Role of human leukocyte antigen DRB1*0307 and DRB1*0308 in susceptibility to juvenile rheumatoid arthritis.

OBJECTIVE: To study the prevalence of Human Leukocyte Antigen (HLA) DR alleles in children with juvenile rheumatoid arthritis (JRA). METHODS: DNA samples from 64 children with oligoarticular and seronegative polyarticular JRA and 64 controls of the same ethnic background were analyzed using PCR-sequence specific primers (PCR-SSP) method. Analysis took into account the onset subtype, the presence of antinuclear antibodies (ANA) and the presence of chronic anterior uveitis, a recognised serious complication of JRA. RESULTS: A high prevalence of DR3 alleles were detected in children with oligoarticular JRA compared to controls (p < 0.05). DR3 alleles were the commonest also in patients with positive ANA as well as those with chronic anterior uveitis. The interesting finding in this study is the absence of two DR3 alleles, namely DRB1*0307 and DRB1 *0308 in the control group while present in significant proportion in children with JRA. DRB1*0307 was present in 16% of children with oligoarticular subtype and 15% of those with polyarticular JRA. DRB1*0308 was only detected in children with oligoarticular JRA, none of the children with polyarticular JRA or the controls had this allele. CONCLUSION: These findings support earlier observations linking these two DR3 alleles, namely 0307 and 0308, to the genetic susceptibility to JRA.

Prevalence of human leukocyte antigen (HLA) DRB1 alleles in Kuwaiti children with juvenile rheumatoid arthritis.

The prevalence of human leukocyte antigen (HLA) DR alleles has been determined in 69 Kuwaiti Arab children with juvenile rheumatoid arthritis (JRA) and compared to that in 212 ethnically matched normal healthy controls using a PCR-sequence specific primers (PCR-SSP) method. A very high incidence of DR3 was detected in JRA patients compared to the controls (P < 0.0001, RR = 2.235). The high incidence of HLA-DR3 in JRA patients was accounted for mainly by an excess of DRB1*0307 (P < 0.05, RR = 3.072) and DRB1*0308 (P < 0.009, RR = 2.663) compared to the controls. Moreover, DR3 was more prevalent when patients with ANA-positive JRA were analysed separately; 73% compared to 58% for the whole JRA patient group. The frequency of DR1 was also higher in the JRA group compared to controls (P = 0.019, RR = 3.585). Although the incidence of some alleles was higher in the control group (DR13 and DR7), none reached a statistically significant level. All the patients with iridocyclitis had either a DR1 or DR3 allele, except for one child. The frequency of DRB1*03 was found to be much higher in the polyarticular subtype of Kuwaiti JRA cases compared to the oligoarticular subgroup and the controls. Also, a non-significant increase in the frequency of the DRB1*04, *11 and *15 alleles was detected in the polyarticular subtype of the Kuwaiti JRA cases compared to the controls.

Angiotensin converting enzyme gene insertion/deletion polymorphism in idiopathic nephrotic syndrome in Kuwaiti Arab children.

OBJECTIVE: Angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influence the circulating and cellular levels of ACE and has been shown to be a risk factor in a number of diseases including IgA nephropathy. We have investigated the association of ACE gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome (INS) in Kuwaiti children. MATERIALS AND METHODS: The genotypes for ACE gene I/D polymorphism were determined in 102 subjects (54 INS cases and 48 healthy controls) using a PCR method. RESULTS: The distribution of DD, ID and II genotypes was 70%, 20% and 10% in INS cases compared with 52%, 46% and 2% in the controls. The mean age of onset of the disease was significantly lower in the INS cases with DD genotype (37 months) compared with cases with II genotype (65 months, p < 0.05). The clinical manifestation of the disease was considerably severe in cases with DD genotypes compared with cases having ID and II genotypes. The INS cases with DD genotype also showed a significantly higher incidence of steroid sensitivity and steroid dependence. Seventy-three per cent of the INS cases with minimal change lesion had a DD genotype. Also 70% of the cases which needed cytotoxic drugs had DD genotype. CONCLUSION: Our data suggest an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation of INS in Kuwaiti Arab children.

Retinopathy of prematurity: mutations in the Norrie disease gene and the risk of progression to advanced stages.

