Frequency Of A1 Allele Research Articles

P53 polymorphisms in Russia and Belarus: correlation of the 2-1-1 haplotype frequency with longitude

Four different polymorphisms in the human p53 gene (a 16-bp duplication in intron 3, and three RFLPs: for Bsh1236I at codon 72, for MspI in intron 6 and for BamHI in the 3' flanking region) and extended haplotypes were studied in nine geographically diverse populations from Russia and Belarus. The Yakuts differed from all other populations, as they had a significantly higher frequency of the BamHI A1 allele. Most populations did not differ significantly from each other in the frequency of the Bsh1236I polymorphism. The 16-bp duplication A1 allele and MspI A2 allele frequencies were significantly higher in the Yakut and Khant populations. Linkage disequilibrium values (D') between BamHI and other polymorphic sites were not significant in many cases; for this reason we have used the 16 bp-Bsh1236I-MspI haplotype frequencies only. Of eight possible haplotypes, five were observed in the populations investigated. Haplotype 1-2-2 was the most frequent in all populations. The next most common haplotype, 1-1-2, was present at very similar frequencies among the Byelorussians and Russians from Smolensk, but was more frequent in other populations. The frequency of haplotype 2-1-1 showed a nearly continuous decrease from West to East (from 17.857% among the Byelorussians to 0.685% in the Yakuts from the Verkhoyansk) and correlated with longitude (Spearman's r = -0.8667, P = 0.0025), which may be due to natural selection and adaptation. The relationships among populations were evaluated by means of Nei's D(A) distances for the 16 bp-Bsh1236I-MspI haplotype frequencies. Based on the multidimensional scaling analysis a correlation between p53 haplotype frequencies and ethnicity is supposed.

An affected pedigree member analysis of linkage between the dopamine D2 receptor gene TaqI polymorphism and obesity and hypertension

Background Dopamine modulates a variety of physiological functions including natriuresis and satiety. We have previously reported that the TaqI polymorphism of the dopamine D2 receptor (DD2R) gene is associated with both blood pressure and obesity indices in a normoglycaemic Hong Kong Chinese population. In this study, we present evidence confirming the linkage between this gene polymorphism, obesity and hypertension. Methods Two hundred and seventy-four siblings from 96 normoglycaemic hypertensive families were recruited, including 133 who were hypertensive. Central obesity was defined as a waist-to-hip ratio of ≥0.9 and ≥0.85 in males and females, respectively, and was identified in 99 of the siblings. The DD2R gene TaqI polymorphism was identified with a polymerase chain reaction based restriction fragment length polymorphism protocol. The affected pedigree member (APM) linkage analysis (sib-pair program, version 0.99.9, by D.L. Duffy) was used to assess for linkage between this gene polymorphism, obesity and hypertension in 73 families with siblings discordant for hypertension. Results The A1 allele frequencies were similar in the 133 hypertensive, and 141 normotensive siblings, including the 99 centrally obese siblings at 0.431, 0.421 and 0.418, respectively. APM linkage analysis suggested that the DD2R gene TaqI polymorphism had evidence of linkage with blood pressure ( T=−1.86, P=0.013), as well as with obesity ( T=−1.58, P=0.007). Conclusion Our data in normoglycaemic Hong Kong Chinese supports that the DD2R gene TaqI polymorphism is a marker associated with the pathogenesis of obesity and hypertension.

The Study of Cytosolic Phospholipase A2 Gene Polymorphism in Schizophrenia Using Eye Movement Disturbances as an Endophenotypic Marker

Phospholipase A₂ (PLA2) is a key enzyme of the phospholipid metabolism which shows alteration in schizophrenia. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives, and they have been suggested as an endophenotypic marker in genetic studies of this illness. Here we report an association between the Ban I polymorphism of the cytosolic PLA2 gene (single nucleotide polymorphism in the first intron of the gene) and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 126 schizophrenic patients. The mean intensity of both kinds of eye movement disturbances was significantly higher in individuals homozygous for the A2 genotype compared with the remaining phenotypes. There was also a trend for greater A2 allele frequency in schizophrenic patients with a higher degree of eye movement disturbances. The relative frequency of the A2/A2 genotype was higher in patients with a greater degree of eye movement disturbances occurring during both fixation and smooth pursuit tests. Our results correspond to the other studies showing an association between the cPLA2 polymorphism and schizophrenia (predominance of the A2 allele in schizophrenic subjects).

