Pharmacogenetics in ghana: reviewing the evidence

Different clinical response of different patients to the same medicine has been recognised and documented since the 1950's. Variability in response of individuals to standard doses of drug therapy is important in clinical practice and can lead to therapeutic failures or adverse drug reactions. Pharmacogenetics seeks to identify individual genetic differences (polymorphisms) in drug absorption, metabolism, distribution and excretion that can affect the activity of a particular drug with the view of improving efficacy and reducing toxicity. Although knowledge of pharmacogenetics is being translated into clinical practice in the developed world, its applicability in the developing countries is low. Several factors account for this including the fact that there is very little pharmacogenetic information available in many indigenous African populations including Ghanaians. A number of genes including Cytochrome P450 (CYP) 2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, MDR1 and TPMT have been genotyped in the Ghanaian population since the completion of the Human genome project. There is however, an urgent need to increase pharmacogenetic research in Ghana to increase availability of data. Introducing Pharmacogenetics into the curriculum of Medical and Pharmacy training institutions will influence translating knowledge of pharmacogenetics into clinical practice. This will also equip health professionals with the skill to integrate genetic information into public health decision making.     

The Effect of Interleukin-1α Polymorphisms on Bone Mineral Density and the Risk of Vertebral Fractures

Interleukin-1α (IL-1α) stimulates bone resorption via osteoclasts. Mononuclear cells from patients with osteoporosis show increased IL-1α production, and IL-1α mRNA is more often detected in bone biopsies from osteoporotic compared to normal postmenopausal women. Polymorphisms have been identified in the IL-1α gene; however, none of these has been examined for an effect on bone phenotypes in Caucasians. We investigated if the polymorphisms in the IL-1α gene affect the risk of osteoporotic fractures, bone mineral density (BMD), and bone turnover in 462 osteoporotic patients and 336 normal controls. Based on previous studies of polymorphisms in the gene and data from the International Hap-Map Project, four polymorphisms needed examination in order to investigate the effect of known polymorphisms in the IL-1α gene. We examined C⁻¹²⁰²-T(rs1800794), C^–889-T(rs1800587), T^{155 + 209}-C(rs2071373), C^{155 + 320}-T(rs2856838), and G³⁹⁸-T(rs 17561) by Taqman and restriction fragment-length polymorphism assays. BMD was examined by dual-energy X-ray absorptiometry. Bone turnover was evaluated by serum osteocalcin, serum carboxy-terminal propeptide of human type I procollagen, serum bone-specific alkaline phosphatase, serum carboxy-terminal telopeptide of type I collagen, and urinary hydroxyproline/creatinine. Genotype distributions were in Hardy-Weinberg equilibrium. All polymorphisms were in strong linkage disequilibrium. The C allele of the C^{155 + 320}-T polymorphism tended to be more common among patients with vertebral fractures (P = 0.06) and patients with BMD T score <–2.5 (P = 0.05). Furthermore, haplotype 1 was associated with reduced risk of having BMD T score <–2.5 (P = 0.02). None of the other polymorphisms or haplotypes was associated with fracture risk or BMD T score <–2.5. BMD and bone turnover were not associated with any of the genetic variants. In conclusion, all the polymorphisms within the IL-1α gene are in strong linkage disequilibrium and not convincingly associated with fracture risk, BMD, or bone turnover.     

2型糖尿病人群CDKN2A／B基因多态性与冠心病风险的相关性研究

目的观察T2DM人群细胞周期蛋白依赖激酶抑制基因2A／B（CDKN2A／B）基因多态性是否与冠心病风险相关,以早期筛查DM人群中冠心病的高危人群。方法对我院因胸痛症状行冠脉造影或冠脉CT检查的T2DM患者,根据冠脉造影或冠脉CT结果分为冠心病组及非冠心病组。冠心病组共220例,非冠心病组共89例。根据Hapmap数据库选取CDKN2A／B共7个单倍型标记的单核苷酸多态性（SNP）：CDKN2Ars2811708（G〉T）、rs3088440（A〉G）和rs3731239（C〉T）,CDKN2Brs3217986（A〉C）、rs1063192（C〉T）、rs2285327（A〉G）和rs3217992（A〉G）。对所有个体进行PCR扩增并通过RFLP或基因测序方法读取个体的基因型。结果在T2DM人群中,冠心病组中cDKN2Ars2811708的次要等位基因T频率（26．4％）显著高于非冠心病组（17．4％）（P〈0．05）,基因型分布在两组问存在显著性差异（P〈0．05）,G／T基因型携带者较G／G基因型携带者发生冠心病的风险显著增加（P（0．05）,在校正心血管其他风险因素（如性别、年龄、BMI、DM病程、高血压病病史、脂代谢异常病史、吸烟史）后,这种相关性仍然存在（P〈0．01）。结论T2DM人群中,CDKN2A／B基因单核苷酸多态性可能与冠心病的风险相关。     

