Environmental and genetic effects on the risk of calcium urolithiasis

• Main Authors: Chia-Chu Liu, 劉家駒
• Other Authors: Chun-Hsiung Huang
• Format: Others
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/75309848511738224286

博士 === 高雄醫學大學 === 醫學研究所 === 100 === Urolithiasis is a global problem and affects almost populations of every region, culture, and race. During recent decades, the prevalence and incidence of urolithiasis have steadily increased worldwide. Since the occurrence of urolithiasis will cause patients not only pain and distress but also loss of work hours and burden of medical expenditure, how to identify the high-risk subjects and prevent them from occurrence become very crucial. So this proposal is focused on the environmental and genetic effects on the risk of calcium urolithiasis, the most common components of urolithiasis. The aim of the first chapter was designed to evaluate the independent and combined effects of alcohol drinking, cigarette smoking and betel quid chewing on the risk of calcium urolithiasis. Just second to caffeine, they are three most commonly used psychoactive substances in the world. A total of 354 cases diagnosed with calcium urolithiasis and 354 age- and sex- matched healthy controls were recruited from Kaohsiung Medical University Hospital between 2003 and 2007. The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital. Each subject provided signed informed written consent before participation. All subjects completed a detailed questionnaire survey and provided blood and urine samples for biochemical evaluation. We found that current cigarette smoking (odds ratio=1.66, 95 % confidence interval=1.11-2.50, P=0.014) and current betel quid chewing (odds ratio=1.97, confidence interval=1.06-3.64, P=0.032), but not current alcohol drinking, were independent risk factors for the development of calcium urolithiasis. The joint risk of current cigarette smoking and current betel quid chewing was increased to 3.73 fold (odds ratio=3.73, confidence interval=1.81-7.70, P<0.001) compared to those who had neither habit. Melamine, a widely used chemical found in many daily use products, emerged as a public health concern in September 2008 due to an outbreak of childhood urinary stones caused by melamine-tainted formula in China. It was still unclear whether low-dose of melamine exposure may also cause urolithiasis in adults. The aim of the second chapter was designed to examine the relationship between urinary melamine concentration and calcium urolithiasis risk in adults. A total of 211 patients diagnosed with calcium urolithiasis and 211 age- and sex-matched controls were selected as the study subjects from Kaohsiung Medical Center between 2003 and 2007. The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital. Each subject provided signed informed written consent before participation. All subjects completed a detailed questionnaire and provided blood and urine samples for biochemical evaluation. Urinary melamine concentration was measured using triple-quadrupole liquid chromatography tandem mass spectrometry method. Compared to those whose urinary melamine levels below method of detection limit (MDL), subjects with urinary melamine levels of MDL-3.11 ng/ml and ?d3.12 ng/ml had 3.01- and 7.64-fold risks, respectively, to have calcium urolithiasis after adjusting for other covariates. The population attributable risk percentage of calcium urolithiasis for urinary melamine ranged 47.9%-52.9%, after considering for other covariates. Matrix-assisted laser desorption / ionization time-of-flight mass spectrometry can detect melamine content in the stones from 9 out of 9 stone patients (100%) with detectable urinary melamine levels. Osteopontin (OPN) is an important modulator of urolithiasis formation. Three functional polymorphisms (-66T/G, -156delG/G, -443T/G) on the promoter region of the OPN gene have been found to affect the gene expression and transcriptional activity. The aim of the third chapter was designed to investigate the association of those three functional polymorphisms with the risk of calcium urolithiasis. A total of 249 cases diagnosed with calcium urolithiasis and 247 age- and sex- matched healthy controls were selected as the study subjects from Kaohsiung Medical University Hospital between 2003 and 2007. The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital. Each subject provided signed informed written consent before participation. All subjects completed a detailed questionnaire survey, and provided blood and urine samples for biochemical evaluations. Three single nucleotide polymorphisms were determined by using TaqMan 5’ allelic discrimination assay. In -156delG/G polymorphism, we found that subjects who carried delG allele had a significantly higher risk of developing calcium urolithiasis than those with G allele (odds ratio=1.39, 95% confidence interval=1.02-1.90, p= 0.037). In stone cases, subjects with delG/G and delG/delG genotypes also had significantly higher urinary ratio of calcium to OPN than those with G/G genotype (11.8±15.9 vs 7.08±5.26, p=0.021). In conclusion, these studies confirmed that both environmental and genetic factors can play the important roles in the risk of calcium urolithiasis. As regards to the environmental factors, we found that cigarette smoking, betel quid chewing and low-dose melamine exposure can increase the risk of calcium urolithiasis formation. In addition, the -156 delG/G polymorphism of OPN gene could serve as a candidate genetic marker used to evaluate the risk of calcium urolithiasis. Subjects who carried delG allele had a significantly higher risk of developing calcium urolithiasis than those with G allele. In clinical practice, patients should be informed to avoid those environmental risk factors in order to reduce the risk of calcium urolithiasis formation, especially those who have higher genetic risk.