Ethanol consumption and DRD2 gene TaqI a polymorphism among socially drinking males.

The dopaminergic system in the human brain is thought to play a major role in the development of alcohol consumption habits and alcoholism. It has been reported that homozygous D2-/- knock-out mice lacking D2 receptors consume about 50% to 60% less ethanol than wild-type D2+/+ mice, and heterozygous mice have an intermediate level of alcohol consumption. The DRD2 gene TaqI A polymorphism has been suggested to associate with a low D2 receptor density in post mortem and in vivo measurements. Numerous association studies on this polymorphism and alcoholism have shown most controversial results. We studied whether DRD2 TaqI A genotype affects alcohol consumption in an ethnically homogeneous, representative sample of 1,019 Finnish Caucasian males. After excluding the abstainers from the study, the self-reported alcohol consumption among the remaining 884 non-abstainers was compared in the TaqI A genotype groups (A1/A1, A1/A2, A2/A2). The alcohol consumption of the homozygous A1/A1 group was about 30% lower than in A1/A2 group, and 40% lower than in A2/A2 group (P = 0.042 and 0.041 in a sociodemographic variable-adjusted multivariate model). The results indicate an association between DRD2 genotype and alcohol consumption habits in humans. These results in the large sample of non-alcoholic males are also opposite to some previous findings on the higher A1 allele frequency among alcoholic populations.

Association between the Pl A platelet glycoprotein GPIIIa polymorphism and extent of coronary artery disease

Background: The Pl A2 allele of the gene encoding for GPIIIa subunit of the platelet membrane receptor glycoprotein (GP) IIb/IIIa has been suggested as a significant risk factor for thrombotic complications of coronary artery disease (CAD). The aim of the current investigation was to investigate the association between Pl A GPIIIa polymorphism and the extent of angiographically confirmed CAD in patients from the north region of Poland. Methods: The study was performed in 397 male Caucasian patients. All subjects had significant coronary artery stenosis confirmed by elective coronary angiography. Screening for the Pl A GPIIIa genotypes was performed by polymerase chain reaction of genomic DNA, followed by NciI digestion and agarose gel electrophoresis. Results: The genotype distribution of the Pl A GPIIIa polymorphism in our study group was Pl A1/A1 —75%, Pl A1/A2 —24% and Pl A2/A2 —1% with Pl A1 and Pl A2 allele frequencies of 0.87 and 0.13, respectively. The prevalence of the homozygous Pl A1/A1 genotype among subjects with multiple-vessel CAD (two or three vessels with at least 50% stenosis) was significantly higher than in patients with single-vessel disease; the odds ratio of Pl A2/A2 or Pl A1/A2 patients for having multiple-vessel CAD was 0.46 (95% CI 0.27–0.77, P<0.01). The mean CAD score for Pl A1/A1 patients was significantly higher in comparison to Pl A2/A2 and Pl A1/A2 patients (7.58±2.20 and 6.98±2.37, respectively, P<0.05). Conclusions: Our results suggest, that the Pl A1/A1 genotype of Pl A GPIIIa polymorphism is associated with more severe CAD in male Caucasian patients from the north region of Poland.

Lack of association in Japanese patients between neuroleptic malignant syndrome and the TaqI A polymorphism of the dopamine D2 receptor gene.

The molecular basis of neuroleptic malignant syndrome (NMS) is unclear, but clinical studies have noted a genetic predisposition. A recent genetic study suggested an association between NMS and the I A polymorphism in the dopamine D2 receptor (DRD2 ) gene. We further examined the association in a larger number of subjects. We studied 49 Japanese patients previously diagnosed with NMS, and 123 schizophrenic patients treated with neuroleptics without occurrence of NMS. PCR and RFLP analyses were performed to screen the I A polymorphism. The I A1 allele frequency was 0.408 in NMS patients and 0.415 in patients without NMS. No significant differences in allelic or genotypic frequencies were observed between the two groups. We cannot conclude that the I A polymorphism is associated with development of NMS.

Gender-specific molecular heterosis and association studies: dopamine D2 receptor gene and smoking.

