positive patients are more severe organoleptically than those of the negative patients. Moreover, this is the first study of halitosis on H. pylori in which qualitative-quantitative measurements were made by gas chromatography (GC). In addition, the backgrounds (age, gender, oral periodontal parameters and tongue coating) were compared between the 31 H. pylori positive and 49 negative patients. The H. pylori positive group was significantly older than the H. pylori negative group. There were no significant differences in gender, periodontal parameters or visual tongue coating assessment between the two groups. The oral odour assessed with patient holding breath by organoleptic measurement, the gastric H. pylori positive patients was more severe than that of the negative patients (Odds ratio: 2.76, 95% CI: 1.78 to 3.74). There were no significant differences in oral odour assessed with patient exhaling breath and tongue coating odour. The levels of H_2S and (CH_3)_2S but not CH_3SH, in oral air measured by GC were significantly higher in the H. pylori positive patients than in the negative patients (p<0.05). Further research confirming the relation between gastric H. pylori infection and halitosis is needed