Twin Studies: Current Status and Future Directions

See article vol. 31: 1539-1555

Articles regarding risk factors for coronary artery disease using monozygotic (MZ) twins have been recognized since the 1970s^{1, 2)}. These methods of studying gene-environment interactions are based on the hypothesis that since MZ twins are identical with respect to genes, differences between two MZ pairs must necessarily be caused by environmental or lifestyle factors. Indeed, those results have shown the strength of the genetic influence on HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels. In addition, studies have compared dizygotic (DZ) and MZ twins because the genetic effects on blood lipid levels are more similar in MZ twin pairs than in DZ twin pairs³⁾. However, there is evidence that the intrauterine environment (e.g., low birth weight) has an influence on the development of components of the metabolic syndrome. Indeed, because the intrauterine environment may be more unfavorable in MZ twins than in DZ twins, MZ twins are more likely to develop various metabolic abnormalities, which should be interpreted with caution⁴⁾.

In this study, Nishihara et al. examined factors affecting LDL-C and HDL-C in identical twins and attempted to identify genes with altered expression in pairs with large differences in LDL-C or HDL-C⁵⁾.

From the database of 263 pairs of MZ twins registered at the Osaka University Twin Research Center, the parameters affecting LDL-C or HDL-C were examined within MZ twins, and RNA sequencing of peripheral blood mononuclear cells was newly analyzed in 59 pairs with large differences in LDL-C or HDL-C. The results showed that ΔLDL-C was significantly associated with older age, ΔTriglyceride(TG), and ΔBMI; ΔHDL-C was associated with ΔBMI, ΔTG, ΔTotal protein, and ΔLDL-C; and HDL-C was influenced by smoking and exercise habits. RNA sequencing analysis showed that the expression of genes related to inflammatory pathways was suppressed in the group with the highest ΔHDL-C among 59 pairs, in accordance with HDL-C levels. These results suggest that weight control and exercise habits, in addition to dietary guidance, are important to control LDL-C and HDL-C levels.

In this study, the authors were able to present factors involved in changes in LDL-C and HDL-C levels, as well as possible intervention methods to control these levels. The RNA sequencing of peripheral blood mononuclear cells was attempted for the first time in this study, which is commendable. Although a causal relationship is not clear, the relationship between HDL-C and inflammatory response has been repeatedly demonstrated in the past, and the results of this analysis are convincing enough⁶⁾.

Epigenetic mechanisms such as DNA methylation⁷⁾, chromatin remodeling⁸⁾, and noncoding RNAs^{9, 10)} are possible links between environmental factors and disease onset and degree of pathogenesis when genetic factors are matched. In the future, more twin studies may reveal these epigenomic influences.

Conflicts of Interest

The author has no conflicts of interest to declare regarding this article.

References

• 1)  Feinleib M, Garrison RJ, Fabsitz R, Christian JC, Hrubec Z, Borhani NO, Kannel WB, Rosenman R, Schwartz JT, Wagner JO: The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. Am J Epidemiol, 1977; 106: 284-285
• 2)  Berg K: Twin studies of coronary heart disease and its risk factors. Acta Genet Med Gemellol (Roma), 1987; 36: 439-453
• 3)  O’Connell DL, Heller RF, Roberts DC, Allen JR, Knapp JC, Steele PL, Silove D: Twin study of genetic and environmental effects on lipid levels. Genet Epidemiol, 1988; 5: 323-341
• 4)  Poulsen P, Vaag A: The impact of genes and pre- and postnatal environment on the metabolic syndrome. Evidence from twin studies. Panminerva Med, 2003; 45: 109-115
• 5)  Nishihara S, Koseki M, Tanaka K, Omatsu T, Sawabe H, Inui H, Saga A, Okada T, Higo T, Ohama T, Nishida M, Sakata Y, Watanabe M, Osaka Twin Research G: Twin Study: The Factors Affecting the Serum LDL-C and HDL-C Levels and an RNA-Seq Analysis in Mononuclear Cells in Monozygotic Twins. J Atheroscler Thromb, 2024; 31: 1539-1555
• 6)  Moore RE, Navab M, Millar JS, Zimetti F, Hama S, Rothblat GH, Rader DJ: Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation. Circ Res, 2005; 97: 763-771
• 7)  Li Z, Wang W, Li W, Duan H, Xu C, Tian X, Ning F, Zhang D: Co-methylation analyses identify CpGs associated with lipid traits in Chinese discordant monozygotic twins. Hum Mol Genet, 2024; 33: 583-593
• 8)  Oldoni F, Palmen J, Giambartolomei C, Howard P, Drenos F, Plagnol V, Humphries SE, Talmud PJ, Smith AJ: Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3. Atherosclerosis, 2016; 246: 193-201
• 9)  Horie T, Ono K, Horiguchi M, Nishi H, Nakamura T, Nagao K, Kinoshita M, Kuwabara Y, Marusawa H, Iwanaga Y, Hasegawa K, Yokode M, Kimura T, Kita T: MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci U S A, 2010; 107: 17321-17326
• 10)  Li W, Baumbach J, Larsen MJ, Mohammadnejad A, Lund J, Christensen K, Christiansen L, Tan Q: Differential long noncoding RNA profiling of BMI in twins. Epigenomics, 2020; 12: 1531-1541