**6. Studies of SNPs in association with human diseases**

#### **6.1. Cancer**

Cancer is a disease that involves abnormal cell growth. There are several kinds of cancers. Gemignani et al. studied polymorphisms in dopamine receptor gene, *DRD2*, in association with colorectal cancer risk utilizing the APEX system which is primer extension assays that use fluorescence and mass detection [61]. They genotyped seven SNPs of *DRD2* in 370 case and 327 control samples and found three of the seven SNPs to be highly associated with colorectal cancer, related to reduced levels of D2 dopamine receptor. Hartikainen et al. investigated genes associated with breast cancer in an eastern Finnish population [62]. Ten SNPs were genotyped in the 22q12-q13 region from DNA of 497 patients and 458 control subjects using the TaqMan® assay. The SNP, rs733655, in matriptase-2 gene (*TMPRSS6*) was found to have a strong association with risk of breast cancer. Ribas et al. genotyped 899 SNPs in 175 candidate cancer genes from Spanish population using BeadARRAY™ and SNPlex™ methods to evaluate applicability of HapMap data (for subjects of European ancestry) to cancer research. They found that allele frequencies and haplotype distributions obtained in the study were consistent with the HapMap data [63]. Shatalova et al. examined SNPs in sulfotransferase 1A1 (*SULT1A1*) and UDP-glucorono-syltransferase 1A1 (*UGT1A1*) genes in 119 patients with breast cancer and 121 controls using Pyrosequencing™ [64]. They found only *UGT1A1* gene to be associated with risk of breast cancer. Copson et al. genotyped a T/G SNP (SNP309) in the *MDM2* gene in 116 patients with pathogenic mutations in *BRCA1* gene and 102 healthy controls [65]. Results suggested that the *MDM2* SNP309 locus does not have a significant association with accelerated cancer development in carriers of known pathogenic mutations of *BRCA1*.

#### **6.2. Schizophrenia**

Schizophrenia is a severe psychiatric disorder characterized by hallucinations, delusions, cognitive deficits, and apathy, with a lifetime prevalence of ∼1%. Epidemiologic studies on twins indicate that schizophrenia has a complex genetic background with heritability estimated at 73–90%.

Arinami et al. genotyped 5861 SNPs of 602 individuals from 236 Japanese families using the BeadARRAY™ Linkage Panel (IV) for the genome-wide linkage analysis [66]. They found a strong association of schizophrenia to the region 1p21-p13 and implied that schizophrenia might have common susceptibility loci across populations with different ethnicity-specific effects.

Panichareon B et al. used GWAS-discovered SNPs of Europeans ancestry in OPCML gene and investigated SNPs in Thai schizophrenia patient by using polymerase chain reaction (PCR) and high-resolution melting (HRM) analysis. The results of this study found a strong association between an intronic SNP (rs1784519) and the risk of schizophrenia in a Thai population [*p* = 0.00036, odds ratio for the minor A allele: 2.11(1.57–2.84)] [67].

#### **6.3. Dyslipidemia**

be associated with the absorbance and clearance of therapeutic agents. The association of different SNPs with a wide range of human diseases such as cancer, infectious diseases autoim-

Cancer is a disease that involves abnormal cell growth. There are several kinds of cancers. Gemignani et al. studied polymorphisms in dopamine receptor gene, *DRD2*, in association with colorectal cancer risk utilizing the APEX system which is primer extension assays that use fluorescence and mass detection [61]. They genotyped seven SNPs of *DRD2* in 370 case and 327 control samples and found three of the seven SNPs to be highly associated with colorectal cancer, related to reduced levels of D2 dopamine receptor. Hartikainen et al. investigated genes associated with breast cancer in an eastern Finnish population [62]. Ten SNPs were genotyped in the 22q12-q13 region from DNA of 497 patients and 458 control subjects using the TaqMan® assay. The SNP, rs733655, in matriptase-2 gene (*TMPRSS6*) was found to have a strong association with risk of breast cancer. Ribas et al. genotyped 899 SNPs in 175 candidate cancer genes from Spanish population using BeadARRAY™ and SNPlex™ methods to evaluate applicability of HapMap data (for subjects of European ancestry) to cancer research. They found that allele frequencies and haplotype distributions obtained in the study were consistent with the HapMap data [63]. Shatalova et al. examined SNPs in sulfotransferase 1A1 (*SULT1A1*) and UDP-glucorono-syltransferase 1A1 (*UGT1A1*) genes in 119 patients with breast cancer and 121 controls using Pyrosequencing™ [64]. They found only *UGT1A1* gene to be associated with risk of breast cancer. Copson et al. genotyped a T/G SNP (SNP309) in the *MDM2* gene in 116 patients with pathogenic mutations in *BRCA1* gene and 102 healthy controls [65]. Results suggested that the *MDM2* SNP309 locus does not have a significant association with accelerated

mune, neuropsychiatric and others can be used as targets for drug therapy [60].

**6. Studies of SNPs in association with human diseases**

cancer development in carriers of known pathogenic mutations of *BRCA1*.

Schizophrenia is a severe psychiatric disorder characterized by hallucinations, delusions, cognitive deficits, and apathy, with a lifetime prevalence of ∼1%. Epidemiologic studies on twins indicate that schizophrenia has a complex genetic background with heritability estimated at

Arinami et al. genotyped 5861 SNPs of 602 individuals from 236 Japanese families using the BeadARRAY™ Linkage Panel (IV) for the genome-wide linkage analysis [66]. They found a strong association of schizophrenia to the region 1p21-p13 and implied that schizophrenia might have common susceptibility loci across populations with different ethnicity-specific effects.

Panichareon B et al. used GWAS-discovered SNPs of Europeans ancestry in OPCML gene and investigated SNPs in Thai schizophrenia patient by using polymerase chain reaction (PCR) and high-resolution melting (HRM) analysis. The results of this study found a strong

**6.1. Cancer**

18 Genetic Diversity and Disease Susceptibility

**6.2. Schizophrenia**

73–90%.

Dyslipidemia is an abnormal of lipid and/or lipoproteins in the blood. It is a major risk factor of coronary heart disease and atherosclerosis. A genome-wide association study (GWAS) examined the concentrations of HDL-C and triglyceride in European ethic and identified the SNP at 15 loci which associated with HDL-C levels (such as, APOA1/C3/A4/A5 gene cluster) and SNPs at 12 loci associated with triglycerides (such as APOB, APOE gene) [68]. Thongket et al. examined SNP in apolipoprotein E receptor 2 gene using real-time PCR and HRM analysis and found that the rs2297660 showed strong association with risk of dyslipidemia in Thai population [69].

#### **6.4. Diabetes mellitus**

Diabetes mellitus (DM) is a group of metabolic disorders. Untreated diabetes patient can cause many complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death [70]. SNPs in the gene encoding aldose reductase (*AKR1B1*) were studied for their association with diabetic nephropathy by Wolford et al. They genotyped eight SNPs of *AKR1B1* gene in two different case control sets by Pyrosequencing™ method and found that common *AKR1B1* SNPs were unlikely to be major determinants of diabetic nephropathy [71]. Altshuler et al. genotyped SNPs from 3000 individuals to investigated the association of two polymorphisms, a missense variant in *PPARG* (Pro12Ala) and a silent C/T polymorphism in exon 22 of *ABCC8*, with type 2 diabetes using FRET and FP methods. It was found that only Pro12Ala showed a significant association with decreased risk of type 2 diabetes [72].