If the concept of the gender-specific molecular heterosis is not considered and tested, incorrect conclusions would easily be drawn in association studies. Therein, heterosis and its gender effect in the genetic effect of DRD2 gene for smoking were examined with 187 healthy Korean individuals. The male smokers showed a higher A1 allele frequency (P = 0.016) and prevalence (P = 0.049) than those of the male non-smokers, and the female smokers showed a lower frequency of heterozygotes (P = 0.018) than the female non-smokers. However, the association of DRD2 gene with smoking found in each gender disappeared when both males and females were considered as one group because of the opposite genetic effect of DRD2 gene for smoking: (1) while 75% of heterozygotes males were smokers, only 22% of female heterozygotes were; (2) males showed an excess of heterozygotes and the deviation from Hardy-Weinberg expectations in smokers, while these were true in the female non-smokers; and (3) in non-smokers, females were different from the males exhibiting a significantly higher prevalence (P = 0.005) and frequency (P = 0.015) of A1 allele, and significantly different genotype (P = 0.017) distribution, and higher frequency of heterozygotes (P = 0.055). Meanwhile, in smokers, males showed higher frequency of heterozygotes (P = 0.019) compared to females. The results indicate that gender-specific molecular heterosis at DRD2 gene for smoking is also applicable in healthy individuals as well as schizophrenics. Moreover, this concept has general applicability to other candidate genes and biological phenotypes.

D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes.

The D2 dopamine receptor (DRD2) has been one of the most extensively investigated gene in neuropsychiatric disorders. After the first association of the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number of international studies have followed. A meta-analysis of these studies of Caucasians showed a significantly higher DRD2 A1 allelic frequency and prevalence in alcoholics when compared to controls. Variants of the DRD2 gene have also been associated with other addictive disorders including cocaine, nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is a reinforcement or reward gene. The DRD2 gene has also been implicated in schizophrenia, posttraumatic stress disorder, movement disorders and migraine. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress response, personality and treatment outcome characteristics. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the treatment of these disorders.

Endothelial nitric oxide synthase gene and the development of diabetic nephropathy

Background: Endothelial nitric oxide synthase gene and the development of diabetic nephropathy Background: Intron 4 insertion/deletion polymorphism of the constitutive endothelial nitric oxide synthase (ecNOS) gene may be related to diabetic nephropathy. Methods: A case-control study was performed in three groups of Japanese patients with Type 2 diabetes mellitus, which including 123 patients with advanced diabetic nephropathy, 107 patients with overt proteinuria and normal serum creatinine level, and a control group of 203 patients with normal renal function despite having diabetes for over 10 years. Additionally, logistic regression analysis was used to assess the findings. Results: When we examined the a-deletion/b-insertion in intron 4 of ecNOS gene, the genotype and allele frequencies were not significantly different between the patients with advanced diabetic nephropathy (a/a 2.4, a/b 21.9, b/b 75.5, ‘a’ 13.4, ‘b’ 86.6%), the patients with overt proteinuria (a/a 2.8, a/b 15.8, b/b 81.4, ‘a’ 10.7, ‘b’ 89.3%) and the control group (a/a 1.4, a/b 21.6, b/b 76.8, ‘a’ 12.8, ‘b’ 87.7%). Logistic regression analysis showed that the ecNOS intron4 a-allele frequency was not the related to nephropathy ( P=0.88). Conclusion: We conclude that there is no association of the ecNOS gene polymorphism with the development of diabetic nephropathy in Japanese patients with type 2 diabetes.

Cytochrome P450c17alpha (CYP17) gene polymorphism is not associated with leiomyoma susceptibility

