Autosomal Genome-Wide Linkage Analysis to Identify Loci for Gallbladder Wall Thickness in Mexican Americans

Abstract

The significance of gallbladder wall thickness (GBWT) in regard to gallbladder disease (GBD) is not completely understood. Thickening of the gallbladder wall has been observed in patients with acute calculous and acalculous cholecystitis and chronic cholecystitis. However, various pathologic processes, such as gallbladder cancer and nonbiliary disorders such as liver cirrhosis and viral hepatitis, could also cause thickening of the gallbladder wall. To date, there is no report available on the genetic factors influencing GBWT. Therefore we sought to estimate the heritability (h^sup 2^) of GBWT and to perform a genome-wide search to identify the susceptibility genes for GBWT, using data from the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), a family study of Mexican Americans. GBWT was measured by ultrasound. After adjusting for the significant effects of age, sex, GBD (i.e., asymptomatic gallstones), metabolic syndrome, and duration of type 2 diabetes (T2DM), GBWT was found to be under significant and appreciable additive genetic influences (h^sup 2^ ± SE = 0.38 ± 0.09, P ≤ 0.0001). The strongest evidence for linkage occurred between markers D11S912 and D11S968 on chromosome 11q24-q25 (LOD = 2.7), where we have already shown suggestive evidence for linkage of GBD (LOD = 2.7) in a subset of our SAFDGS data. Potential evidence for linkage occurred at markers D1S1728 (1p31.1; LOD = 1.4) and D16S748 (16p13.1; LOD = 1.4), respectively. In conclusion, our study provides suggestive evidence for linkage of GBWT on chromosome 11q in Mexican Americans, and future tasks of mapping susceptibility gene(s) for GBD and its related traits, such as GBWT, in this chromosomal region can be fruitful.

KEY WORDS: GALLBLADDER DISEASE, CHOLELITHIASIS, CHOLECYSTITIS, FAMILY STUDY, VARIANCE COMPONENTS ANALYSIS, MEXICAN AMERICANS, SAN ANTONIO FAMILY DIABETES/GALLBLADDER STUDY (SAFDGS).

Gallbladder disease (GBD) is one of the most common diseases afflicting people worldwide. The presence of gallstones composed of cholesterol is the common manifestation of GBD in the United States (Diehl et al. 1994; Paigen and Carey 2002; Nakeeb et al. 2002; Sandler et al. 2002). Nearly 20 million people develop gallstones and more than 700,000 cholecystectomies are performed every year in the United States (Lawrence and Hall 1999; Hall and Lawrence 1998; Everhart et al. 1999; Diehl 2000). Cholecystitis is inflammation of the gallbladder wall, usually resulting from a gallstone obstructing the cystic duct. Acute cholecystitis is the initial presentation of symptomatic gallstones in 15-20% of the patients and is the sudden onset of inflammation of the gallbladder; chronic cholecystitis is long-standing inflammation of the gallbladder. Thickening of the gallbladder wall has been observed in patients with acute calculous and acalculous cholecystitis and chronic cholecystitis (Deitch 1981; Jeffrey and Sommer 1993; Chen et al. 1995; Schiller et al. 1996; A. J. Wang et al. 2003). Although gallbladder wall thickness (GBWT) is associated with cholecystitis, various pathologic processes, such as gallbladder cancer and nonbiliary disorders (e.g., liver cirrhosis, viral hepatitis, chronic congestive heart failure, hypoalbuminemia, and acute pyelonephritis), also cause thickening of the gallbladder wall (Herbener 1994; Paulson 2000; Zissin et al. 2000; Goldstein et al. 1986; Somer et al. 1984; Schirmer et al. 2005).

GBWT was reported to be associated with several infectious diseases, for example, mononucleosis (Yoshie et al. 2004), dengue fever (Venkata Sai et al. 2005), hepatitis A (Hermier et al. 1985), Ascaris-induced cholecystitis and pancreatitis (Grover et al. 2001), clonorchiasis (K. X. Wang et al. 2004), and AIDS (Romano et al. 1988). Recently, Zuber-Jerger et al. (2005) reported an association between gallstone ileus and GBWT. Furthermore, differential layering patterns of the gallbladder wall have been correlated with the pathologic conditions of associated diseases such as chronic cholecystitis, acute cholecystitis, adenomyomatosis, and gallbladder carcinomas (Jung et al. 2005). Prominent changes in the muscular and serosal layers of the gallbladder wall were dependent on the normal or abnormal levels of liver enzymes in patients with acute hepatitis (Kim et al. 2003). In patients with mononucleosis syndromes a relationship between GBWT and the severity of the disease was also reported.

The significance of GBWT in relation to GBD is not completely understood. The major risk factors associated with GBD are age, female sex, obesity, type 2 diabetes (T2DM), hypertriglyceridemia, parity, certain hypolipidemic drugs, and Native and Mexican American ethnicity (Diehl 1991 ; Hanis et al. 1993; Misciagna et al. 1996; Everhart et al. 1999; Duggirala et al. 1999b; Paigen and Carey 2002; Mendez-Sanchez et al. 2004; Lee 2004). Also, a strong relationship is observed between GBD and metabolic syndrome and or its major components, such as hyperinsulinemia, dyslipidemia, and abdominal adiposity (Boland et al. 2002; Tsai et al. 2004; Grundy 2004). We recently reported that metabolic syndrome [as defined by the NCEP/ATPIII criteria (Expert Panel 2001])] is a significant correlate of GBD in our own data (Puppala et al. 2006). The accumulating evidence based on family or twin data, albeit limited, indicates that the development of GBD has a genetic basis (Kesaniemi et al. 1989; Sarin et al. 1995; Duggirala et al. 1999b; Nakeeb et al. 2002; Kosters et al. 2003). This is also supported by the fact that there are ethnic group-based differences in its prevalence (Weiss et al. 1984; Diehl and Stern 1989; Everhart et al. 2002; Paigen and Carey 2002; Mendez-Sanchez et al. 2004).