A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations.

Rheumatoid arthritis (RA) is a common systemic autoimmune disease and its onset and prognosis are controlled by genetic, immunological, and environmental factors. The HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. However, they cover only a part of its genetic components and their relative contribution is different between populations. To identify novel genetic determinants, we took a candidate gene approach in a trans-ethnic manner. After critical selection of 169 genes based on their immunological function, we performed SNP discovery of these genes by the resequencing of exons and surrounding areas using European and Japanese DNAs. We then generated a panel of 1,509 SNPs for case-control association study in both populations. The DerSimonian-Laird test for meta-analysis, using the combined results of the two populations, identified rs7551957 at the 5'-flanking region of the low-affinity Fc-gamma receptor IIa (FCGR2A) gene as the strongest candidate for the association (p = 8.6 × 10(-5), odds ratio = 1.58 with 95%CI 1.25-1.99). Suggestive signals were also obtained for three SNPs in the dihydropyrimidine dehydrogenase (DPYD) gene (rs6685859; p = 1.3 × 10(-4), rs7550959; p = 1.5 × 10(-4) and rs7531138; p = 1.7 × 10(-4)) and an intronic SNP, rs2269310, of the erythrocytic spectrin beta (SPTB) gene (p = 7.9 × 10(-4)).

A polymorphism of the POLG2 gene is genetically associated with the invasiveness of urinary bladder cancer in Japanese males.

Urinary bladder cancer (UBC) is a common cancer with male predominance. Pathologically it is classified into two distinct tumor entities related to the risk of patients. The low-grade tumors with relatively well-differentiated tumor histology (G1 and G2) at stage Ta are non-invasive and pose a minimal risk, whereas high-grade tumors (G2 and G3) with stages T1 to T4 are aggressive with invasion, and therefore, pose a serious risk for the patients. DNA repair and metabolic process genes may have major roles in cancer progression and development. To identify genes associated with invasiveness of UBC, we have extensively genotyped 802 single nucleotide polymorphisms in 114 genes related to DNA repair mechanisms and metabolic processes. A genetic association study was performed between non-invasive (G1 and G2 with Ta) and invasive (G2 and G3 with T1 to T4) groups of Japanese UBC patients. We found that rs17650301 in POLG2 showed marked difference in genotype distribution between the two groups in males (P=6.93 × 10(-4)), which was further confirmed in an independent sample set (overall P=1.67 × 10(-4)). We also found by an in silico analysis that the risk allele of rs17650301 increased the transcription of POLG2. In conclusion, rs17650301 is a good candidate marker for UBC invasiveness in Japanese males.

The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.

Papillary thyroid cancer (PTC) among individuals exposed to radioactive iodine in their childhood or adolescence is a major internationally recognized health consequence of the Chernobyl accident. To identify genetic determinants affecting individual susceptibility to radiation-related PTC, we conducted a genome-wide association study employing Belarusian patients with PTC aged 0-18 years at the time of accident and age-matched Belarusian control subjects. Two series of genome scans were performed using independent sample sets, and association with radiation-related PTC was evaluated. Meta-analysis by the Mantel-Haenszel method combining the two studies identified four SNPs at chromosome 9q22.33 showing significant associations with the disease (Mantel-Haenszel P: mhp = 1.7 x 10(-9) to 4.9 x 10(-9)). The association was further reinforced by a validation analysis using one of these SNP markers, rs965513, with a new set of samples (overall mhp = 4.8 x 10(-12), OR = 1.65, 95% CI: 1.43-1.91). Rs965513 is located 57-kb upstream to FOXE1, a thyroid-specific transcription factor with pivotal roles in thyroid morphogenesis and was recently reported as the strongest genetic risk marker of sporadic PTC in European populations. Of interest, no association was obtained between radiation-related PTC and rs944289 (mhp = 0.17) at 14p13.3 which showed the second strongest association with sporadic PTC in Europeans. These results show that the complex pathway underlying the pathogenesis may be partly shared by the two etiological forms of PTC, but their genetic components do not completely overlap each other, suggesting the presence of other unknown etiology-specific genetic determinants in radiation-related PTC.