Estrogen plays a role in the pathogenesis of leiomyoma. The CYP17 gene codes for the cytochrome P450c17alpha enzyme, which is involved in the biosynthesis of estrogen. Our aim was to investigate if CYP17 polymorphism could be a useful marker to predict the susceptibility to leiomyoma. Our sample of female subjects was divided into two groups: (1) with leiomyoma (n = 159); (2) without leiomyoma (n = 128). A 169-bp fragment encompassing the A1/A2 polymorphic site of the CYP17 gene was amplified by polymerase chain reaction (PCR), restricted by enzyme MspA1I and electrophored on agarose gel. Genotypes and allelic frequencies for this polymorphism in both groups were compared. There was no significant difference between the two groups regarding the distribution of the CYP17 gene polymorphism frequencies. The A1 homozygote/heterozygote/A2 homozygote proportions for CYP17 in both groups were: (1) 17.0/46.5/36.5%, and (2) 17.2/45.3/37.5%. The proportions for alleles A1 and A2 were also comparable in the two groups. A1 and A2 allele frequencies were: 7% (40.3/59) in group 1, and 2% (39.8/60) in group 2. No significant association was observed between the risk of leiomyoma and polymorphisms of the CYP 17 gene. So, CYP17 gene polymorphism does not appear to be a useful marker for the prediction of leiomyoma susceptibility.

Role of genetic polymorphism in the SA gene on the blood pressure and prognosis of renal function in patients with immunoglobulin A nephropathy.

The SA gene has been shown to be much more highly expressed in the kidneys of spontaneously hypertensive rats than in the corresponding wild-type strain. Genetic polymorphism of this gene has been shown to play a role in human hypertension, although the details of this association remain controversial. We investigated the possible associations between SA gene polymorphism and both hypertension and the prognosis of renal function in patients with immunoglobulin A nephropathy (IgAN). Genomic DNA was isolated from the peripheral blood of 367 individuals, including 274 patients with histologically proven IgAN and 100 controls without any history of renal disease. The SA genotype was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) with Pst I. The frequencies of genotypes and alleles were not different between the patients with IgAN and those without renal disease. In the group without renal disease, the SA gene polymorphism was not associated with hypertension. However, in the patients with IgAN the A1 allele frequency was significantly higher in the hypertensives than in the normotensives. The renal survival of the patients with the A2 allele tended to be better than that of those without the A2 allele. The findings thus suggest that SA gene polymorphism may be associated with the renal prognosis of IgAN through its effect on blood pressure. Further, they suggest that the sensitivity to this gene polymorphism increases in patients with renal injury.

Modulation of blood pressure and obesity with the dopamine D2 receptor gene TaqI polymorphism.

Pharmacological data suggest that obesity and blood pressure (BP) may be modulated through the dopamine D2 receptor (DD2R), which may represent an underlying mechanism that links these conditions. A TAQ:I polymorphism near the DD2R gene has been associated with indices of obesity in white populations. We compared anthropometric and fasting plasma biochemical parameters between 209 nondiabetic hypertensive and 174 gender-matched normotensive Chinese subjects. The hypertensives had increased dyslipidemia, increased fasting plasma glucose concentrations, and a greater degree of obesity. The A1 and A2 alleles of the DD2R gene TAQ:I polymorphism were identified with a polymerase chain reaction-based restriction fragment length polymorphism protocol. The A1 allele frequency was decreased in the hypertensives (42.0%) compared with the control subjects (52.0%, P=0.006), and genotype frequencies were different (P=0.05) between the 2 groups. In the combined population (n=383), systolic, diastolic, and mean arterial BPs were 6, 5, and 6 mm Hg lower, respectively, in subjects with the A1A1 genotype relative to the A2A2 genotype (all P<0.05), whereas skinfold thickness was increased at the iliac (P<0.001) and triceps (P<0.03) sites but not at the biceps or subscapular sites. Furthermore, this DD2R gene polymorphism was shown to be a significant independent predictor of diastolic BP and iliac and triceps skinfold thicknesses (all P<0.03). These contrasting associations of the DD2R TAQ:I polymorphism A1 allele with lower BP but increased markers of "gynoidal" or peripheral subcutaneous obesity (iliac and triceps skinfold thicknesses) in our Chinese population may provide some insight into the underlying relationship between BP and body fat distribution, but the exact nature of this link remains to be determined.

Study of two ectopeptidases in the susceptibility to celiac disease: two newly identified polymorphisms of dipeptidylpeptidase IV.

Study of two ectopeptidases in the susceptibility to celiac disease: two newly identified polymorphisms of dipeptidylpeptidase IV.

P53 mutations, polymorphisms, and haplotypes in Pakistani ethnic groups and breast cancer patients.

