|
Article Excerpt
We examined six newly identified polymorphisms in the [delta]-aminolevulinic acid dehydratase (ALAD) single-nucleotide polymorphisms (SNPs) to determine if these SNPs could modify the relationship between blood lead (PbB) and some renal parameters. This is a cross-sectional study of 276 lead-exposed workers in Vietnam. All workers were measured for PbB, urinary retinol-binding protein (URBP), urinary [c.sub.1]-microglobulin (U[alpha]1m), urinary [[beta].sub.2]-microglobulin (U[beta]2m), urinary N-acetytl-[beta]-D-glucosaminidase (NAG), urinary aminolevulinic acid (ALAU), serum [[alpha].sub.1]-microglobulin (S[alpha]m), serum [[beta].sub.2]-microglobulin (S[beta]2m), and urinary albumin (Ualb). The six SNPs were Msp and Rsa in exon 4, Rsa39488 in exon 5, HpyIV and HpyCH4 in intron 6, and Sau3A in intron 12. Analysis of covariance (ANCOVA) with interaction of PbB x SNPs were applied to examine modifying effect of the SNPs on the association of renal parameters and PbB, adjusting for potential confounders of age, gender, body mass index, and exposure duration. HpyCH4 was found to be associated with certain renal parameters. For HpyCH4 1-1, an increase of I [micro]g/dL PbB caused an increase of 1.042 mg/g creatinine (Cr) U[alpha]1m, 1.069 mg/g Cr U[beta]2m, 1.038 mg/g Cr URBP, and 1.033 mg/g Cr Ualb, whereas in HpyCH4 1-2, an increase of 1 [micro]g/dL PbB resulted in an increase of only 1.009 mg/g Cr U[alpha]1m, 1.012 mg/g Cr U[beta]2m, 1.009 mg/g Cr URBP, and 1.007 mg/g Cr Ualb. HpyCH4 SNP appeared to modify the lead toxicity to kidney with wild-type allele being more susceptible than variants. The mechanism for this effect is not clear. Further studies are needed to confirm this observation. Key words: [delta]-aminolevulinic acid dehydratase (ALAD), HpyCH4, intron, lead, SNP (single-nucleotide polymorphism), urinary albumin (Ualb), urinary retinol-binding protein (URBP), urinary [[alpha].sub.1]-microglobulin (U[alpha]m), urinary [[beta].sub.2]-microglobulin (U[beta]2m). Environ Health Perspect 113:1313-1317 (2005). doi:10.1289/ehp.7904 available via http://dx.doi.org/[Online 1 June 2005]
**********
The first and most common [delta]-aminolevulinic acid dehydratase (A/AD) polymorphism studied was the Msp single-nucleotide polymorphism (SNP) in exon 4. Since it was first reported (Battistuzzi et al. 1981), many reports (e.g., Onalaja and Claudio 2000) have been published on its association with inorganic lead (henceforth referred to as lead). Epidemiologic studies have tried to determine if the Msp polymorphism is important in human susceptibility to lead regarding various lead-targeted systems (Alexander et al. 1998; Bergdahl et al. 1997; Hu et al. 2001; Schwartz et al. 1995, 2000).
In recent years, reports have been published on the association between the Msp SNP and renal effects of lead exposure. Smith et al. (1995) suggested that the Msp-2 variant is a more susceptible allele because Msp-2 carriers had higher concentrations of blood uric acid and blood urea nitrogen (BUN). The differences achieved only borderline significance after adjusting for potential confounders. Bergdahl et al. (1997) found that serum creatinine is higher for Msp)-2 carriers than for Msp 1-1 homozygotes in a sample of 89 lead workers. A linear relationship was observed between patella lead concentration, using X-ray fluorescence method, and serum uric acid when patellar lead passes 15 [micro]g/g bone mineral for Msp-2 carriers, but the similar linear relation can be seen only when patella lead was > 101 [micro]g/g bone mineral for the Msp 1-1 group (Wu et al. 2003). Wu et al. (2003) postulated that lead toxicity became apparent at a lower exposure level for Msp-2 carriers than for Msp 1-1 persons. These studies suggested that Msp-2 carriers were more susceptible to lead effects than were Msp 1-1 homozygotes. However, the reports were not consistent. Some studies had reported that the Msp-2 variant was associated with higher creatinine clearance as well as lower mean serum creatinine and BUN (Weaver et al. 2003).
Renal parameters such as creatinine clearance, BUN, and serum creatinine are insensitive to renal function changes. As much as 50-70% of kidney nephrons must be damaged before variation can be detected (Goyer 1989). The consensus may not be so clear, however, regarding the effects of lead on the renal system because no good longitudinal studies have been conducted to establish the predictive value of early biologic exposure markers in lead-exposed workers. Roels et al. (1994) studied 76 male lead smelter workers and 68 controls matched for age, gender, socioeconomic state, residence, and work shift characteristics. Although the tibia bone lead, blood lead (PbB), and urinary lead levels of the exposure group were significantly higher than those of the control group, no significant differences were observed in either common and stimulated creatinine clearance. More recently, however, Weaver et al. (2003) reported that higher lead levels were associated with lower BUN and serum creatinine levels and higher calculated creatinine clearance among those with the ALAD 1-2 genotype.
Renal parameters such as low-molecular-weight proteins [e.g., retinol-binding protein, [[alpha].sub.1]-microglobulin, [[beta].sub.2]-microglobulin, N-acetyl-[beta]-D-glucosaminidase (NAG)] representing proximal tubule injury are considered good alternatives because early lead-induced nephropathy usually involves damage of proximal tubule cell (Nolan and Shaikh 1992). To date, several studies have shown that these renal parameters have good correlation with lead exposure indices. NAG has been found to be the only marker elevated in early nephropathy in five studies reviewed by Bernard and Lauwerys (1989). One study in Japan (Endo et al. 1993) claimed that urinary [[alpha].sub.1]-microglobulin (U[[alpha].sub.1]m) can be a useful indicator of renal impairment. A study of 128 lead workers (Chia et al. 1995) reported that U[[alpha].sub.1]m appears to be the most sensitive parameter compared with urinary [[beta].sub.2]-microglobulin (U[[beta].sub.2]m) and urinary retinol-binding protein (URBP). Another study of environmental lead exposure in children showed that URBP is increased by lead with good dose-effect and dose-response relations with PbB (Bernard et al. 1995).
To date, 111 SNPs have been reported in the National Center for Biotechnology Information website (NCBI 2005). But when we assessed the website in June 2004, 46...
|
