Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B. Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10−3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10−5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

Pewarisan Karakter Kualitatif dan Kuantitatif pada Hipokotil dan Kotiledon Tomat (Solanum lycopersicum L.) Silangan IPB T64 x IPB T3

<p>ABSTRACT<br />Hypocotyl and cotyledon are potentially used as effective morphological markers since they can be detected earlier. Information on inheritance of tomato hypocotyl and cotyledon was not available. The aims of this research was to study the inheritance of qualitative and quantitative characters of tomato hypocotyl and cotyledon. This research used six population, P1 green hypocotyl (IPB T64), P2 purple hypocotyl (IPB T3), F1, F1R, BCP1, BCP2, and F2. Analysis of qualitative characters used Mendelian and gene action of quantitative characters used joint scaling test. The results of Mendelian indicated that the character of hypocotyl color was controlled by two genes of dominant-recessive epistasis. The gene controlling purple color was dominant to the green color gene. Based on the F2 distribution test, hypocotyl length, cotyledon length and width were controlled by polygenes. There was no influence of maternal effect. The results of the joint scaling test showed gene action of hypocotyl length was controlled by additive gene with influence of additive-dominant epistasis. Length and width of the cotyledon were controlled by additive gene and influence of duplicate epistasis effect. All characters had high level of broad sense heritability and medium level of narrow sense heritability.<br />Keywords: cotyledone, gene action, heritability, hypocotyle, morphology marker.</p><p>ABSTRAK<br />Hipokotil dan kotiledon berpotensi untuk dijadikan sebagai marka morfologi yang efektif karena dapat dideteksi lebih dini. Informasi pola pewarisan karakter hipokotil dan kotiledon tomat belum banyak tersedia. Penelitian ini bertujuan untuk mempelajari pola pewarisan karakter kualitatif dan kuantitatif dari hipokotil dan kotiledon tomat sebagai marka morfologi pada tahap awal pertumbuhan tanaman. Penelitian ini menggunakan enam set populasi yaitu P1 hipokotil hijau (IPB T64), P2 hipokoti ungu (IPB T3), F1, F1R, BCP1, BCP2, dan F2. Karakter kualitatif menggunakan analisis Mendel dan pendugaan aksi gen karakter kuantitatif menggunakan analisis skala gabungan. Hasil analisis Mendel menunjukkan bahwa karakter warna hipokotil dikendalikan oleh dua pasang gen epistasis dominan-resesif. Gen pengendali warna ungu bersifat dominan terhadap warna hijau pada hipokotil tomat. Panjang hipokotil, panjang dan lebar kotiledon dikendalikan oleh banyak gen dan tidak ada pengaruh tetua betina berdasarkan uji sebaran populai F2. Hasil analisis skala gabungan menunjukkan bahwa aksi gen karakter panjang hipokotil dikendalikan oleh gen aditif dengan pengaruh epistasis aditif dominan, panjang dan lebar kotiledon dikendalikan oleh gen dominan dengan pengaruh epistasis duplikat. Semua karakter yang diamati memiliki nilai heritabilitas arti luas dalam tingkatan yang tinggi, sedangkan heritabilitas arti sempit dalam tingkatan yang sedang.<br />Kata kunci: aksi gen, heritabilitas, hipikotil, kotiledon, marka morfologi.</p>

Detection of SNP epistasis effects of quantitative traits using an extended Kempthorne model

Epistasis effects (gene interactions) have been increasingly recognized as important genetic factors underlying complex traits. The existence of a large number of single nucleotide polymorphisms (SNPs) provides opportunities and challenges to screen DNA variations affecting complex traits using a candidate gene analysis. In this article, four types of epistasis effects of two candidate gene SNPs with Hardy-Weinberg disequilibrium (HWD) and linkage disequilibrium (LD) are considered: additive × additive, additive × dominance, dominance × additive, and dominance × dominance. The Kempthorne genetic model was chosen for its appealing genetic interpretations of the epistasis effects. The method in this study consists of extension of Kempthorne's definitions of 35 individual genetic effects to allow HWD and LD, genetic contrasts of the 35 extended individual genetic effects to define the 4 epistasis effects, and a linear model method for testing epistasis effects. Formulas to predict statistical power (as a function of contrast heritability, sample size, and type I error) and sample size (as a function of contrast heritability, type I error, and type II error) for detecting each epistasis effect were derived, and the theoretical predictions agreed well with simulation studies. The accuracy in estimating each epistasis effect and rates of false positives in the absence of all or three epistasis effects were evaluated using simulations. The method for epistasis testing can be a useful tool to understand the exact mode of epistasis, to assemble genome-wide SNPs into an epistasis network, and to assemble all SNP effects affecting a phenotype using pairwise epistasis tests.