Inactivation of the p53 gene has been found to be associated with the pathogenesis of several neoplasias. Three biallelic polymorphisms in the p53 gene have been linked to predisposition to the development of various malignancies. These include a 16-bp duplication in intron 3 and BstU I and Msp I restriction fragment length polymorphisms (RFLPs) in exon 4 and intron 6, respectively. The prevalence of these polymorphisms was studied in breast cancer patients and nine major ethnic groups of Pakistan. Differences in allele frequencies for all three polymorphisms were observed among the various ethnic groups and breast cancer patients. The absence of the 16-bp duplication was common among the northern ethnic groups, being highest in the Hazara (0.90). The Msp I A1 allele frequency in the southern Makrani population was significantly higher in comparison with the other ethnic groups. In the cancer patients, the absence of the 16-bp duplication in combination with the BstU I Pro and absence of Msp I restriction site were the most frequent. In these patients, ten substitution mutations were found in the p53 gene, seven of which have been reported previously for breast cancer. The remaining three mutations have been found in other malignancies, but not in carcinoma of the breast.

The DRD2 gene and the risk for alcohol dependence in bipolar patients

The high co-morbidity between bipolar disorder and alcohol dependence may have different explanations, one of them being the existence of common genetic factors for the two disorders. Several candidate genes may be involved but the genes acting in the dopaminergic pathway may be more specifically involved. We have thus tested the role of the gene encoding the D2 dopamine receptor (TaqI A1 allele) in the potentially shared vulnerability to alcohol dependence and bipolar disorder. One hundred and twenty-two French (for at least two generations) patients were recruited on the basis of hospital or outpatient files and were interviewed with the DIGS. The A1 allele frequencies were compared between four groups, namely, with bipolar patients and co-morbid alcohol dependence ( N = 21), with bipolar patients without alcohol morbidity ( N = 31), with alcohol dependence without mood disorder ( N = 35) and unaffected controls ( N = 35). The Hardy Weinberg equilibrium for the DRD2 Taq1 A1 genotypes was respected for the sample as a whole, and for each subsample. We observed that 42.9% of control subjects have at least one A1 allele, a frequency which is not significantly different from the one observed in the affected sample as a whole (39.1%), neither from patients with alcohol dependence (37.1%), patients with bipolar disorder (48.4%) nor patients with alcohol dependence and bipolar disorder (28.6%). The regression analysis based on the three variables (bipolar disorder, alcohol dependence and interaction between these two disorders) does not explain the presence of the A1 allele of the DRD2 gene. We thus found no evidence for a significant role of the A1 allele of the D2 dopamine receptor gene in the specific association between bipolar disorder and alcohol dependence in our sample.

D2 dopamine receptor and alcohol dehydrogenase 2 genes with Polynesian alcoholicsAssociation of D2 dopamine receptor and alcohol dehydrogenase 2 genes with Polynesian alcoholics

Alleles of the D2 dopamine receptor (DRD2) and the alcohol dehydrogenase 2 (ADH2) genes were determined in 69 French Polynesian alcoholic patients and 57 controls matched for racial origin. Three racial groups were studied: pure Polynesians (PP), Polynesians mixed with Caucasian (PCA) ancestry and Polynesians mixed with Chinese (PCH) ancestry. DRD2 A1 allele frequencies in the alcoholics compared to their controls in these groups were: PP, .26 vs .32 ( P = .69); PCA, .44 vs .35 ( P = .46); PCH, .40 vs 0.39 ( P = .88). ADH2 1 allele frequencies in alcoholics compared to their controls groups were: PP, .56 vs .62 ( P = .66); PCA, .75 vs .56 ( P = .09); PCH, .78 vs .32 ( P = .009). In the PCA group, the combination of the DRD2 A1 genotypes and the ADH2 1 homozygotes was strongly associated with alcoholism ( P = .0027). This preliminary study shows the importance of ascertaining racial ancestry in molecular genetic association studies. Moreover, it suggests that a combination of genes are involved in susceptibility to the development of alcoholism.

The D2 dopamine receptor A1 allele and opioid dependence: Association with heroin use and response to methadone treatment

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.

Allele frequency of human endothelial nitric oxide synthase gene polymorphism in abdominal aortic aneurysm.