Genetic polymorphisms in the cyclooxygenase-1 and cyclooxygenase-2 genes and risk of colorectal adenoma

Purpose  Cyclooxygenase (COX) enzymes, COX1 and COX2, are key in converting arachidonic acid (AA) into prostaglandins that have been associated with colorectal carcinogenesis. The aim of our study was to investigate associations of polymorphisms in COX genes, alone and in interaction with exposures known to be related to inflammation and AA metabolism, with risk of colorectal adenomas. Materials and methods  In a community-, colonoscopy-based case–control study with 162 incident, sporadic colorectal adenoma cases and 211 controls, we investigated associations of two promoter polymorphisms (−842 A  > G in COX1 and −765 G > C in COX2) and two polymorphisms in the 3′-UTR of COX2 (8473 T > C and 9850 A > G) with risk of adenomas. Multiple logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) of colorectal adenoma after adjusting for potential confounders. Results  Overall, there was no evidence for an association between any of the four polymorphisms and colorectal adenomas. However, we found a statistically significant interaction between the COX2 8473 T > C polymorphism and nonsteroidal anti-inflammatory drug (NSAIDs) use (P _interaction = 0.03): The greatest reduced risk was observed for individuals with the 8473 C variant allele who also regularly used NSAIDs (OR = 0.35, 95% CI 0.16–0.75). Conclusion  These results suggest that the C allele of COX2 8473 T > C polymorphism may interact with NSAIDs to reduce risk for colorectal adenoma.     

非酒精性脂肪性肝病基因多态性的巢式病例-对照研究

目的 探讨广东省汉族人中代谢综合征(MS)相关基因多态性和非酒精性脂肪性肝病(NAFLD)发病易感性的关系.方法 在广东省流行病学调查中抽取符合中华医学会肝病学分会诊断标准.且B超、临床和实验室检查结果为典型的成年NAFLD患者50～117例,采用巢式病例-对照方法,现场按1 : 1匹配,选择非NAFLD人群作对照.各受试者均由静脉血中提取DNA,采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)法检测7个候选基因9个位点单核苷酸多态性(SNP).结果 基因SNP和NAFLD的发病易感性相关.正相关的因子(即增加易感性)为:肿瘤坏死因子-α(TNF-α)-238、脂联素-45、瘦素-2548、过氧化物酶体增殖物激活受体-γ-161、磷脂酰乙醇胺N-甲基转移酶-175.负相关的因子(即降低易感性)为:脂联素-276、肝脂肪酶-514.不相关的因子为:TNF-α-380、PPAR共激活因子-1α-482.结论 多数MS相关的细胞因子基因SNP和NAFLD发病易感性相关.     

Endothelial nitric oxide synthase T-786C polymorphism in rheumatoid arthritis: association with extraarticular manifestations

Several genetic factors were implicated in the pathogenesis of rheumatoid arthritis (RA). A case–control study was carried out to verify the associations of T-786C polymorphism in the promoter region of the endothelial nitric oxide synthase (eNOS) gene with RA. One hundred and five consecutive RA patients and 100 healthy controls were genotyped. The distribution of the T-786C genotype and alleles did not differ significantly between RA patients and controls. Nevertheless, the frequency of extraarticular manifestations was significantly greater among the carriers of the C/C genotype than among carriers of the T/C and T/T genotypes (P = 0.022). The C/C genotype was significantly associated with extraarticular manifestations compared with the T/T and T/C genotypes taken together (OR = 4.9, 95% CI = 1.3–18.9). The C allele was significantly associated with extraarticular manifestations of RA (P _corr = 0.032). The results suggested the existence of an association between the T-786C polymorphism of the eNOS gene and extraarticular manifestations of RA.     

