Human enomic alterations causing disease phenotypes in Thai population are proposed to be different from those found in other populations. Our group is thus employing genetic/genomic and molecular biology approaches to study certain complex diseases relevant to Thais. These diseases include kidney stone, distal renal tubular (dRTA), diabetes mellitus (DM) and dengue virus infection. Kidney stone disease in the Northeastern Thai population shows familial aggregation with relative risk (_R) of 3.18 among family members, supporting the role of genetic factor in its pathogenesis. Genetic variations of prothrombin (F2) encoding a urinary stone inhibitor, prothrombin fragment 1, were first shown to be associated with kidney stone risk in the female patients. Genome-wide association and genome-wide linkage studies using DNA microarray are being conducted to identify the causative genes for kidney stone disease. Mutations of the human SLC4A1 gene encoding erythroid and kidney anion exchanger 1 (eAE1 and kAE1) result in erythrocyte abnormalities or distal renal tubular acidosis (dRTA). SLC4A1 mutations and hemoglobinopathies (e.g. thalassemia or hemoglobin E) were observed in Thai population, presenting a combined effect of red cell morphological changes and hemolytic anemia aggravating by acidosis. Novel SLC4A1 mutations were discovered in Thai and other populations. The wild-type and mutant kAE1 proteins were expressed and co-expressed in cultured epithelial cells to examine their interaction, trafficking, and cellular localization. Impaired trafficking and intracellular retention of the mutant kAE1 may lead to decrease functional kAE1 at the basolateral membrane of the kidney _-intercalated cells in the distal nephron resulting in dRTA. The causes of diabetes mellitus (DM) are heterogeneous; abnormality at different biological pathways can lead to hyperglycemia. Six known genes responsible for maturity-onset diabetes of the young (MODY), including HNF-4alpha, GCK, HNF- 1alpha, IPF-1, HNF-1beta, and NeuroD1/beta2, were analyzed in Thai patients with MODY and early-onset type 2 diabetes. Mutations of these six known MODY genes account for a small proportion of classic MODY (19%) and early-onset type 2 diabetes (10%) in Thais. A novel frameshift mutation of HNF-1alpha was identified in a Thai family with MODY. The functional defect of this mutant on the transactivation of its target-gene promoters is likely to account for the _-cell dysfunction associated with the pathogenesis of MODY. Dengue virus-infected liver cells undergo apoptosis but the underlying molecular mechanism remains unclear. We found that dengue virus capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx, a Fasassociated protein. The two proteins were predominantly co-localized in the cellular nuclei. Fas-mediated apoptotic activity in liver cells constitutively expressing DENV C was induced by anti-Fas antibody, indicating that the interaction of DENV C and Daxx involves in apoptosis of dengue virus-infected liver cells. Upon treatment with anti-Fas antibody, the liver cells expressing the wild-type DENV C showed significantly more apoptosis compared with the cells expressing mutant DENV C that could not enter the nucleus. The glycosylated envelope protein of dengue virus, DENV E, is processed in the endoplasmic reticulum of host cells and therefore reliant on host processing functions. Our group found that domain III of DENV E interacts with human immunoglobulin heavy chain binding protein (BiP). The association of DENV E with two other chaperones, calnexin and calreticulin was also observed. Knocking-down expression of BiP, calnexin, or calreticulin by siRNA significantly decreased the production of infectious dengue virions, indicating that the interaction of these three chaperones with DENV E plays an important role in virion production. Dengue virus nonstructural protein 1 (NS1) is a key glycoprotein involved in the production of infectious virus and the pathogenesis of dengue diseases. However, very little is known how NS1 interacts with host cellular proteins and functions in dengue virus-infected cells. Human heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2 was identified as NS1-interacting host cellular proteins in dengue virus-infected cells. Their interaction may have implications in virus replication and/or cellular responses favorable to survival of the virus in host cells. In conclusion, our group is employing genetic/genomic and molecular biology approaches to investigate into genetic factors and molecular mechanisms of four certain diseases (kidney stone, dRTA, DM, and dengue-virus infection) relevant to Thai population and made significant discoveries and progresses in the studies of these diseases. However, further investigations of these diseases are required to gain complete understanding and to develop appropriate methods for prevention, control, and intervention.