This study was performed to examine the role of the endothelial constitutive NO synthase (ecNOS) gene in patients with abdominal aortic aneurysm (AAA). We determined the distributions of polymorphism in intron 4 of the ecNOS (ecNOS4) gene, amplified by polymerase chain reaction, and compared the allele frequencies between subjects with abdominal aortic aneurysms (AAAs) and healthy individuals. Fifty-eight patients with AAAs and 410 race-matched healthy controls were studied. Two alleles of the ecNOS4 gene, containing 4 (a-allele) and 5 (b-allele) repeats, were identified. We found that the a-allele frequency of this gene was significantly higher in the surgical than in the non-surgical group. The results of this study suggest that the a-allele of the ecNOS4 gene is indicative of the need for surgery for AAA. Analysis of the alleles of the ecNOS4 gene polymorphism could provide useful information concerning the clinical course of AAA progression.

The alpha1-antichymotrypsin A-allele in German Parkinson disease patients.

An increased frequency of the A-allele of the alpha-antichymotrypsin (ACT) gene has been recently described in Japanese patients suffering from Parkinson disease (PD). In the present study, we have analyzed 62 German PD patients with regard to their ACT and APOE genotypes and compared them to 53 controls without clinical or pathological evidence of neurodegenerative disease. The A-allele frequency was 47% in PD patients compared to 54% in control cases excluding ACT as a major susceptibility factor for PD in the Caucasian population. Yet, ACT-A allele frequencies were significantly different (p < 0.001) between Japanese and German controls. Therefore, although our data do not suggest that the alpha1-ACT polymorphism is a significant risk factor for the development of PD, a consideration of differences in genetic background seems warranted when evaluating susceptibility factors for neurodegenerative disease.

Pronatriodilatin gene polymorphisms, microvascular permeability, and diabetic nephropathy in type 1 diabetes mellitus.

Approximately 30% of diabetic patients develop nephropathy, the appearance of which is partially under genetic control. Atrial natriuretic peptide (ANP) has associated physiologic effects on the kidney. This study was conducted to examine the relationship between a newly identified and known polymorphism at the pronatriodilatin (PND) gene locus and renal involvement in type 1 diabetic subjects. Of 454 type 1 diabetic patients (219 men, 235 women), 323 showed no sign of nephropathy, 79 had incipient renal involvement, and 52 established nephropathy; 58 healthy control subjects were examined for comparison. Allele frequencies (C708 versus T708) were: 0.95 and 0.05 in normoalbuminuric patients, respectively; 0.88 and 0.12 in microalbuminuric patients; 0.96 and 0.04 both in those with overt nephropathy and in healthy control subjects (P = 0.011). Patients with incipient nephropathy were in disequilibrium compared with the total diabetic cohort (P = 0.02). In the same populations, an additional genotype for ScaI polymorphism of the PND gene was tested. The A1 and A2 allele frequencies were: 0.21 and 0.79 in normoalbuminuric patients; 0. 13 and 0.87 in microalbuminuric patients; 0.06 and 0.94 in type 1 diabetic subjects with overt nephropathy; and 0.20 and 0.80 in healthy control subjects, respectively (P < 0.0001). A subset of 55 normotensive patients with type 1 diabetes, well matched for clinical features, plasma ANP levels, and microvascular permeability to macromolecules, was investigated on the basis of the C708/T and A2/A1 polymorphisms. Both transcapillary escape rate of albumin (TERalb) and plasma ANP levels were significantly lower in patients with the T708 than with C708 allele, as well as in the A1 than in A2 allele (TERalb: T708 versus C708: 5.5+/-1.7 versus 7.8+/-2.0%/h, P = 0.0001; plasma ANP levels: 8.3+/-3.9 versus 15.3+/-7.7 pg/ml, P = 0.0003; A1 versus A2: 6.05+/-2.2 versus 7.3+/-2.1%/h, P = 0.044; 8.53+/-4.6 versus 14.5+/-7.4 pg/ml, P = 0.0024, respectively). Thus, in a large ethnically homogeneous cohort of diabetic subjects, our data show: (1) a significant association of C708/T polymorphism with microalbuminuria in long-term diabetes and with both lower plasma ANP levels and widespread albumin leakage; and (2) a strong association between ScaI polymorphism and both diabetic nephropathy and plasma ANP concentrations. These results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes.