Interleukin-6 (IL6) has come to be regarded as a potential osteoporotic factor because it has stimulatory effects on cells of the osteoclast lineage, and, thus, may play a role in the pathogenesis of bone loss associated with estrogen deficiency. We previously described association of the IL6 microsatellite with bone mineral density (BMD), as well as genetic linkage of the IL6 locus to human osteoporosis, by means of sib-pair analysis. However, the molecular mechanism by which this locus regulates BMD remains unknown. Accordingly, we searched for polymorphisms in the 5Ј and 3Ј flanking regions and in all five exons of the IL6 gene in a Japanese population sample. We identified three single-nucleotide sequence variations: a C/G substitution at nucleotide (nt) Ϫ634 in the promoter region, a G/A substitution at nt 4391 in the 3Ј noncoding region, and a variation in the AnTn tract around nt Ϫ447. The last of these had already been observed in Caucasians, as well as in Japanese. The single-nucleotide polymorphism at Ϫ634 created a restriction site for the BsrBI endonuclease, and the frequency of the minor (G) allele was 0.184. Five haplotypes were constructed among three variations examined in the population. Linkage disequilibrium was observed between the variation at Ϫ634 and the variation at 4391, as well as between the variation at Ϫ634 and the AnTn tract variation. We found a significant correlation, in 470 subjects, between the presence of the G allele and decreased BMD, by analysis of variance. When BMD values were compared among the three genotypic groups (G/G, G/C, C/C) at nt Ϫ634, BMD was lowest among the G/G homozygotes (mean Ϯ SD; 0.284 Ϯ 0.062 g/cm 2 ), highest among the C/C homozygotes (0.314 Ϯ 0.059 g/cm 2 ), and intermediate among the heterozygotes (0.303 Ϯ 0.066 g/cm 2 ; P Ͻ 0.05).Given the several lines of evidence from different genetic studies, we suggest that IL6 is, indeed, one of the genes affecting bone metabolism, in which variations can lead to osteoporosis.

Genes that can be implicated in hypertension in experimental animals are plausible candidates in the pathogenesis of human hypertension. A recent genome-wide search for quantitative-trait loci (QTL) in hypertensive rats revealed a strong correlation between the interleukin-6 (IL-6) locus on rat chromosome 4 and systolic, diastolic, and mean arterial pressure in this mammalian species. To investigate a possible association between genetic variations of the IL-6 gene and hypertension in humans, we identified two novel single-nucleotide sequence variations, a C/G substitution at −634 in the promoter region and a G/A substitution at 4391 in a 3 ′ non-coding portion of exon 5, and a previous reported sequence variant, an A/T variation in the composition of the A n T n tract around −447 in the promoter region ( Fishman D et al. J Clin Invest 1998; 102: 1369-1376, within a test population of 96 Japanese subjects. Allelic associations involving these variations were analyzed in 150 hypertensive and 143 normotensive Japanese women. The distribution of alleles of the three polymorphisms, as well as a dinucleotide repeat present at the IL-6 locus, was similar in the two groups. Therefore, the IL-6 gene appears to play a minimal role in the genetic etiology of essential hypertension in Japanese women.

A strong correlation between bone mass and genetic factors has been shown in twins and family studies. Some of the genes involved would regulate bone metabolism, bone formation, and resorption, all processes that determine bone mass. One candidate genes, calcium-sensing receptor (CASR) in the parathyroid gland, regulates calcium homeostasis by sensing decreases in extracellular calcium level and effecting an increase in secretion of parathyroid hormone (PTH) and calcium (Ca) reabsorption in the kidney. We have investigated a possible association between the CA-repeat polymorphism at the human CASR gene locus and the bone mineral density (BMD) of radial bone in 472 postmenopausal Japanese women. Genotypes were classified into nine groups according to the number of CA repeats present, from 20 to 12. BMD was expressed as the adjusted BMD, which was the body mass index (BMI), and age-adjusted average BMD. The 247 women who had an A3 allele (228 bp, containing 18 repeats of CA) had significantly lower adjusted BMD (mean +/- SD: 0.303 +/- 0.059 versus 0.316 +/- 0.063 g/cm(2); P = 0.0308) than the participants (n = 201) who did not carry an allele of that size. This result suggests that genetic variation at the CASR gene locus is associated with some determinants for BMD in postmenopausal women.

The transcriptional factor nuclear factor kappabeta (NFKB) consists of a multicomponent protein complex that plays a major role in the regulation of many viral and cellular genes. The NFKB complex has two alternative DNA binding subunits. We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the NFKB subunit 1 (NFKB1) gene located at 4q23-24. High heterozygosity (0.813) makes this polymorphism a useful marker in the genetic study of disorders affecting the immune response and cell differentiation.

Aldehyde dehydrogenase isoform 1 (ALDH1) is a useful marker of cancer-initiating cells (CICs) in various organs. In this study, we investigated whether alterations in ALDH1 immunostaining and enzymatic activity in tumor cell populations predicted clinicopathological factors of prognostic importance for cancer progression and contributed to the characteristics of CICs in cisplatin-treated oral squamous cell cancer (OSCC) cells. We evaluated the association between the proportion of ALDH1-positive tumor cells and the clinicopathological features in 90 patients with OSCC. We also examined ALDH1 enzymatic activity, ABCG2 expression, invasive capacity and the ability to self-renew in OSCC cells treated with or without cisplatin. The clinicopathological results showed that elevated ALDH1 expression correlated with local recurrence. In in vitro experiments, the percentage of cells exhibiting ALDH1 enzymatic activity significantly increased among cisplatin-surviving cells (CiSCs) according to flow cytometry. Furthermore, CiSCs demonstrated upregulated expression of ABCG2, their invasive capacity increased, and their ability to generate cancer spheres was enhanced. An increased population of cells exhibiting ALDH1 immunostaining is a predictive marker of local recurrence. ALDH1 expression and activity contributes to the characteristics of CICs in OSCC.

We identified a new common amino acid polymorphism of isoleucine/valine at codon 796 in exon 16 of the gene for human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), a central regulator of lipid synthesis and metabolism in animal cells. It can be detected as an MslI restriction fragment length polymorphism. The allelic frequencies were: isoleucine (A) allele, 0.57 and valine (G) allele, 0.43. This polymorphism may be useful for genetic studies of disorders affecting intracellular lipid metabolism and hyperlipidemia.

Although frequent bladder recurrence was observed in laparoscopic cases, the most important risk factor was the longer operation time. Technical improvements including shortening of operation time and earlier ureteral ligation may decrease the bladder recurrence.

Osteoporosis, a condition characterized by low bone mineral density (BMD) leading to bone fragility [1], is a major public health concern in Japan as well as in other countries. Although genetic predisposition seems to be a factor in the pathogenesis of osteoporosis [2-4], the precise cohort of genes that may be involved is not well defined. The COLIA1 and COLIA2 genes encode polypeptide constituents of collagen type Ialpha1 and Ialpha2, respectively. Both are important candidates as genetic regulators of BMD, since mutations in either gene result in osteogenesis imperfecta, a disorder characterized by severe osteoporosis [5]. Some patients with adult osteoporosis also carry mutations in COLIA1 or COLIA2 genes [6].http://link.springer-ny. com/link/service/journals/00223/bibs/65n5p352.html