No association of two common SNPs at position -1727 A/T, -50 C/T of GSK-3 beta polymorphisms with schizophrenia and bipolar disorder of Korean population

Recent studies have suggested the involvement of Glycogen synthase kinase-3 beta (GSK-3 beta) in pathogenesis and treatment target of schizophrenia and bipolar disorder, which led to consider GSK-3 beta as one of the candidate genes for those disorders. However, the association analysis between GSK-3 beta and either schizophrenia or bipolar disorder is yet to be reported in Korean population. Along with 350 healthy individuals, a sample of 138 schizophrenia and 120 bipolar patients was analyzed for two common SNPs at position -1727 A/T and -50 C/T polymorphism localized in intron 1 of the gene. The results showed that allele, genotype and haplotype distributions for the two SNPs do not differ between the controls and neither schizophrenia nor bipolar disorder patients. We also analyzed the association between the controls and the combined samples of schizophrenia and bipolar disorder, but no association was found. In conclusion, these results suggest that the GSK-3 beta is not associated with the development of schizophrenia and bipolar disorder in Korean population.     

Polymorphic alleles of the human MEI1 gene are associated with human azoospermia by meiotic arrest

Genetic mechanisms are implicated as a cause of some male infertility, yet are poorly understood. Mouse meiotic mutant mei1 (meiosis defective 1) was isolated by a screening of infertile mice. Male mei1 mice have azoospermia due to meiotic arrest, and the mouse Mei1 gene is responsible for the mei1 phenotype. To investigate whether human MEI1 gene defects are associated with azoospermia by meiotic arrest, we isolated the human MEI1 cDNA based on the mouse Mei1 amino acid sequence. MEI1 is expressed specifically in the testis. Mutational analysis by direct sequencing of all MEI1 coding regions was performed in 27 men (13 European Americans, 13 Israeli and 1 Japanese) having azoospermia due to complete early meiotic arrest. This identified four novel, coding single-nucleotide-polymorphisms (cSNPs), i.e., SNP1 (T909G), SNP2 (A1582G), SNP3 (C1791A) and SNP4 (C2397T) in exons 4, 8, 9 and 14, respectively. Using these cSNPs, an association study was carried out between 26 non-Japanese patients with azoospermia and two sets of normal control men (61 normal European Americans and 60 Israelis). Consequently, SNP3 and SNP4 were shown to be associated with azoospermia among European Americans (P =0.0289 and P =0.0299 for genotype and allele frequencies at both the polymorphic sites, respectively), although no such association was observed among Israelis (P >0.05). Haplotype estimation revealed that the frequencies of SNP3–SNP4 (C–T), SNP3–SNP4 (A–C) and SNP3–SNP4 (A–T) were higher in the European American patients, and the frequency of SNP3–SNP4 (A–T) was also higher than in both control groups. These results suggest that MEI1 may play a role in meiosis during spermatogenesis, especially in European Americans.     

Influence of mannose-binding lectin on HIV infection and tuberculosis in a Western-European population

Mannose-binding lectin (MBL) is a serum lectin that mediates phagocytosis and activates complement. Its deficiency has been associated with increased susceptibility to infectious diseases, mainly in childhood. However, non-producer mbl-2 alleles are common in most populations, suggesting a selective advantage of these alleles. We have analysed the association of mbl-2 structural and promoter polymorphisms with HIV infection and tuberculosis (TBC) in a white Spanish population, including 615 HIV patients with and without TBC, 127 no-HIV TBC patients, 142 TBC household contacts and 344 controls. The frequency of low or non-producer mbl-2 genotypes was lower in HIV patients than in controls. HIV-TBC patients presented lower frequencies of low or non-producer alleles and genotypes than HIV no-TBC patients and controls. Additionally, we found a significantly positive correlation between the incidence of TBC and the frequency of non-producer mbl-2 alleles in Western Europe. Therefore, MBL deficiency may be associated with a lower risk of HIV infection, and also of active TBC, at least in HIV patients. The protective role of low-producer mbl-2 genotypes against TBC together with the positive correlation observed between non-producer mbl-2 alleles and TBC incidence, suggest a balancing selection: in spite of an increased susceptibility to respiratory infections associated with MBL deficiency, mbl-2 deficient alleles would have been selected along different populations as a consequence of its selective advantage against intracellular pathogens, such as M. tuberculosis.     

Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease

The proteins cathepsin D, encoded by CTSD gene, and alpha2-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of beta-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C-->T and A2M-Ile/Val A-->G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI)=1.01-3.72], and 2.07 (95% CI=1.01-4.21) after adjustment for age, sex and APOE epsilon4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI=1.13-6.34) [2.82 (95% CI=1.12-7.17) after adjustment], and to 3.29 (95% CI=1.33-8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk.