Setsuya Naito

Haplotype study on C4 polymorphism in Japanese. Associations with MIHC Alleles, complotypes, and HLA-complement haplotypes

Genetic polymorphism of the fourth component of human complement (C4) was investigated in 83 Japanese families which have been typed for HLA-A, -B, -C, -DR, C2, and BF. Four common C4A alleles and four common C4B alleles were observed. The allele frequencies estimated from unrelated parents were as follows: C4A3, 0.686; A4, 0.132; A2, 0.106; AQ0, 0.067; ARares, 0.009; C4B1, 0.587; B2, 0.167; B5, 0.088; and BQ0, 0.158. Eight different C4 haplotypes were observed with frequencies of more than 0.01. The estimated haplotype frequencies were as follows: C4A3-B1, 0.513; A4-B2, 0.114; A2-BQ0, 0.106; A3-B5, 0.088; AQ0-B1, 0.059; A3-BQ0, 0.047; A3-B2,0.038; A4-B1, 0.015; and Rares, 0.021. Strong positive gametic associations were found in the following C4-HLA haplotypes: C4A2BQ0-A24, C4A2BQ0-Bw52, C4A3B5-Bw54, C4A3B5-Bw59, C4A4B2-Bw46, C4A3B5-Cw1, C4A2BQ0-DR2, and C4A3B5-DR4. Eleven complotypes were observed with frequencies of more than 0.01. C4A2BQ0 and C4A3B5 were exclusively associated with BFS-C2C. BFF was associated with C4A3B1, C2AT, C2B, and C2BH were associated with C4A3B1, A4B2, and C4A3B1, respectively. Eight different HLA-complement haplotypes were found to be characteristic of Japanese. These combinations are considerably different from those reported in Caucasoid populations.

Glomerulonephritis in Diabetic Patients and Its Effect on the Prognosis

Renal biopsies were obtained from 164 patients with diabetes mellitus. Their histological changes were evaluated together with clinical findings and prognosis. In 36 patients, various types of glomerulonephritis were complicated: mesangial proliferative glomerulonephritis (17 patients), membranous glomerulonephritis (8), endocapillary proliferative glomerulonephritis (5), membranoproliferative glomerulonephritis (4) and minimal change nephrotic syndrome (2). Superimposed glomerulonephritis was suspected in diabetic patients with a short history of less than 5 years, persistent proteinuria, occasional hematuria and no retinopathy. They may, however, produce little effects on the long-term prognosis of diabetic patients except membranoproliferative glomerulonephritis.

Lipoprotein and apolipoprotein losses during continuous ambulatory peritoneal dialysis.

The daily loss of apolipoproteins into the dialysate from 5 patients on continuous ambulatory peritoneal dialysis (CAPD) was measured. The mean excretion of apolipoprotein (apo) AI and apo AII, major proteins of high-density lipoproteins (HDL), were 84 and 17 mg/day, respectively, while that of apo B, a major protein of low-density lipoproteins (LDL) was 39 mg/day. The peritoneal clearance of apo AI and apo AII were similar; both being significantly greater than that of apo B. The fractional catabolic rates of various proteins found in the CAPD dialysate showed molecular sieving effects of the peritoneal membrane and indicated that the apolipoproteins were excreted as lipoproteins. These findings suggest that there is continuous and selective loss of HDL compared to LDL which may also indicate an increased predisposition of these patients to atherosclerosis.

Serum Lipoprotein (a) Levels in Maintenance Hemodialysis Patients

To further understand lipoprotein (a) [Lp(a)] and atherosclerosis, we measured serum Lp(a), lipoprotein, and apolipoprotein levels in 55 patients (males, 24-73 years old) on maintenance hemodialysis, and compared them with those of 82 controls (males, 21-81 years old). The serum Lp(a) levels in patients on maintenance hemodialysis were significantly higher than those of the normal controls, while serum total cholesterol (TC), high-density lipoprotein-cholesterol, (HDL-C), HDL2-C, HDL3-C, apolipoprotein (apo) Al, apo All levels, and lecithin-cholesterol acyltransferase (LCAT) activities were significantly (p < 0.05) reduced in the patient group. The frequency distribution of serum Lp(a) levels in the patients was different from that in the control group, and no prognostic tendency of serum Lp(a) levels was noted by the etiology of renal failure as histologically determined by the renal biopsies. In the patient group, we also found that serum Lp(a) levels negatively correlated with serum triglycerides (TG) and total protein (TP) concentrations (p < 0.05), but no correlation was found between the duration of hemodialysis therapy or patient age and the serum levels of TC, TG, apo B and Lp(a) levels when tested for simple regression. Significant (p < 0.05) positive correlations were also found between TP and serum TG, apo B, and LCAT activities. These opposing tendencies of Lp(a) and serum TG, apo B, when measured against TP concentrations, indicate that serum TP levels may not affect serum lipoprotein and Lp(a) levels in the same direction. These data suggest that hemodialysis or end-stage renal disease itself, rather than hypoproteinemia, may hold the key to high serum Lp(a) levels in hemodialysis patients.

Evaluation and correlation of clinical and histological features of focal segmental glomerulosclerosis.

Clinico-histological features in 32 patients with nephrotic syndrome (NS) due to focal segmental glomerulosclerosis (FSGS) were examined. Thirteen (group A1) were diagnosed as cases of FSGS within 2 years of the onset of NS, and 8 (61%) showed progressive renal dysfunction. Ten (group A2) developed FSGS more than 2 years after the onset of NS and had a favorable prognosis. Nine (group B) differed from groups A1 and A2 in that the remaining nonsclerosed glomeruli showed slight mesangial proliferation. All but 1 patient of group B developed FSGS within 2 years of the onset of NS, and the prognosis was poor. No patient studied showed a transition between groups A and B. In some patients, lipoid nephrosis preceded FSGS, in group A2. Thus, for an accurate prediction of the prognosis, FSGS should be divided into three subclasses, based on clinico-histological features.

An HLA study on 149 Japanese patients with Crohn’s disease

SummaryTo search for possible immunogenetic roles in the pathogenesis of Crohn’s disease, we examined the HLA-A, -B, -C, -DR and -DQ locus antigens in 149 Japanese patients with Crohn’s disease. All patients were living on Kyushu island. We also examined the HLA of 136 healthy controls who resided in Kyushu. The results were compared with both controls throughout Japan and Kyushu controls. In Japanese patients with Crohn’s disease, HLA-DR4, especially -DR4.1, and -DQ4 were more frequent than in the controls throughout Japan and in Kyushu. In light of these observations, an immunogenetic factor may have some role in the development of Crohn’s disease. The susceptibility to Crohn’s disease may relate to HLA-DR4, especially -DR4.1, and -DQ4, in Japanese patients.

Association of Class II Antigens of HLA with Primary Glomerulopathies

HLA antigens of Japanese patients with primary glomerulopathies were determined, and the frequency of each HLA antigen was compared with that of Japanese normal controls. IgA nephropathy with HLA-DR4, idiopathic membraneous glomerulopathy with DR2, lipoid nephrosis with DRw53 and poststreptococcal glomerulonephritis with DR1 were definitely or probably associated. It was suggested that primary glomerulopathies might all be associated with HLA class II and not class I antigens. Japanese patients with HLA-Bw48 and -DRw8 were less susceptible to primary glomerulopathies.

The infantile form of sialidosis type II associated with congenital adrenal hyperplasia: Possible linkage between HLA and the neuraminidase deficiency gene

SummaryThe possible genetic linkage between HLA and neuraminidase deficiency was studied in a female patient with combined abnormalities of the infantile form of sialidosis type II and congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, and six members of her family. Her parents were consanguineous. The patient has the homozygous HLA haplotypes, TS-1, Cw3, DRw9. Four of the tested family members, including a distant male relative with congenital adrenal hyperplasia, were heterozygous of this HLA complex, and the neuraminidase activities in their skin fibroblasts and/or lymphocytes showed values between those of the patient and controls (25–48%), suggesting a carrier state of sialidosis. This indicates that the neuraminidase deficiency gene, similar to the 21-hydroxylase deficiency gene, is closely linked to the HLA genotype and is located on chromosome 6.

Association of DQB1*0302 Alloantigens in Japanese Pediatric Patients with Steroid-Sensitive Nephrotic Syndrome

We identified human leukocyte alloantigens (HLA) class II alleles in 24 Japanese children with steroid-sensitive nephrotic syndrome (SSNS) by deoxyribonucleic acid (DNA) typing. The DQA1 and DQB1 alleles were identified using sequence-specific oligonucleotide probes for DQA and DQB. The frequency of DQB1*0302 was significantly higher in the patients than in the controls (54.0 vs. 16.0%, respectively; relative risk, RR = 6.2; pc < 0.00009. We also found that the frequency of DQA1*0103 in the patients was significantly lower than in the controls (RR = 0.194, pc < 0.04). Several studies have identified an association between certain HLA by serotyping. In the present study, we investigated the HLAs of Japanese patients with SSNS by DNA typing and observed a significant increase in the frequency of DQB1*0302 in patients with the disease. HLA-DQ3, which was proven to be associated with SSNS, consists of HLA DQ7, 8 and 9. DQB1*0302 is a component of HLA-DQ8. So we proposed the increase of DQ3 was due to an increase in DQ8.

Role of HLA in IgA nephropathy

Abstract One hundred and four Japanese patients with IgA nephropathy were typed for HLA-A, HLA-B, and HLA-C antigens, and 75 of them were tested for HLA-D region antigens. A significant association was found only with HLA-DR4 (corrected P