BACKGROUND: Retinopathy of prematurity (ROP) is a retinal vascular disease that occurs in infants with short gestational age and low birth weight and may lead to retinal detachment and blindness. Missense mutations in the Norrie disease (ND) gene have been associated with the risk of progression to advanced stages in cases of ROP from the US and also in clinically similar ND and familial exudative vitreoretinopathy. METHODS: We have screened two ND gene mutations, namely A105T and Val60Glu, by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific PCR methods, respectively, in 210 Kuwaiti premature newborns to replicate these findings in a different ethnic group. RESULTS: In the Kuwaiti premature newborn cohort, 115 of 210 babies had no eye problems and served as controls, while 95 were cases of ROP. In 71 of 95 ROP cases, the disease regressed spontaneously on or before stage 3, while in 24 of 95 ROP cases the disease progressed to advanced stages 4 and 5. In case of missense mutation (A105T), the AA genotype was detected in 96% of controls compared with 87% of ROP cases (NS); similarly no significant difference was found between spontaneously regressed ROP cases and those who progressed to advanced stages. For the Val60Glu mutation, no significant association was detected between the genotype and progression of ROP to advanced stages. CONCLUSIONS: Unlike data from the US, our findings from a Kuwaiti cohort of ROP cases and controls suggest a lack of association between the two ND gene mutations (A105T and Val60Glu) and ROP and the risk of progression of the disease to advanced stages.

Angiotensin-converting enzyme gene insertion/deletion polymorphism and renal damage in childhood uropathies.

BACKGROUND: The activation of the renin-angiotensin system in various renal disorders is well established. Congenital urological abnormalities, such as obstruction and reflux, are common causes of renal failure in children contributing to approximately 25% of chronic renal failure in this age group. While the outlook relates to the severity of initial renal damage, there is considerable heterogeneity in renal parenchymal destruction among individuals and the reasons for this heterogeneity are not fully understood. A polymorphism within intron 16 of the angiostensin-converting enzyme (ACE) gene has been shown to influence the activity of the renin-angiotensin system, thus, it may also have an impact on the expression of renal disorders. We have determined the incidence of this ID polymorphism of the ACE gene in 47 Kuwaiti children with different urological abnormalities leading to variable degrees of renal impairment and in 48 healthy control subjects with a similar ethnic background. METHODS: Blood samples were collected from the patients (n = 47) and controls (n = 48), total genomic DNA extracted and the ACE genotypes were determined using a polymerase chain reaction-based method. RESULTS: The DD genotype was detected in 27/47 (57%) cases compared with 25/48 (52%) controls (P = 0.439). The heterozygous genotype ID was found in 14/47 (29%) cases compared with 22/48 (46%) controls (P = 0.0138). The homozygous II genotype was detected in 6/47 (13%) cases compared with 1/48 (2%) controls (P = 0.0247). The D allele of ACE gene was detected in 41/47 (87%) uropathy cases when individuals with homozygous DD and heterozygous ID genotypes were considered collectively. The incidence of parenchymal damage was considerably higher in uropathy cases with DD genotype (62%) compared with those having ID (26%) and II (12%) genotypes. CONCLUSIONS: Our data suggest an association of D allele of the ACE gene insertion/deletion polymorphism and congenital urological abnormalities, which result in parenchymal damage in Kuwaiti Arab children.

Missense mutations in norrie disease gene are not associated with advanced stages of retinopathy of prematurity in Kuwaiti arabs.

Retinopathy of prematurity (ROP) is a disease characterized by retinal neovascularization, possibly leading to retinal detachment and finally blindness. In a proportion of ROP cases, the disease progresses to advanced stages despite rigorous intervention. Missense mutations of the Norrie disease (ND) gene have been associated with progression of the disease in ROP cases from the USA. We have investigated the presence of ND gene mutations in 102 premature newborns of Kuwaiti Arab origin to replicate this finding in a different population/racial group. 56 (55%) of these newborns had normal eyes and served as controls. In 35 (34%) cases, the ROP regressed spontaneously during stage 1-3. In 11 (11%) cases, ROP progressed to advanced stages. A PCR-RFLP method was used to detect the mutations in exon 3 of the ND gene and confirmed the DNA sequence by direct sequencing of the PCR product. The [R121W] mutation of the ND gene was not detected in the premature newborns screened from our Kuwaiti population/group. For the second mutation [L108P], a genotype (PP) was present in 98% of the premature newborns screened and only in 1 of 56 normal infants was the (LL) genotype detected. Our population is genetically homogenous in that genotype (PP) was detected at codon 108 in almost all controls and ROP cases. We did not find an association between the presence or absence of missense mutations of the ND gene and the risk of severe ROP.